EA043716B1 - PROSTATE CANCER TREATMENT - Google Patents

Description

Cross reference to related applications

This application claims priority to US Provisional Application No. 62/402150, filed September 30, 2016, and US Provisional Application No. 62/402004, filed September 30, 2016, the disclosures of which are incorporated herein by reference in their entirety.

Field of invention

This invention relates to methods of treating prostate cancer, including advanced prostate cancer, and hormone-dependent or hormone-sensitive prostate cancer, in a subject using an oral formulation. This also includes the treatment of men with castration-resistant prostate cancer. In particular, the present invention relates to methods of reducing the levels of one or more sex hormones in a subject by orally administering a once daily dosage form. This invention also relates to a dose package containing a separate loading dose of an oral formulation and a maintenance dose of an oral formulation.

State of the art

Prostate cancer is the second most common form of cancer in men and the second leading cause of cancer death in men in the United States. According to the National Cancer Institute, approximately 2.9 million men in the United States are currently living with prostate cancer, and approximately 180,000 men per year are newly diagnosed with prostate cancer in the United States.

Once prostate cancer is diagnosed, treatment generally involves a combination of surgery and radiation therapy, but also includes anti-androgen therapy, or AAT. Prostate cancer responds to surgical castration, and the effectiveness of this therapy is a result of androgen elimination. Androgen can refer to any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. Androgens include testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone, and androstenedione. Most prostate cancers are androgen-dependent, and androgens such as testosterone promote the growth of prostate cancer cells. AAT dramatically reduces serum testosterone levels, blocks androgen receptor signaling, and delays the progression of prostate cancer. AAT serves as an alternative to surgical castration and is important in the treatment of prostate cancer.

Castration by orchiectomy or gonadotropin-releasing hormone (GnRH) agonist (GnRH receptor agonist) is the mainstay of therapy for localized advanced cancer and metastatic cancer, and GnRH agonists such as leuprolide acetate are widely used. When multiple doses of a GnRH agonist are administered, there is a transient increase in gonadotropin secretion. This is followed by a decrease in the response (desensitization) of the pituitary gland and a decrease in the secretion of sex hormones from the pituitary gland, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which leads to a decrease in sex hormones that are produced by the testes, such as testosterone and DHT. The initial increase in hormone levels caused by GnRH agonists leads to a temporary worsening of symptoms known as a clinical flare, such as increased bone pain and, more seriously, spinal cord compression. The effectiveness of GnRH agonist therapy begins to appear approximately 3-4 weeks after the first dose. In addition, known GnRH agonists are peptides that cannot be administered orally and must be administered subcutaneously (SC), intravenously (IV), intramuscularly, or intranasally. Often these GnRH agonists are administered in a depot form once every 1-3 months. Therefore, there is a need to develop a new treatment that is easy and convenient to administer, that does not cause clinical exacerbations, and that allows treatment to be suspended for variable periods of time and serum testosterone levels to increase within a short period of time after treatment is stopped.

Brief description of the invention

One aspect of the invention relates to a method of treating prostate cancer in a subject in need of increasing serum testosterone levels above 50 ng/dL, the method comprising administering to the subject once daily an oral formulation containing from about 80 mg to about 480 mg compound 1 K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy3-pyridazinyl)-2,4-dioxo-1,2,3,4 -tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, wherein when once daily dosing is suspended for the period of suspension, the subject experiences an increase in serum testosterone levels.

Another aspect of the invention relates to a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject once daily an oral formulation containing from about 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof ;

suspending administration of the oral formulation for a period of suspension to allow serum testosterone levels to rise; And

- 1 043716 resumption of once-daily administration of the oral formulation to the subject at the end of the suspension period.

One aspect of the invention provides an oral formulation containing from about 80 mg to about 480 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject in need thereof.

Another aspect of the invention relates to an oral formulation containing from about 80 mg to about 480 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject in need thereof, comprising administering to the subject once per day oral ready-made form;

suspending administration of the oral formulation for a period of suspension to allow serum testosterone levels to rise; and resuming administration of the once daily oral formulation to the subject at the end of the suspension period.

In some embodiments, any of the above or the following, after a period of suspension, administration of the once daily oral formulation of the invention is not resumed.

In some embodiments, any of the foregoing or the following increases the serum testosterone level to a level higher than that of therapeutic castration. In some embodiments, the serum testosterone level increases to greater than about 55 ng/dL or to greater than about 350 ng/dL. In some embodiments, the serum testosterone level increases from about 300 ng/dL to about 600 ng/dL.

In some embodiments, any of the above or the following increases the serum testosterone level to the subject's serum testosterone level prior to administration of the once daily oral formulation of the present invention. In some embodiments, any of the foregoing or the following increases the serum testosterone level to the subject's serum testosterone level prior to administration of a once daily oral formulation of the present invention for 7 days after the start of the suspension period. In some embodiments, any of the foregoing or the following increases the serum testosterone level to the subject's serum testosterone level prior to administration of a once daily oral formulation of the present invention for 45 days after the start of the suspension period.

In some embodiments, any of the above or the following, the prostate cancer is hormone-dependent prostate cancer. In some embodiments, prostate cancer is an advanced stage of prostate cancer. In some embodiments, the prostate cancer is metastatic, non-metastatic, late-stage, late-stage, late-stage hormone-sensitive, late-stage castration-resistant, or recurrent cancer. In some embodiments, the prostate cancer is castration-resistant metastatic prostate cancer. In some embodiments, the prostate cancer is castration-resistant non-metastatic prostate cancer. In some embodiments, the prostate cancer is hormone-sensitive metastatic prostate cancer. In some embodiments, the prostate cancer is hormone-sensitive, non-metastatic prostate cancer.

In some embodiments of any of the foregoing or the following, said administration includes administering a once daily loading dose of an oral formulation of about 240 mg to about 480 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, over 1 to 3 days at the onset treatment. In some embodiments, said administration includes administering a once-daily loading dose of an oral formulation of about 240 mg to about 480 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, for 1 to 3 days at the start of treatment following a period of suspension. In some embodiments, said administration includes administration of a once daily maintenance dose of an oral formulation of about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments of any of the above or the following, administration of the once daily maintenance dose of the oral loading formulation begins the day after the last dose of the daily oral loading formulation.

In some embodiments of any of the foregoing or the following, the period of suspension is up to 52 weeks, up to 36 weeks, up to 24 weeks, up to 12 weeks, up to 8 weeks, or up to 4 weeks.

In some embodiments, any of the above or the following, the suspension period is interrupted when the subject's prostate-specific antigen (PSA) level is

- 2 043716 >20% nadir of subject's PSA level during treatment. In some embodiments, the suspension period is terminated when the subject's PSA level is >50% of the subject's pre-treatment PSA level. In some embodiments, the suspension period is interrupted when the subject's PSA level is greater than the subject's PSA level at the beginning of the suspension period. In some embodiments, the suspension period is interrupted when the subject experiences a return of prostate cancer symptoms. In some embodiments, the suspension period may be interrupted when the subject's PSA level is >3, >10, >20, or >30 ng/mL.

In some embodiments, any of the foregoing or the following, the oral formulation is administered once daily for 12 consecutive weeks or more, for 24 consecutive weeks or more, for 48 consecutive weeks or more, for 52 consecutive weeks or more, in for 72 consecutive weeks or more or for 96 consecutive weeks or more.

In some embodiments, any of the above or the following once daily administration of the oral formulation of the present invention is discontinued after at least 24 consecutive weeks of treatment, at least 36 consecutive weeks of treatment, or at least 52 consecutive weeks of treatment.

In some embodiments of any of the foregoing or the following, the subject requires an increase in serum testosterone levels due to intercurrent illness, radiation therapy, bed rest, previous trauma, previous surgical or invasive procedure, or a desire to obtain restored sexual function over a period of time. In some embodiments, the subject requires an increase in serum testosterone levels due to an intercurrent illness or surgical or other invasive procedure with an expected time to full recovery of at least two weeks. In some embodiments, the once-daily oral formulation of the invention is suspended prior to surgery or other invasive procedure or radiation therapy. In some embodiments, the once-daily oral formulation of the invention is withheld after or during a surgical or other invasive procedure or radiation therapy. In some embodiments, any of the above or the following, once-daily administration of the oral formulation of this invention is performed before and during surgery or other invasive procedure or radiation therapy, and once-daily administration of the once-daily oral formulation of this invention is suspended after surgery or other invasive procedure or radiation therapy. In some embodiments, the surgical procedure is cardiac surgery, knee replacement, hip replacement, abdominal surgery, pelvic surgery, vascular surgery, spine surgery, or an emergency procedure due to trauma. In certain embodiments of any of the above or the following, the subject is identified as being at risk for acute postoperative weakness. In some embodiments, administration of the once daily oral formulation of the present invention is suspended during intercurrent illness or when the subject is bedridden. In some embodiments, the once-daily oral formulation of the invention is discontinued following an accident or injury requiring prolonged recovery. In some embodiments, the once-daily oral formulation of the present invention is discontinued following a stroke, cerebral hemorrhage, myocardial infarction, congestive heart failure, hip fracture, or other event resulting in limited mobility and requiring prolonged recovery. In some embodiments, administration of the once daily oral formulation of the present invention is resumed after the subject has been cured of the intercurrent illness, is no longer bedridden, has resumed normal activities of daily living, or has regained a normal level of physical activity. In some embodiments, the invasive procedure is a colonoscopy, angioplasty, stent placement, endovascular coil placement, endovascular aneurysm repair, endoscopy, laparoscopy, arthroscopy, coronary catheterization, or other catheter-based procedure.

In some embodiments of any of the above or the following, the serum testosterone level is above therapeutic castration levels for 7 days after stopping the once daily oral formulation of the present invention.

In some embodiments of any of the above or the following, the loading dose of the oral formulation contains about 240 mg, about 360 mg, or about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some such embodiments, a loading dose of the oral formulation contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments of any of the above or the following, the maintenance dose of the oral formulation contains about 80 mg, about 120 mg, or about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some such embodiments, the maintenance dose of the oral formulation contains about 120 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments of any of the above or the following, the loading dose of the oral formulation contains about 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof and is administered once per day 1 of treatment and the maintenance oral formulation contains about 120 mg of Compound 1 or an appropriate amount thereof pharmaceutically acceptable salt and is administered once daily.

In some embodiments of any of the above or the following, the oral formulation contains from about 80 mg to about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, any of the above or the following is administered before a meal. In some embodiments, administration is at least 1 hour before a meal or at least 2 hours after a meal. In some embodiments, administration is at least 30 minutes before a meal or on an empty stomach.

In some embodiments of any of the above or the following, the oral formulation, loading dose of the oral formulation, and maintenance dose of the oral formulation are immediate release formulations.

In some embodiments of any of the above or the following, the maintenance dose of the oral formulation contains 102 to 204 mg of mannitol, 6 to 12 mg of hydroxypropylcellulose, 10 to 20 mg of sodium starch glycolate, and 2 to 4 mg of magnesium stearate.

One aspect of the present invention relates to any of the above or below methods or uses, further including the administration of an anti-androgen. In some such embodiments, the anti-androgen is selected from the group consisting of flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide (fluridil), and cimetidine.

In some embodiments of any of the above or below methods or uses, the methods or uses further comprise administering a CYP17 lyase inhibitor. In some such embodiments, the CYP17 lyase inhibitor is abiraterone.

In some embodiments, any of the above or the following, the subject's serum testosterone level is reduced before and after discontinuation of the once daily oral formulation of the present invention.

In some embodiments, any of the above or the following method or use does not include administering an anti-androgen.

In some embodiments, any of the above or the following method or use does not involve administering prednisone. In some embodiments, the method or use further includes administering prednisone.

In some embodiments of any of the foregoing or the following, the method or use further includes suspending the once daily oral formulation of the invention for a subsequent suspension period after completion of the suspension period and resuming the once daily oral formulation of the invention. In some embodiments, the subsequent suspension period occurs at least 12 weeks after resuming administration of a once-daily oral formulation containing from about 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, any of the foregoing or the following, during about 4 to about 8 days of the first administration of the once daily oral formulation, or the loading dose of the oral formulation and the maintenance dose of the oral formulation, the subject's serum testosterone levels are at or below level during therapeutic castration. In some embodiments, within 4 days of the first once-daily administration of the oral formulation, or the loading dose of the oral formulation and the maintenance dose of the oral formulation, the subject's serum testosterone levels are at or below the level of therapeutic castration.

One aspect of the present invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of prostate cancer. In some such embodiments, the prostate cancer is hormone-sensitive prostate cancer, advanced prostate cancer, metastatic, non-metastatic, localized advanced prostate cancer, advanced hormone-sensitive cancer, advanced castration-resistant cancer, recurrent, castration-resistant castration-resistant metastatic prostate cancer, castration-resistant non-metastatic prostate cancer, hormone-sensitive metastatic prostate cancer, or hormone-sensitive non-metastatic prostate cancer. In some embodiments, the drug contains from 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

Other objects and advantages of the present invention will become apparent from the detailed description that follows.

Brief description of graphic materials

Fig. 1 graphically illustrates the mean serum testosterone concentrations over a 28-day treatment period according to Example 6.

Fig. 2 is a table of individual changes in serum testosterone concentrations for each dose level of Compound 1 according to Example 6, in which serum testosterone concentrations are graphically depicted in FIG. 1 and 7.

Fig. 3 graphically illustrates mean serum LH concentrations during the treatment period (Part A) according to Example 6.

Fig. 4 graphically illustrates mean serum FSH concentrations during the treatment period (Part A) according to Example 6.

Fig. 5 graphically illustrates mean serum concentrations of dihydrotestosterone (DHT) during the treatment period (Part A) in accordance with Example 6.

Fig. 6 graphically illustrates the mean serum concentrations of sex hormone binding globulin (SHBG) during the treatment period (Part A) in accordance with Example 6.

Fig. 7 graphically illustrates mean serum testosterone concentrations during the treatment period (Part B) in accordance with Example 6.

Fig. 8A and 8B graphically illustrate mean serum testosterone concentrations during the treatment period (Part B) for 80 mg of Compound 1 and 120 mg of Compound 1 according to Example 6.

Fig. 9 graphically illustrates mean serum LH concentrations during the treatment period (Part A) according to Example 6.

Fig. 10 graphically illustrates mean serum FSH concentrations during the treatment period (Part A) according to Example 6.

Fig. 11 graphically illustrates the mean serum concentrations of DHT during the treatment period (Part A) according to Example 6.

Fig. 12 graphically illustrates mean serum concentrations of sex hormone binding globulin (SHBG) at 80 mg and 120 mg maintenance doses or during the treatment period (Part A) in accordance with Example 6.

Fig. 13 is a table of serum prostate-specific antigen (PSA) and change in serum PSA level in a subject prior to treatment with each dose level of Compound 1 (Part A) in accordance with Example 6.

Fig. 14 is a table of serum PSA and changes in a subject's pre-treatment serum PSA level at each dose level of Compound 1 (Part B) in accordance with Example 6.

Fig. 15A, 15B, 15C graphically illustrate the average plasma concentrations of unchanged Compound 1 during the treatment period (Part A) in accordance with Example 6.

Fig. 16 is a table of plasma pharmacokinetic (PK) parameters of Compound 1 during the treatment period (Part A) according to Example 6.

Fig. 17A and 17B graphically illustrate the average residual plasma concentrations of unchanged Compound 1 during the treatment period (Part B) in accordance with Example 6.

Fig. 18A and 18B graphically illustrate the mean plasma concentration profiles as a function of time of Compound 1 after a single oral dose (Part 1) in accordance with Example 7.

Fig. 19 graphically illustrates the mean plasma concentration profiles as a function of time of Compound 1 following a single oral dose (Part 1) under fasted and fed conditions according to Example 7.

Fig. 20 is a table of mean pharmacokinetic (PK) parameters in plasma and urine following a single oral dose of Compound 1 (Part 1) according to Example 7.

Fig. 21A and 21B graphically illustrate the mean plasma concentration profiles over time of Compound 1 following single and multiple oral dosing (Part 2) in accordance with Example 7.

Fig. 22 is a table of the average pharmacokinetic (PK) parameters of Compound 1 in plasma and urine obtained 1 day after oral administration of Compound 1 (Part 2), in accordance with Example 7.

Fig. 23 is a table of the average pharmacokinetic (PK) parameters of Compound 1 in plasma and urine obtained 14 days after repeated oral administration of Compound 1 (Part 2), in accordance with Example 7.

Fig. 24 is a table of data on the average serum concentration of LH (IU/l) in

- 5 043716 depending on time during the treatment period (part 1) in accordance with example 7.

Fig. 25 graphically illustrates the average decrease in serum testosterone levels following a single dose of Compound 1 (Part 1) according to Example 7.

Fig. 26 is a data table of mean serum testosterone concentration (nmol/L) as a function of time during the treatment period (Part 1) in accordance with Example 7.

Fig. 27 is a table of mean serum FSH concentrations (IU/L) as a function of time during the treatment period (Part 1) according to Example 7.

Fig. 28 is a table of mean serum dihydrotestosterone (DHT) concentrations (nmol/L) as a function of time during the treatment period (Part 1) according to Example 7.

Fig. 29 is a table of mean serum LH concentrations (IU/L) as a function of time during the treatment period (Part 2) according to Example 7.

Fig. 30 graphically illustrates the average decrease in serum testosterone levels following repeated dosing of Compound 1 (Part 2) according to Example 7.

Fig. 31A and 31B are data tables of mean serum testosterone concentration (nmol/L) as a function of time during the treatment period (Part 2) in accordance with Example 7.

Fig. 32 is a table of mean serum FSH concentrations (IU/L) as a function of time during the treatment period (Part 2) according to Example 7.

Fig. 33 is a table of mean serum dihydrotestosterone (DHT) concentrations (nmol/L) as a function of time during the treatment period (Part 2) according to Example 7.

Fig. 34 is a table of mean serum LH concentrations (IU/L) as a function of time during the treatment period (Part 3) according to Example 7.

Fig. 35 graphically illustrates the average decrease in serum testosterone levels following repeated dosing of Compound 1 (Part 3) according to Example 7.

Fig. 36 is a data table of mean serum testosterone concentration (nmol/L) as a function of time during the treatment period (Part 3) in accordance with Example 7.

Fig. 37 is a table of mean serum FSH concentrations (IU/L) as a function of time during the treatment period (Part 3) according to Example 7.

Fig. 38 is a table of mean serum dihydrotestosterone (DHT) concentrations (nmol/L) as a function of time during the treatment period (Part 3) according to Example 7.

Fig. 39 is a data table of mean serum LH concentration (IU/L) as a function of time during the treatment period (Part 4) in accordance with Example 7.

Fig. 40 graphically illustrates the average decrease in serum testosterone levels following repeated dosing of Compound 1 (Part 4) according to Example 7.

Fig. 41 is a table of mean serum testosterone concentrations (nmol/L) as a function of time during the treatment period (Part 4) according to Example 7.

Fig. 42 is a table of mean serum FSH concentrations (IU/L) as a function of time during the treatment period (Part 4) according to Example 7.

Fig. 43 is a table of mean serum dihydrotestosterone (DHT) concentrations (nmol/L) as a function of time during the treatment period (Part 4) according to Example 7.

Fig. 44A, 44B, 44C and 44D graphically illustrate the decrease in serum testosterone levels after treatment (Part 2) with Compound 1 in healthy men for 14 days in accordance with Example 7.

Fig. 45 graphically illustrates the correlation between decreases in serum testosterone levels and steady-state exposure to Compound 1 in healthy men (Part 2) according to Example 7.

Fig. 46A, 46B, 46C and 46D graphically illustrate the decrease in serum testosterone levels after treatment (Parts 3 and 4) with Compound 1 in healthy men for 28 days in accordance with Example 7.

Fig. 47A and 47B graphically illustrate the percentage of subjects achieving serum testosterone levels below castration levels after 28 days of treatment (parts 3 and 4) with Compound 1 in Example 7.

Fig. 48 graphically illustrates the correlation between decreases in serum testosterone levels and stable exposure to Compound 1 in healthy men (Parts 3 and 4) according to Example 7.

Fig. 49 is a table of castration and castration rate data for Compound 1 compared to degarelix according to Example 9. CI=confidence interval, P4H=every four weeks, p/s=once daily. (a) Castration rate was defined as the estimated proportion

- 6,043,716 patients who had serum testosterone concentrations <50 ng/dL at all scheduled visits from day 1 of week 5 to a specific time point (day 1, week 25). (b) Two-sided 95% CI was calculated using the normal distribution approximation method; if the number of non-castrated patients was 5 in any treatment group, an exact CI was provided. (c) The complete castration rate was defined as the estimated proportion of patients who had serum testosterone concentrations <20 ng/dL at all scheduled visits from day 1 of week 13 to a specific time point (day 1, week 25).

Fig. 50 graphically illustrates the Kaplan-Meier survival curve for time to serum testosterone level recovery (ie, to the subject's pre-treatment serum testosterone level or >280 ng/dL) according to Example 9. AAT=anti-androgen therapy, p/ s=once a day, s/c=subcutaneously. (a) Time to serum testosterone recovery was defined as the time from day 1 after the last dose of Compound 1 or day 1 plus 4 weeks after the last dose of degarelix until testosterone recovery. Serum testosterone recovery was defined as a return to the subject's pretreatment serum testosterone level or >280 ng/dL, whichever occurred first. It was censored for patients starting alternative AAT without recovery at the last laboratory testosterone assessment before starting AAT.

Fig. 51 is a table of the time to recovery of serum testosterone (i.e., to the subject's pre-treatment serum testosterone level or >280 ng/dL) according to Example 9. CI=confidence interval, max=maximum, min=minimum, ND =not assessed, R4N=once every four weeks, r/s=once a day. *Denotes censored observation. (a) Time to serum testosterone recovery was defined as the time from day 1 after the last dose of Compound 1 or day 1 plus 4 weeks after the last dose of degarelix until testosterone recovery. Serum testosterone recovery was defined as a return to the subject's pretreatment serum testosterone level or >280 ng/dL, whichever occurred first. It was censored for patients starting alternative AAT without recovery at the last laboratory testosterone assessment before starting AAT. (b) Probability of event (n=number of subjects at increased risk). (c) 4, 8, or 12 weeks from day 1 after the last dose of compound 1 or day 1 plus 4, 8, or 12 weeks after the last dose of degarelix. (d) Two-sided 95% CI for the part was calculated using the normal distribution fitting method.

Fig. 52 graphically illustrates the PSA decline shown in Example 8.

Fig. 53 graphically illustrates the recovery of serum testosterone levels as presented in Example 9.

Fig. 54 graphically illustrates the clinical trial detailed in Example 11. Compound 1 will be administered daily (from day 1 to week 48, day 7). Leuprolide acetate will be administered every 12 weeks (day 1; week 13, day 1; week 25, day 1; and week 37, day 1). *Testosterone restoration visits +60 days and +90 days will occur with a subgroup of patients.

Detailed description of the invention

Disclosed herein are methods of using an orally active GnRH antagonist (GnRH receptor antagonist) Compound 1 or a pharmaceutically acceptable salt thereof once daily for the treatment of prostate cancer. Prostate cancer can be hormone-dependent prostate cancer, late-stage prostate cancer, late-stage hormone-sensitive prostate cancer, metastatic, non-metastatic, local late-stage cancer, local late-stage hormone-dependent cancer, late-stage castration-resistant cancer , recurrent castration-resistant metastatic prostate cancer, castration-resistant non-metastatic prostate cancer, hormone-sensitive metastatic prostate cancer, or hormone-sensitive non-metastatic prostate cancer. Once administered to a subject, formulations containing Compound 1 or a pharmaceutically acceptable salt thereof rapidly inhibit the production of sex hormones such as testosterone, LH and FSH and are not associated with an initial worsening of symptoms, also known as clinical or hormonal flares.

Unlike GnRH agonists such as leuprolide acetate, Compound 1 or a pharmaceutically acceptable salt thereof is in an oral formulation and is not a depot or slow-release formulation, and upon interruption of treatment, hormone levels increase and may return to serum hormone levels subject before treatment (ie, baseline levels) after discontinuation of once daily administration of Compound 1 or a pharmaceutically acceptable salt thereof, thereby providing greater control for patients and their physicians. Thus, unlike treatments that employ depot injections, the treatments and uses of the present invention provide for suspension periods in which subjects can stop treatment for a period of time and then resume treatment without any side effects. The interruption of treatment may be planned (eg, before, during, or after a planned surgical or invasive procedure (eg, knee replacement or colonoscopy)) or may occur after the subject experiences, for example, an intercurrent illness

- 7 043716 or injury. In any scenario (planned or unplanned), the increase in serum testosterone levels promotes recovery or helps maintain the subject's physical health.

In addition, some patients receiving GnRH antagonists or GnRH agonists do not achieve pretreatment serum testosterone levels for significant periods of time, even after discontinuation of treatment. Miranda et al., The Journal of Urology, May 16, 2017, vol. 197, issue 4, e1221-e1222 (noting that 23% of patients receiving GnRH agonist AAT maintained testosterone levels during therapeutic castration 24 months after AAT discontinuation); Tsumura et al., World J. Radiol., Dec. 28, 2015, 7(12): 494-500 (noting that five years after discontinuation of GnRH agonist therapy, approximately one-fifth of patients still had testosterone levels similar to therapeutic castration). One advantage of Compound 1 or a pharmaceutically acceptable salt thereof is that, as shown in Example 9 and FIG. 50 and 53, 43% of patients achieved pretreatment serum testosterone levels or serum testosterone levels of or near 280 ng/dL by week 12, compared with only 5.3% with degarelix.

The disclosure discloses methods and uses for treating prostate cancer in a subject in need thereof, comprising once daily administration of formulations containing Compound 1 or a pharmaceutically acceptable salt thereof. Subjects receiving once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof experienced an increase in serum testosterone levels after the last dose of the formulation containing Compound 1 or a pharmaceutically acceptable salt thereof. Accordingly, the disclosure discloses methods of using oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer in a subject in need of increasing serum testosterone levels above 50 ng/dL. Administration of once daily formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may be suspended during the suspension period, resulting in an increase in the subject's serum testosterone levels shortly after the start of the suspension period.

For example, for most subjects, serum testosterone levels will increase within 1 week of the start of the suspension period. Increasing serum testosterone levels may be very beneficial for subjects who have an intercurrent illness, are receiving radiation therapy, are on bed rest, have had trauma, have undergone a surgical or invasive procedure, or are desiring renewed sexual function over a period of time (eg, 25th wedding anniversary) . Higher levels of serum testosterone may be beneficial for such subjects, as testosterone has anabolic effects, helping to repair tissue, increase weight and muscle mass, and stimulate bone growth and mineralization. Treatment may also be suspended to improve the subject's quality of life and energy levels; to assist with recovery from injury, intercurrent illness, surgery, or radiation therapy; to help subjects control their lifestyle, including improving sexual function; and help restore strength and mobility after intercurrent illness or injury. Even before serum testosterone levels reach the subject's pre-treatment serum testosterone level, the benefit of increasing serum testosterone levels above that of therapeutic castration may be important to the subject's recovery, for example, after surgery such as knee replacement or hip (whether planned or unplanned). Testosterone's contribution to tissue repair and increased muscle mass may be a factor in successful physical therapy after surgery and restoration of range of motion, mobility, and strength. Administration of once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may be resumed at the end of the suspension period. Alternatively, once-daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof are optionally resumed after once-daily dosing is suspended, for example, if prostate-specific antigen (PSA) levels remain at an acceptable level during the period of suspension. .

Following initial treatment or resumption of administration of Compound 1 or a pharmaceutically acceptable salt thereof after a period of suspension, serum testosterone levels generally fall to or below therapeutic castration levels within about 4 days to about 8 days after the first administration of the once daily oral formulation according to this invention. This is different from leuprolide and other GnRH agonists. If a subject stops and restarts treatment with leuprolide, or other GnRH agonists, it may take up to one month to see a decrease in serum testosterone levels. In addition, the maximum reduction in PSA, or PSA nadir, occurs more rapidly with once-daily administration of Compound 1 or a pharmaceutically acceptable salt thereof than with GnRH agonists. Once daily administration of Compound 1 or a pharmaceutically acceptable salt thereof after a period of suspension also results in a rapid (within several days) and complete decrease in FSH, in contrast to GnRH agonists. There is a correlation between higher FSH levels and prostate cancer progression because FSH stimulates FSH receptors expressed on tumor blood vessel endothelial cells in prostate cancer specimens. In addition, patients with low FSH levels have a significantly longer time until castration resistance occurs.

These advantages of these methods and applications are important both in treatment settings, such as when a subject may be undergoing radiation therapy, and when a pathology or procedure unrelated to the treatment of prostate cancer is occurring. For example, as noted earlier, consider a subject undergoing treatment for prostate cancer who is involved in a car accident. Whether or not surgery is required to aid in recovery from a car accident, higher levels of serum testosterone will assist the subject in recovery, such as repairing damaged tissue, or promoting bone mineralization in the event of fractures. Unlike a treatment regimen using a depot formulation, which is administered by injection and requires an extended period of time to increase the subject's serum testosterone levels even after completion of the nominal treatment period, these methods and uses allow treatment to be suspended by discontinuing the once-daily oral formulation. , resulting in an immediate increase in serum testosterone levels, without side effects in response to unexpected factors. Additionally, when upcoming surgeries, such as hip or knee replacement, may be planned, treatment may be withheld shortly before or during surgery to allow for optimal patient recovery after surgery and potentially better results due to higher levels of the anabolic hormone testosterone. The methods and uses disclosed herein may involve resuming administration of Compound 1 or a pharmaceutically acceptable salt thereof once daily during the postoperative recovery phase if the subject's prostate cancer begins to worsen or spread. When administration of Compound 1 or a pharmaceutically acceptable salt thereof is resumed after a period of suspension for surgery, serum testosterone levels generally fall to or below therapeutic castration levels within about 4 days to about 8 days after the first administration of the once daily oral formulation according to this invention. Because it may take up to one month to detect a decrease in a subject's serum testosterone levels following administration of depot-formulated GnRH agonists, treatments using these agonists may not have the same flexibility as treatments using once-daily administration of Compound 1 or a pharmaceutically acceptable salt thereof. The maximum decline in PSA or PSA nadir may also occur more rapidly with once-daily administration of Compound 1 or a pharmaceutically acceptable salt thereof after a period of suspension than with the use of GnRH agonists. Once daily administration of Compound 1 or a pharmaceutically acceptable salt thereof after a period of suspension may result in a rapid (within a few days) and complete decrease in FSH, unlike GnRH agonists.

Intermittent therapy allowed by the methods, uses and formulations of this invention can prevent the transition from hormone-dependent to androgen-independent prostate cancer. Androgen independence may be an intrinsic but inactive property of some prostate cancer cells that is activated in response to androgen deprivation. Compound 1, or a pharmaceutically acceptable salt thereof, intermittent therapy disclosed herein may be dosed such that complete and continuous androgen deprivation does not occur, possibly preventing androgen independence. Rather than having a consistently low level of serum testosterone, Compound 1 or a pharmaceutically acceptable salt thereof may allow testosterone to fluctuate up and down (many peaks and valleys). Intermittent treatment, intermittent therapy, or intermittent dosing can refer to starting, stopping, or taking a break from medication. An example of intermittent treatment is to discontinue once-daily oral formulations of the present invention as soon as the PSA level drops to a very low level and resume once-daily dosing if the PSA level begins to rise. Another form of intermittent therapy using the claimed methods and uses may provide therapy for fixed periods of time, for example, with administration of 6 months and without administration of 6 months.

Compound 1 or a pharmaceutically acceptable salt thereof has a more rapid onset of action than currently available GnRH agonists, and unlike the available peptide GnRH agonists, which are administered either subcutaneously or intranasally, Compound 1 is a non-peptide drug that can be administered orally and once a day. Compared to GnRH agonists such as leuprolide acetate, which are typically administered in a depot form, Compound 1 or a pharmaceutically acceptable salt thereof offers several advantages. Such benefits may include, but are not limited to, oral administration, rapid onset of decrease in serum testosterone levels within four days, rapid onset of decrease in serum FSH, rapid decrease in PSA, absence of clinical flare, no need for anti-androgen therapy for protection patient from clinical exacerbation of symptoms. The ability to suspend treatment for periods of time may result in serum testosterone levels increasing shortly after treatment is interrupted, and may also return serum testosterone levels to pre-treatment serum testosterone levels after treatment is interrupted depending on the period of interruption, and each These results can quickly lead to improved quality of life, recovery, and renewed vigor.

Compound 1 or a pharmaceutically acceptable salt thereof also has advantages over other GnRH antagonists. Oral administration of once daily formulations containing Compound 1 or a pharmaceutically acceptable salt thereof allows hormone levels, such as serum testosterone levels, to return to the subject's pre-treatment serum hormone levels more quickly than a depot formulation of a GnRH antagonist such as as degarelix, after suspension. The ability to increase serum testosterone levels, including returning to the subject's pre-treatment serum testosterone level, is desirable for patients wishing to reverse any undesirable effects of decreased hormone levels. A more rapid return of hormonal levels to the subject's pre-treatment serum hormonal levels also helps restore energy and strength in men, for example, for reasons such as those described above. However, when symptoms or markers (eg, PSA levels) of prostate cancer indicate that treatment should be resumed, once-daily administration of Compound 1 or a pharmaceutically acceptable salt thereof can be resumed promptly, with a rapid onset of action and without clinical exacerbation.

This document provides the use of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treatment in accordance with any of the methods described herein. Also provided are oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

Described below herein are additional embodiments of the present invention that illustrate some, but not all, embodiments of the invention.

Each embodiment disclosed herein may be used alone or in combination with any other embodiment disclosed herein.

Publications, patents and published patent applications mentioned in this application are expressly incorporated herein by reference.

Connections.

As used herein, Compound 1, namely N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4 -dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, shown by the formula

Compound 1 and pharmaceutical compositions containing Compound 1 can be prepared by the methods described in US Patent No. 7300935, US Patent No. 8058280, US Patent No. 9346822, US Patent No. 9758528, US Patent No. 8735401 and WO 2016136849, the disclosures of which are incorporated herein document by reference.

In some embodiments, Compound 1 is a pharmaceutically acceptable salt. Physiologically acceptable, pharmaceutically acceptable or pharmacologically acceptable compounds and compositions may contain substances that are not biologically or otherwise undesirable. For example, the substance can be administered to an individual without causing any substantially undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained. In some such embodiments, the pharmaceutically acceptable salt of Compound 1 is a pharmaceutically acceptable acid addition salt. Such salts include, but are not limited to, salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) and salts with organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).

Throughout this disclosure, amounts of Compound 1 described refer to the amount of free form of Compound 1 present in the formulated form. The term appropriate amount, as used herein, refers to the amount of a pharmaceutically acceptable salt of Compound 1 required to obtain the amount of free form of Compound 1 indicated in the finished form. One skilled in the art will appreciate how to calculate the appropriate amount of salt of a compound, such as the appropriate amount of a pharmaceutically acceptable salt of Compound 1, taking into account the difference in molecular weight between the free form of the compound and the salt form. For example, 80.0 mg of the free base of the compound corresponds to 84.7 mg of the HC1 salt.

Compound 1 was characterized as an orally active non-peptide GnRH antagonist. Compound 1 has been shown to antagonize GnRH through GnRH receptors that are present in the anterior pituitary basophils (secretory cells) and inhibit GnRH-stimulated secretion of LH and FSH by these cells. As a result, the drug reduces the concentration of hormones in the blood, including testosterone. Compound 1 or a pharmaceutically acceptable salt thereof improves the clinical symptoms observed in patients with prostate cancer. Administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof also causes a rapid decrease in serum PSA levels. Because Compound 1 is a GnRH antagonist, it does not cause clinical exacerbations and has a faster onset of action than GnRH agonists. Unlike GnRH agonists, Compound 1 is not a peptide drug.

Therapeutic uses and treatments.

Disclosed herein are methods of using an orally active, once daily GnRH antagonist Compound 1 or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer.

The present invention provides oral formulations containing at least 80 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, which can be used in methods and applications for treating prostate cancer in a subject in need thereof. Prostate cancer can include any cancer of the prostate gland, such as those described herein. Most prostate cancers are adenocarcinomas, but rarely may also include transitional cell (urothelial) cancers, squamous cell carcinomas, small cell carcinomas, neuroendocrine tumors, or sarcomas. Prostate cancer can spread outside the prostate gland (eg, metastatic prostate cancer) or it can be non-metastatic. Non-metastatic prostate cancer can refer to prostate cancer that has not spread from the primary site of prostate cancer and may be hormone sensitive. Hormone therapy is used to reduce serum testosterone levels in prostate cancer. Hormone therapy can also be used to reduce serum PSA and FSH levels in prostate cancer. The patient or subject may be mammalian or non-mammalian. Examples of mammals include, but are not limited to, any member of the class mammals - humans, non-human primates such as chimpanzees, and other species of primates and apes; farm animals such as cattle, horses, sheep, goats, pigs; pets such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. Non-mammal examples include, but are not limited to, birds, fish, and the like. In some embodiments of the present invention, the mammal is a human. In some embodiments of the present invention, the patient or subject is a human.

In some embodiments of the methods and uses described herein, the prostate cancer is hormone-dependent prostate cancer. Hormone-dependent prostate cancer, hormone-sensitive prostate cancer, androgen-dependent prostate cancer, or androgen-sensitive prostate cancer can refer to prostate cancer that requires relatively high levels of androgens for the tumor to grow in the early stages of its development. Such prostate cancer may be referred to as androgen/hormone-dependent or androgen/hormone-sensitive because treatments that reduce androgen levels or block androgen activity can effectively inhibit tumor growth.

In some embodiments of the methods and uses described herein, prostate cancer represents advanced stages of prostate cancer. Prostate cancer is usually considered to be in advanced stages if it has spread beyond the prostate gland and the area around the prostate gland. It may spread to nearby tissue, lymph nodes, bones, or other parts of the body. When it spreads to the tissue immediately adjacent to the prostate gland, it is often called localized advanced prostate cancer. When it spreads beyond the tissue immediately adjacent to the prostate gland, it is usually called metastatic prostate cancer. Metastatic prostate cancer can usually

- 11 043716 involve bones, lungs, liver, brain, lymph nodes outside the pelvis, or other organs, and may be hormone sensitive. The following types of prostate cancer are also generally considered to be advanced stages of cancer: biochemical PSA recurrence after primary surgery or radiation therapy for curative intent; newly diagnosed metastatic prostate cancer; local advanced disease for which immediate radiation or surgery is not indicated, or men whose disease progresses after prostatectomy or radiation therapy. Clinical recurrence of advanced prostate cancer occurs when it causes symptoms. Consequently, advanced prostate cancer may be present with or without signs based on medical imaging findings, and with or without clinical symptoms. The treatments and uses of this invention include palliative treatment of advanced prostate cancer.

In some embodiments of the methods and uses described herein, the prostate cancer represents advanced stages of hormone-sensitive prostate cancer. The terms advanced hormone-sensitive prostate cancer, advanced hormone-sensitive prostate cancer, advanced androgen-dependent prostate cancer, or advanced androgen-sensitive prostate cancer, as used herein, may refer to prostate cancer that has spread beyond prostate gland and the area around the prostate gland. The growth of prostate cancer is suppressed, or the tumor may even shrink when androgen levels are reduced (eg, hormone therapy that reduces serum testosterone levels below castration levels of <50 ng/dL).

In some embodiments of the methods and uses described herein, the prostate cancer is an advanced localized cancer, an advanced castration-resistant cancer, or a recurrent cancer. Late-stage localized prostate cancer can refer to cancer that has started to leave the prostate gland or has spread to an area outside or near the prostate gland. It can also be characterized as stage T3 or T4 prostate cancer. It may involve one or more of, for example, the following: the prostate capsule, seminal vesicles, pelvic lymph nodes, bladder, and anus (rectum). Late-stage castration-resistant prostate cancer or late-stage hormone-resistant prostate cancer can refer to castration-resistant prostate cancer that has spread beyond the prostate gland and the area around the prostate gland. This type of cancer continues to grow and progress even when androgen levels in the body are extremely low or undetectable. Recurrent prostate cancer can refer to prostate cancer that was discovered or returned after initial treatment, such as surgery, radiation therapy, and/or hormone therapy. Recurrent prostate cancer may have biochemical and/or clinical recurrence. Some patients may only experience a rise in PSA levels as evidence of prostate cancer recurrence (biochemical recurrence), while others will have evidence of prostate cancer recurrence based on x-rays and tomography (clinical recurrence). Biochemical recurrence may refer to the return of prostate cancer after initial treatment, but it cannot be detected by standard imaging techniques. Therefore, prostate cancer may be present with or without signs based on diagnostic imaging findings, and with or without clinical symptoms. The return of prostate cancer is determined by an increase in PSA levels, which is determined by a blood test. Criteria for biochemical recurrence may include increases in PSA nadir + 2 ng/mL for recurrence after radiotherapy, >0.2 ng/mL if recurrence after prostatectomy, and >2 ng/mL if recurrence occurs after all other procedures. Clinical relapse may refer to the return of clinical symptoms associated with the growth or spread of prostate cancer after initial treatment for prostate cancer.

In some embodiments of the methods and uses described herein, the prostate cancer is castration-resistant prostate cancer. In some embodiments of the methods and uses described herein, the prostate cancer is castration-resistant metastatic prostate cancer. In some embodiments of the methods and uses described herein, the prostate cancer is castration-resistant, non-metastatic prostate cancer. Castration-resistant prostate cancer or hormone-resistant prostate cancer can refer to prostate cancer that continues to grow even when androgen levels in the body are extremely low or undetectable. For example, in castration-resistant prostate cancer, the PSA may increase or the cancer may

- 12 043716 strate other signs of growth even after using hormonal therapy to bring serum testosterone levels to castration levels (<50 ng/dL). For castration-resistant prostate cancer, hormonal therapy (eg, decreasing serum testosterone levels) is continued, and additional treatments are added to the treatment protocol in addition to the continued administration of medications used to decrease serum testosterone. Castration-resistant prostate cancer can be either metastatic (castration-resistant metastatic prostate cancer) or non-metastatic (castration-resistant non-metastatic prostate cancer). Metastatic castration-resistant prostate cancer or castration-resistant metastatic prostate cancer can refer to prostate cancer that has spread beyond the prostate gland, and continues to grow and progress (including but not limited to an increase in PSA) in the setting of decreased androgen levels (t i.e. hormonal therapy that reduces serum testosterone levels below castration levels <50 ng/dL). In some embodiments, once-daily administration of an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof reduces serum FSH levels and, therefore, may reduce the incidence of subjects who develop castration-resistant prostate cancer. In some embodiments, once-daily administration of an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof reduces serum FSH levels and therefore may slow the progression of castration-resistant prostate cancer. In some embodiments of the methods and uses described herein, the prostate cancer is hormone-sensitive metastatic prostate cancer. In some embodiments of the methods and uses described herein, the prostate cancer is hormone-sensitive, non-metastatic prostate cancer.

In some embodiments of the methods and uses described herein, the prostate cancer is an advanced stage of hormone-naïve prostate cancer. Late-stage hormone-naïve prostate cancer can be divided into two stages of disease: biochemical recurrence or traditional metastatic prostate cancer, and may be characterized by the absence of prior hormone therapy or anti-androgen therapy (AAT).

In some embodiments, oral formulations according to the methods and uses described herein contain from about 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. As used herein, the term oral formulation includes the terms oral loading dose, oral loading dose, oral loading dose, oral formulation maintenance dose, oral maintenance dosage, and the like, unless the context clearly indicates otherwise. . An oral loading dose, oral loading dose, or oral loading dose is an initial dose of Compound 1 or a pharmaceutically acceptable salt thereof that can be administered at the start of a course of treatment before changing to a different maintenance dose. As described herein, this is typically a large initial dose of Compound 1 or a pharmaceutically acceptable salt thereof, or a series of such doses, administered to rapidly achieve a therapeutically effective amount of drug in the body. A therapeutically effective amount may refer to an amount of a compound sufficient to treat the specified disorder or disease, or one or more symptoms thereof, and/or to prevent the occurrence of the disease or disorder. For example, a therapeutically effective dose for the treatment of prostate cancer contains such that the treatment causes improvement in one or more symptoms of prostate cancer, slows the progression of prostate cancer, results in remission, etc. A maintenance dose of an oral formulation, oral maintenance dosage, or oral maintenance dose is a dose of Compound 1 or a pharmaceutically acceptable salt thereof administered after a specified period of loading dose administration, and is typically a smaller amount of Compound 1 or a pharmaceutically acceptable salt thereof than the loading dose. but at the same time maintains the desired therapeutic effect.

In some embodiments, oral formulations according to the methods and uses described herein contain from about 80 mg to about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, oral formulations according to the methods and uses described herein contain about 120 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, oral formulations according to the methods and uses described herein contain about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, oral formulations according to the methods and uses described herein contain about 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, oral formulations according to the methods and uses described herein contain about 180 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

The methods and uses described herein also include treating prostate cancer in a subject in need thereof by administering to the subject once daily for at least 12 consecutive weeks an oral formulation containing at least 80 mg of the compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some such embodiments, the oral formulation contains about 120 mg, about 180 mg, about 240 mg, or about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some such embodiments, the oral formulation contains about 120 mg or about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. The methods and uses described herein also include treating prostate cancer in a subject in need thereof by administering to the subject once daily for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks, at least 24 consecutive weeks of an oral formulation containing at least 80 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof.

Certain benefits may be obtained in the treatment of prostate cancer by administering to a subject in need of treatment Compound 1 or a pharmaceutically acceptable salt thereof, thereby reducing the levels of one or more sex hormones as described herein. Suppression, as used herein, can occur by inhibiting the production of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the pituitary gland, a hormone required by the testes to produce testosterone and other androgens or sex hormones. Follicle-stimulating hormone (FSH) stimulates FSH receptors expressed on tumor blood vessel endothelial cells in prostate cancer specimens. FSH signaling in prostate cancer may contribute to the progression of castration-resistant prostate cancer. A decrease in serum testosterone levels may indicate that the testes are not producing testosterone in amounts typically observed in the absence of treatment with an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof. The degree of reduction is measured by serum testosterone levels, or levels of other sex hormones in the blood. Sex hormones can refer to any glandular secretions that are responsible for controlling sexual development and reproductive function in men. Such sex hormones include, for example, testosterone, dihydrotestosterone, follicle stimulating hormone (FSH), LH, GnRH, androsterone and inhibin. In accordance with this disclosure, the levels of one or more sex hormones, including testosterone, FSH and LH, can be reduced by once daily administration of Compound 1 or a pharmaceutically acceptable salt thereof to a subject having prostate cancer. In particular, therapeutic castration levels less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone can be achieved and maintained from days 14 to 28 after initiation of once daily dosing. Also, following once-daily administration of an oral formulation of about 180 mg of compound 1 on day 1 or an appropriate amount of a pharmaceutically acceptable salt thereof within 24 to 48 hours of the start of administration, therapeutic castration-like levels of less than or equal to 50 ng may be achieved. /dL (1.73 nmol/L) serum testosterone. Additionally, following once-daily administration of a single loading dose of 360 mg oral formulation and once-daily maintenance doses of 120 mg oral formulation of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, therapeutic castration-like levels are achieved for 48 consecutive weeks. less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone by the beginning of the 5th week, and maintained by the end of the 48th week. Additionally, following once-daily administration of a single loading dose of 240 mg oral formulation and once-daily maintenance doses of 120 mg oral formulation of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, therapeutic castration-like levels are achieved for 48 consecutive weeks. less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone by the beginning of the 5th week, and maintained by the end of the 48th week. As used herein, therapeutic castration generally refers to serum testosterone levels of about <50 ng/dL, and the term complete castration generally refers to serum testosterone levels of about <20 ng/dL.

In accordance with this disclosure, methods and uses are provided for reducing the levels of one or more sex hormones, including testosterone, LH and FSH, in a subject suffering from prostate cancer. In addition, in accordance with this disclosure, methods and uses for reducing serum PSA levels are provided. In some embodiments, the methods and uses include administering to a subject once per

- 14 043716 day for at least one day of an oral dosage form, including at least one loading dose of an oral formulation, wherein the loading dose of an oral formulation contains from about 240 mg to about 480 mg of compound 1 or a corresponding pharmaceutical amount thereof acceptable salt; and administering to the subject once daily for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks, at least 24 consecutive weeks maintenance dose oral formulation, wherein the maintenance dose oral formulation contains from about 80 mg to about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the methods and uses include administering to a subject once daily for at least 24 consecutive weeks, as a maintenance dose of an oral formulation, at least 80 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof.

In the methods and uses of the present invention, the serum testosterone level may be reduced in a subject to a level of less than or equal to 50 ng/dL (1.73 nmol/L), or less than or equal to 20 ng/dL (0.69 nmol/L). l). In some embodiments, following once daily administration of 1 oral formulation of about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, therapeutic castration-like levels of less than or constituting 50 ng/dL (1.73 nmol/L) serum testosterone. In some embodiments, following once-daily administration of a single loading dose of a 360 mg oral formulation and maintenance doses of a 120 mg oral formulation of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof for 48 consecutive weeks, therapeutic castration levels of less than or 50 ng/dL (1.73 nmol/L) serum testosterone by the beginning of the 5th week and maintained by the end of the 48th week. In some embodiments, following once-daily administration of a single loading dose of a 240 mg oral formulation and maintenance doses of a 120 mg oral formulation of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof for 48 consecutive weeks, therapeutic castration levels of less than or 50 ng/dL (1.73 nmol/L) serum testosterone by the beginning of the 5th week and maintained by the end of the 48th week.

The methods of treatment and use according to this invention can provide rapid onset and rapid onset for subjects. Regarding offset, unlike GnRH agonists such as leuprolide acetate, Compound 1 or a pharmaceutically acceptable salt thereof is neither a depot nor a slow release formulation, and hormone levels, particularly serum testosterone levels, are increased and may return to the subject's pre-treatment serum levels of the hormone more quickly after discontinuation of once-daily dosing, providing greater control and treatment options for patients and their physicians. For example, more rapid increases in hormone levels, including increases in serum testosterone levels, in some cases to the subject's pre-treatment serum hormone levels (pre-treatment levels), may be beneficial in the treatment of intercurrent disease, among other conditions and procedures, as well as to restore sexual function and energy in men. The methods and applications described herein may provide faster recovery from short-term therapeutic castration when used for neoadjuvant/adjuvant therapy or intermittent AAT. As noted earlier, this flexibility is important both in the treatment setting, for example, when a subject may be undergoing radiation therapy, or when the occurrence of a condition or procedure unrelated to the treatment of prostate cancer occurs. For example, as noted earlier, consider a subject undergoing treatment for prostate cancer who is involved in a car accident. Whether or not surgery is required to aid in recovery from a car accident, higher levels of serum testosterone will aid the subject in recovery because testosterone has an anabolic effect, helping to repair tissue and increase body weight and muscle mass. Unlike a treatment regimen using a depot form, the presented methods and applications allow treatment to be suspended without side effects in response to unexpected factors (eg, illness, injury, etc.). Additionally, when upcoming surgeries, such as hip or knee replacement, may be planned, treatment may be withheld shortly before or during surgery to allow for optimal patient recovery after surgery and potentially better outcomes due to higher serum testosterone levels.

Subjects receiving treatment in accordance with this disclosure may be able to control their lifestyle and quality of life. Unlike conventional treatments that use depot injections, treatment with the formulations of this invention allows for periods of suspension or intermittent treatment, in which subjects can stop treatment for a period of time and then resume treatment without any side effects, including absence of clinical exacerbation. Clinical or hormonal exacerbation may refer to a transient increase in serum testosterone levels compared to

- 15 043716 with completely reduced levels of serum testosterone in the body caused by certain types of hormone therapy (eg, anti-androgen therapy) used to treat prostate cancer. Clinical exacerbation can be severe, for example causing worsening bone pain and urinary problems. The methods of treatment and use of the present invention may provide subjects with the desired rapid gain/loss capability. The methods of treatment and use of the present invention allow subjects to maintain sexual activity at specified times during the treatment period. Increasing serum testosterone levels may also promote increased energy levels, which may have a positive impact on the subject's (and the subject's family's) quality of life. For example, for important life events (such as attending a daughter's wedding, escorting her to the aisle, and dancing with the bride's mother, or celebrating a major wedding anniversary), these methods and applications may include a period of suspension to allow for increased energy or improved sexual function and , therefore, gain more enjoyment from such events without the potential adverse impact on prostate cancer control associated with clinical exacerbation associated with resumption of treatment after a period of suspension.

The invention provides methods of using oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer in a subject in need of increasing serum testosterone levels above 50 ng/dL. The invention also provides methods and uses for treating prostate cancer in a subject in need thereof, comprising once daily administration of formulations containing Compound 1 or a pharmaceutically acceptable salt thereof. Administration of once daily formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may be suspended for a period of suspension, resulting in an increase in the subject's serum testosterone levels. In some embodiments, once-daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may be resumed at the end of the suspension period. In some embodiments, once-daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof is not resumed after suspension.

The present invention further provides that upon discontinuation of the once daily oral formulations of the present invention, an increase in serum testosterone levels may occur in the subject during the suspension period. In some embodiments, after discontinuation of once-daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof during the suspension period, the subject's serum testosterone level may increase for 1 day after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of this invention during the suspension period, the subject's serum testosterone level may increase for 2 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase for 3 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase for 4 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase for 5 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase for 6 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of this invention during the suspension period, the subject's serum testosterone level may increase for 7 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase for 10 days after the start of the suspension period.

During the suspension period, the subject's serum testosterone level may be increased to the subject's serum testosterone level prior to once daily administration of an oral formulation of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof. With respect to offset, after stopping once daily dosing for the suspension period, the serum testosterone level may increase to the level of the subject's serum testosterone prior to administration of the oral formulation of the present invention for 4 weeks, or for 8 weeks, or for 12 weeks, or within 16 weeks, or within 24 weeks, after

- 16 043716 administration of the last dose before the suspension period. In some embodiments, the serum testosterone level may increase to the subject's serum testosterone level as before administration of a once daily oral formulation of the present invention for 4 weeks to 12 weeks after the last dose. In some embodiments, after discontinuation of the once daily oral formulations of this invention during the suspension period, the serum testosterone level may increase to the level of the subject's serum testosterone as before administration of the oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof within 1 days of suspension of administration. In some embodiments, upon discontinuation of the once daily oral formulations of this invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations during the 2 day suspension period. In some embodiments, after discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 3 day suspension period. In some embodiments, after discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 4 day suspension period. In some embodiments, upon discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 5 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 6 day suspension period. In some embodiments, upon discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 7 day suspension period. In some embodiments, upon discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 8 day suspension period. In some embodiments, upon discontinuation of the once daily oral formulations of this invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of this invention during the 9 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 10 day suspension period. In some embodiments, upon discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 15 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 20 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 30 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 35 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 40 day suspension period. IN

- 17 043716 In some embodiments, upon discontinuation of the once daily oral formulations of this invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of this invention during the 45 day suspension period. In some embodiments, upon discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 50 day suspension period. In some embodiments, upon discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 55 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 60 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 65 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 70 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 75 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 80 day suspension period. In some embodiments, upon discontinuation of the once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 85 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 90 day suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 95 day suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the serum testosterone level may increase to the subject's serum testosterone level as before administration of the oral formulations of the present invention during the 100 day suspension period.

The invention provides an increase in the patient's serum testosterone level to a level exceeding the levels during therapeutic castration. In some embodiments, upon discontinuation of once daily oral formulations of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof, during the period of suspension, the subject's serum testosterone level may increase to greater than that of therapeutic castration within 1 day after the beginning of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration within 2 days of the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration for 3 days after the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to more than

- 18 043716 than with therapeutic castration, within 4 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration for 5 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration for 6 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration for 7 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration for 10 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration for 15 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration for 20 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than that of therapeutic castration for 25 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to above that of therapeutic castration for 30 days after the start of the suspension period.

In some embodiments, upon discontinuation of once daily oral formulations of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof during the period of suspension, the subject's serum testosterone level may increase to greater than 55 ng/dL within 1 day thereof. the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 2 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 3 days of the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 4 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 5 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 6 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 7 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 10 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 15 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 20 days of the start of the suspension period. In some embodiments, after administration is stopped, one

- 19,043,716 times daily oral formulations of this invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL within 25 days after the start of the suspension period. In some embodiments, after discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than 55 ng/dL for 30 days after the start of the suspension period.

Normal serum testosterone levels for European and American men aged 19 to 39 years vary and are reported to range from about 250 ng/dL to about 920 ng/dL (see, The Journal of Clinical Endocrinology & Metabolism, vol. 102, issue 4, 1 April 2017, pp. 1161-1173). Suspension of the once daily oral formulations of the present invention may result in an increase in the subject's serum testosterone levels to a range of about 250 ng/dL to about 920 ng/dL, or to normal serum testosterone levels. The Endocrine Society suggests about 300 ng/dL as the lower limit of normal serum testosterone levels. Other medical societies suggest 150, 200, or 230 ng/dL as the lower limit of normal serum testosterone levels. The methods and uses of this invention can provide a return to normal serum testosterone levels. In some embodiments, after stopping the administration of once daily oral formulations of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof during the period of suspension, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dl, about 70 ng/dl, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng /dl, about 200 ng/dl, about 250 ng/dl, about 280 ng/dl, about 300 ng/dl, about 350 ng/dl, about 400 ng/dl, about 450 ng/dl, about 500 ng/dl , about 550 ng/dL or about 600 ng/dL within 1 day from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 2 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 3 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 4 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 5 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 6 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 7 days from the beginning of the suspension period. In some embodiments, after discontinuation of once-daily oral goto

- 20 043716 formulations of this invention, during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dL, about 80 ng /dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dl, about 280 ng/dl , about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 10 days from the beginning of the suspension period . In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 15 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 20 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 25 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 30 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 35 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 40 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 45 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 50 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dl, about 280 ng/dl, about 300 ng/dl, about 350 ng/dl, about 400 ng/dl, about 450 ng/dl, approx.

- 21 043716 lo 500 ng/dl, about 550 ng/dl or about 600 ng/dl within 55 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 60 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 65 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 70 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 75 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 80 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 85 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 90 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL for 95 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to greater than or equal to about 60 ng/dL, about 65 ng/dL, about 70 ng/dL, about 75 ng/dl, about 80 ng/dl, about 85 ng/dl, about 90 ng/dl, about 95 ng/dl, about 100 ng/dl, about 150 ng/dl, about 200 ng/dl, about 250 ng/dL, about 280 ng/dL, about 300 ng/dL, about 350 ng/dL, about 400 ng/dL, about 450 ng/dL, about 500 ng/dL, about 550 ng/dL or about 600 ng/dL within 100 days from the beginning of the suspension period. In some embodiments, after stopping the once daily oral formulations of this invention during the suspension period, the subject's serum testosterone level may increase to more than about 350 ng/dL from the start of the suspension period.

- 22 043716

In some embodiments, upon discontinuation of once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof, during the period of suspension the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 1 day from the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 2 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 3 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 4 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 5 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 6 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 7 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 10 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to from about 50 ng/dL to

- 23 043716 about 100 ng/dl, from about 100 ng/dl to about 150 ng/dl, from about 150 ng/dl to about 200 ng/dl, from about 200 ng/dl to about 250 ng/dl, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 15 days from the beginning of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 20 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 25 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 30 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 35 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 40 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 45 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 50 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about

- 24 043716

500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 50 days from the beginning of the period suspension. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 60 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 65 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 70 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 75 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 80 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 85 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 90 days of the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the period of suspension, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL, or from about 300 ng/dL to about 600 ng/dL within 95 days of the start of the suspension period. In some embodiments, upon discontinuation of once-daily oral formulations

- 25 043716 according to this invention, during the suspension period, the subject's serum testosterone level may increase to from about 50 ng/dL to about 100 ng/dL, from about 100 ng/dL to about 150 ng/dL, from about 150 ng/dL to about 200 ng/dL, from about 200 ng/dL to about 250 ng/dL, from about 250 ng/dL to about 300 ng/dL, from about 300 ng/dL to about 350 ng/dL, from about 350 ng/dL to about 400 ng/dL, from about 400 ng/dL to about 450 ng/dL, from about 450 ng/dL to about 500 ng/dL, from about 500 ng/dL to about 550 ng/dL, from about 550 ng/dL to about 600 ng/dL or from about 300 ng/dL to about 600 ng/dL within 100 days from the start of the suspension period. In some embodiments, upon discontinuation of once daily oral formulations of the present invention during the suspension period, the subject's serum testosterone level may increase to from about 300 ng/dL to about 600 ng/dL from the start of the suspension period.

In some embodiments, the subject's serum testosterone level may be reduced before and after administration is suspended (e.g., the serum testosterone level is below the therapeutic castration level, the full therapeutic castration level, significantly below the subject's pretreatment level (e.g., less than 50% of the subject's pretreatment level). before treatment, less than 40%, less than 30%, less than 20%, less than 10%, less than 5% or less than 1%)).

With respect to the onset of action of the present invention, it is also proposed that the once daily administration of the oral formulation of the present invention or the loading dose of the oral formulation and the maintenance dose of the oral formulation of the present invention be resumed after a period of suspension to achieve a return to serum testosterone levels as during therapeutic castration. . As noted previously, resuming once-daily dosing of Compound 1 or a pharmaceutically acceptable salt thereof does not involve the adverse clinical exacerbation associated with GnRH agonists and, therefore, should not result in worsening symptoms or worsening treatment gains as occurs with reintroduction treatment after a period of suspension during treatment with GnRH agonists. In some embodiments, during about 4 days to about 8 days of the first once-daily administration of an oral formulation of the present invention, or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention after a period of suspension, the subject's serum testosterone levels may meet the level or be below the level for therapeutic castration. In some embodiments, within 4 days of the first once-daily administration of an oral formulation of this invention, or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention after a period of suspension, the subject's serum testosterone levels may be at or below the level of with therapeutic castration. In some embodiments, within 5 days of the first once-daily administration of an oral formulation of this invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention after a period of suspension, the subject's serum testosterone levels may be at or below the level at therapeutic castration. In some embodiments, within 6 days of the first once-daily administration of an oral formulation of this invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention after a period of suspension, the subject's serum testosterone levels may be at or below the level at therapeutic castration. In some embodiments, within 7 days of the first once-daily administration of an oral formulation of the present invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention following a period of suspension, the subject's serum testosterone levels may be at or below the level at therapeutic castration. In some embodiments, within 8 days of the first once-daily administration of an oral formulation of this invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention after a period of suspension, the subject's serum testosterone levels may be at or below the level at therapeutic castration. In some embodiments, within 3 days of the first once-daily administration of an oral formulation of this invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention after a period of suspension, the subject's serum testosterone levels may be at or below the level at therapeutic castration.

In some embodiments, upon resuming administration of a once-daily oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 24 to 48 hours from the start of administration. In some embodiments, upon resumption of once-daily administration of an oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate pharmaceutical amount thereof

- 26 043716 acceptable salt, after the suspension period, the subject's serum testosterone levels may be at or below the level of therapeutic castration within 3 days of the start of administration. In some embodiments, upon resuming administration of a once-daily oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 4 days from the start of administration. In some embodiments, upon resuming administration of a once-daily oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 5 days from the start of administration. In some embodiments, upon resuming administration of a once-daily oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 6 days from the start of administration. In some embodiments, upon resuming administration of a once-daily oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 1 week from the start of administration.

In some embodiments, upon resuming once-daily administration of an oral formulation of the present invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, after a period of suspension, the subject's serum testosterone levels may be at or below level during therapeutic castration within 24 to 48 hours from the start of administration. In some embodiments, upon resuming once-daily administration of an oral formulation of the present invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, after a period of suspension, the subject's serum testosterone levels may be at or below level during therapeutic castration within 3 days from the start of administration. In some embodiments, upon resuming once-daily administration of an oral formulation of the present invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, after a period of suspension, the subject's serum testosterone levels may be at or below level during therapeutic castration within 4 days from the start of administration. In some embodiments, upon resuming once-daily administration of an oral formulation of the present invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, after a period of suspension, the subject's serum testosterone levels may be at or below level during therapeutic castration within 5 days from the start of administration. In some embodiments, upon resuming once-daily administration of an oral formulation of the present invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, after a period of suspension, the subject's serum testosterone levels may be at or below level during therapeutic castration within 6 days from the start of administration. In some embodiments, upon resuming once-daily administration of an oral formulation of the present invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, after a period of suspension, the subject's serum testosterone levels may be at or below level during therapeutic castration within 1 week from the start of administration.

In some embodiments, upon resuming administration of a once-daily oral formulation of the present invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 24 to 48 hours from the start of administration. In some embodiments, upon resuming administration of a once-daily oral formulation of the present invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 3 days from the start of administration. In some embodiments, upon resumption of once-daily administration of a once-daily oral formulation of this invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level at tera

- 27 043716 peutic castration within 4 days from the start of administration. In some embodiments, upon resuming administration of a once-daily oral formulation of the present invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 5 days from the start of administration. In some embodiments, upon resuming administration of a once-daily oral formulation of the present invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 6 days from the start of administration. In some embodiments, upon resuming administration of a once-daily oral formulation of the present invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, following a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration in within 1 week from the start of administration.

In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, starting the next day after the last dose of the oral loading formulation and continuing for the designated treatment period (e.g., at least 4 consecutive weeks or more, at least 8 consecutive weeks or more, at least 12 consecutive weeks or more, at least 16 consecutive weeks or more, at least 20 consecutive weeks or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, at least 72 consecutive weeks or more, or at least 96 consecutive weeks or more), for at least 24 up to 48 hours from the start of administration and maintained until the end of administration, therapeutic castration levels less than or equal to 50 ng/dL (1.73 nmol/L) of serum testosterone can be achieved. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last dose of the loading oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level during therapeutic castration within 3 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level during therapeutic castration within 4 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level during therapeutic castration within 5 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration maintenance dose of an oral formulation according to this invention containing 120 mg of compound 1 or the corresponding amount of a pharmaceutically acceptable salt thereof, starting the next day after administration of

- 28 043716 the last loading dose of the oral formulation, and continuing during the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 6 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet the level or be below the level of therapeutic castration within 1 week from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet the level or be below the level of therapeutic castration for 2 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet the level or be below the level of therapeutic castration for 3 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may match or be below the level of therapeutic castration for 4 weeks from the start of administration and maintained until the end of administration.

In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration maintenance dose of an oral formulation according to this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, starting the next day after the last loading dose of the oral formulation, and continuing for the designated treatment period (e.g., at least 4 consecutive weeks or more, at least 8 consecutive weeks or more, at least 12 consecutive weeks or more, at least 16 consecutive weeks or more, at least 20 consecutive weeks or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, at least 72 consecutive weeks or more, or at least 96 consecutive weeks or more) for 24 to 48 hours from the start of administration and maintained until the end of administration, therapeutic castration-like levels of less than or equal to 50 ng/dL (1.73 nmol/L) of serum testosterone can be achieved. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or

- 29 043716 be below the level during therapeutic castration within 3 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level during therapeutic castration within 4 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level during therapeutic castration within 5 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level during therapeutic castration within 6 days from the start of administration and be maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet the level or be below the level of therapeutic castration within 1 week from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet the level or be below the level of therapeutic castration for 2 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet the level or be below the level of therapeutic castration for 3 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration maintenance dose of an oral formulation according to this invention containing 120 mg of Compound 1 or an appropriate amount of its pharmaceutically acceptable salt, starting the next day after administration of the last loading dose of the oral formulation, and continuing during the designated treatment period, serum levels The subject's testosterone levels may be at or below therapeutic castration levels for 4 weeks from the start of administration and maintained until the end of administration.

In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration maintenance dose of an oral formulation according to this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, starting the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period (e.g., at least 4 consecutive weeks or more, at least 8 consecutive weeks or more, at least 12 consecutive weeks or more, at least 16 consecutive weeks or more, at least 20 consecutive weeks or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, at least 72 consecutive weeks or more, or at least 96 consecutive weeks or more) for 24 to 48 hours from the start of administration and maintained until the end of administration, complete castration levels less than or equal to 20 ng/dL (1.73 nmol/L) serum testosterone can be achieved. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level of complete castration within 3 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level of complete castration within 4 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level of complete castration within 5 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may correspond to the level or be below the level of complete castration within 6 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet the level or be below the level of complete castration within 1 week from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and administration once daily maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, starting the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, serum levels The subject's testosterone levels may be at or below full castration levels for 2 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet or be below the level of complete castration for 3 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment following a period of withholding and once daily administration a maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may meet or be below the level of complete castration for 4 weeks from the start of administration and maintained until the end of administration.

In some embodiments, after resuming dosing of a once-daily oral formulation of the present invention after a suspension period, the median time from administration of the first oral formulation after the suspension period to the PSA nadir may be less than 5 weeks, less than 6 weeks, less than 7 weeks. weeks, less than 8 weeks, less than 9 weeks, less than 10 weeks, less than 11 weeks, less than 12 weeks, less than 13 weeks, less than 14 weeks, less than 15 weeks, less than 16 weeks, less than 17 weeks, less than 18 weeks, less than 19 weeks, less than 20 weeks, less than 21 weeks, less than 22 weeks, less than 23 weeks, less than 24 weeks or less than 25 weeks. In some embodiments, after resuming dosing of a once-daily oral formulation of this invention after a period of suspension, the median time from administration of the first oral formulation after the suspension period to the PSA nadir may be from about 5 weeks to about 10 weeks, from about 5 weeks up to about 15 weeks, from about 5 weeks to about 20 weeks, from about 5 weeks to about 25 weeks, from about 10 weeks to about 15 weeks, from about 10 weeks to about 20 weeks, from about 10 weeks to about 25 weeks, or from about 15 weeks to about 20 weeks. In some embodiments, once dosing of a once daily oral formulation of the present invention is resumed after a period of suspension, the median time from administration of the first oral formulation after the suspension period to the PSA nadir may be from about 10 weeks to about 20 weeks. In some embodiments, upon resumption of once-daily oral formulations of this invention for 4 weeks, serum PSA levels decrease by more than or about 5%, more than or about 10%, more than, or about 20% more. more than or about 30%, more than or about 40%, more than or about 50%, more than or about 60%, more than or about 70%, more than or about 80% or more than or about 90% of the subject's pre-treatment serum PSA levels. In some embodiments, upon resumption of once-daily administration of oral formulations of this invention for 4 weeks, serum PSA levels decrease by more than or about 50% of the subject's pre-treatment serum PSA levels.

In some embodiments, after administering a once-daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment following a period of suspension and administering a once-daily maintenance dose of an oral formulation of this invention starting the next day after administration of the last loading dose of the oral formulation, and continuing for the designated treatment period, the median time from the start of treatment to the PSA nadir may be less than 5 weeks, less than 6 weeks, less than 7 weeks, less than 8 weeks, less than 9 weeks, less than 10 weeks, less than 11 weeks, less than 12 weeks, less than 13 weeks, less than 14 weeks, less than 15 weeks, less than 16 weeks, less than 17 weeks, less than 18 weeks, less than 19 weeks, less than 20 weeks, less than 21 weeks, less than 22 weeks, less than 23 weeks, less than 24 weeks

- 32 043716 or less than 25 weeks. In some embodiments, after administering a once-daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment following a period of suspension and administering a once-daily maintenance dose of an oral formulation of this invention starting the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the median time from the start of treatment to the PSA nadir may be from about 5 weeks to about 10 weeks, from about 5 weeks to about 15 weeks, from about 5 weeks to about 20 weeks, about 5 weeks to about 25 weeks, about 10 weeks to about 15 weeks, about 10 weeks to about 20 weeks, about 10 weeks to about 25 weeks, or about 15 weeks to about 20 weeks. In some embodiments, after administering a once-daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment following a period of suspension and administering a once-daily maintenance dose of an oral formulation of this invention starting the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the median time from the start of treatment to the PSA nadir may range from about 10 weeks to about 20 weeks. In some embodiments, 4 weeks from the start of a once-daily loading dose of an oral formulation of this invention for 1-3 days after a period of suspension and administration of a once-daily maintenance dose of an oral formulation of this invention beginning on the next day after administration of the last loading dose of the oral formulation, serum PSA levels decrease by more than or about 5%, by more than or about 10%, by more than or about 20%, by more than or about 30%, by more than or about 40 %, greater than or about 50%, greater than or about 60%, greater than or about 70%, greater than or about 80%, or greater than or about 90% of the subject's pre-treatment serum PSA levels. In some embodiments, 4 weeks from the start of a once-daily loading dose of an oral formulation of this invention for 1-3 days after a period of suspension and administration of a once-daily maintenance dose of an oral formulation of this invention beginning on the next day after administration of the last loading dose of the oral formulation, serum PSA levels decrease by more than or about 50% of the subject's pretreatment serum PSA levels.

In some embodiments, upon resumption of once-daily administration of the oral formulation of this invention for 1 week, 4 weeks, 12 weeks, 24 weeks, or 48 weeks after the suspension period, serum FSH levels may be less than or about 7.2 mIU. ml, about 4.8 mIU/ml, about 2.4 mIU/ml, or about 1.2 mIU/ml. In some such embodiments, once daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may result in a continuous decrease in serum FSH levels. Normal FSH levels in adult men typically range from 1.5 to 12.4 mIU/mL but are elevated in patients with prostate cancer. In some embodiments, upon resuming once-daily administration of a once-daily oral formulation of the present invention for 1 week following the suspension period, serum FSH levels may be less than or about 7.2 mIU/mL, about 4.8 mIU/mL, about 2 .4 mIU/ml or about 1.2 mIU/ml. In some embodiments, resuming a once-daily oral formulation of the present invention for 1 week, 4 weeks, 12 weeks, 24 weeks, or 48 weeks after a period of suspension may reduce serum FSH levels by greater than 80% or about 90% of the subject's serum FSH levels before treatment.

In some embodiments, after administration of a once daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment, following a period of suspension and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after administration of the last loading dose of the oral formulation, serum FSH levels may be less than or about 7.2 mIU/mL, about 4.8 mIU/mL, about 2.4 mIU/mL, or about 1.2 mIU/mL after one week , 4 weeks, 12 weeks, 24 weeks or 48 weeks from the start of treatment. In some such embodiments, once daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may result in a continuous decrease in serum FSH levels. In some embodiments, after administration of a once daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment, following a period of suspension and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after administration of the last loading dose of the oral formulation, serum FSH levels may be less than or about 7.2 mIU/mL, about 4.8 mIU/mL, about 2.4 mIU/mL, or about 1.2 mIU/mL after one week after starting treatment. In some embodiments, after administration of a once daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment, following a period of suspension and administration of a once daily maintenance dose of an oral formulation of this invention

- 33 043716 starting the next day after administration of the last loading dose of the oral formulation, serum FSH levels may be reduced by greater than or about 80%, or about 90% of the subject's pretreatment serum FSH levels after 1 week, 4 weeks, 12 weeks, 24 weeks or 48 weeks after starting treatment.

Due to the return to serum testosterone levels above 50 ng/dL after the last dose of the oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof, and the rapid response of the oral formulations of this invention upon resumption of once daily dosing after a period of suspension , administration may be withheld for a period of suspension if necessary to increase serum testosterone levels. In some embodiments, the subject requires an increase in serum testosterone levels to above 50 ng/dL. Increasing serum testosterone levels may be required due to intercurrent illness, radiation therapy, bed rest, previous trauma, previous surgical or invasive procedure, or the desire to achieve restored sexual function over a period of time. An intercurrent disease may refer to a disease occurring during another disease unrelated to the primary disease (eg, the disease is not prostate cancer or a symptom of prostate cancer, but may be, for example, pneumonia, etc.). In some embodiments, the intercurrent disease is an acute disease—a disease with sudden onset. Intercurrent illness may result in loss of physical function or muscle wasting, prolonged bed rest, prolonged inflammation, infection, or prolonged physical therapy. Injury can disrupt the structure or function of the body, and can lead to loss of physical function or muscle wasting, prolonged bed rest, prolonged inflammation, infection, prolonged physical therapy, or recovery from a surgical or invasive procedure. Trauma includes, but is not limited to: wounds, fractures and burns. A surgical procedure or other invasive procedure may refer to a procedure that is performed by entering the body through the skin, or through a body cavity or anatomical orifice, and includes procedures performed in an operating room, surgical suite, or treatment room. The surgical procedure may include, but is not limited to, heart surgery, knee replacement, hip replacement, abdominal surgery, pelvic surgery, vascular surgery, spine surgery, or an emergency procedure due to injury . The invasive procedure may include, but is not limited to, colonoscopy, angioplasty, stent placement, endovascular coil placement, endovascular aneurysm repair, endoscopy, laparoscopy, arthroscopy, coronary catheterization, or other catheter-based procedure. As noted previously, increasing serum testosterone levels may be beneficial in such subjects as testosterone has an anabolic effect, helping to repair tissue, increases weight and muscle mass, and stimulates bone growth and mineralization, which may help counteract the adverse effects of intercurrent surgery. illnesses, injuries, etc., as discussed above. Restored sexual function or restoration of sexual function may refer to the improvement in sexual function observed with an increase in sex hormone levels after discontinuation of once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof. For example, when serum testosterone levels are normalized to levels above therapeutic castration of >50 ng/dL, due to interruption of once-daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof, sexual function improves. Sexual function and libido will continue to improve as serum testosterone levels rise above 50 ng/dL and return to normal (pre-treatment) levels. Improved sexual function may include, but is not limited to, improvements in libido, erectile dysfunction, arousal, orgasm, nocturnal erections, sexual desire, penile morphology, ejaculation, quality of life, overall self-esteem and overall relationships.

Once daily administration may also be suspended to improve the subject's quality of life and energy levels;

help with recovery from injury, intercurrent illness, surgery or radiation therapy;

help subjects control their lifestyle, including improving sexual function; and help restore strength and mobility after intercurrent illness or injury. Once administration is suspended, it may or may not be resumed as needed. In some embodiments, once-daily dosing is resumed after the subject recovers from the intercurrent illness, is no longer on bed rest, has resumed normal activities of daily living, or has regained a normal level of function (e.g., returns to the level of function the subject had before the illness ).

The present invention provides for the suspension of once daily administration of oral formulations of the present invention prior to surgery or other invasive procedure, or radiation therapy. In some embodiments, once daily administration may be suspended prior to a surgical procedure or other invasive procedure. In some embodiments, once-daily administration of the oral formulations of this invention may be withheld following a surgical procedure or other invasive procedure, trauma, or radiation therapy. In some embodiments, once-daily administration of the oral formulations of the present invention occurs before and during a surgical procedure or other invasive procedure, or radiation therapy, and once-daily administration may be suspended after the surgical procedure or other invasive procedure, or radiation therapy. therapy. In some embodiments, once-daily administration of the oral formulations of this invention may be withheld during a surgical procedure or other invasive procedure, trauma, or radiation therapy. In some embodiments, once-daily administration of the oral formulations of the present invention may be withheld because the subject requires an increase in serum testosterone levels due to a surgical procedure or other invasive procedure, with an expected time to full recovery of at least about 1 week, about 2 weeks, about 3 weeks, about weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 36 weeks, about 48 weeks or about 52 weeks. In some such embodiments, the recovery time is about 2 weeks. In some embodiments, once-daily administration of the oral formulations of the present invention is not resumed after administration has been suspended before, after, or during a surgical procedure or other invasive procedure. In some such embodiments, once daily dosing is not resumed after dosing has been suspended following a surgical procedure or other invasive procedure. In some embodiments, the surgical procedure is cardiac surgery, knee replacement, hip replacement, abdominal surgery, pelvic surgery, vascular surgery, spine surgery, or an emergency procedure due to trauma. In some embodiments of the methods and uses described herein, a subject undergoing treatment for prostate cancer is identified as being at risk for acute postoperative weakness.

According to the present invention, it is proposed to suspend the administration of once daily oral formulations according to the present invention before radiation therapy. In some embodiments, once-daily administration of oral formulations of the present invention may be withheld following radiation therapy. Suspension of the once daily oral formulations of the present invention after radiation therapy may aid in recovery from radiation therapy while allowing therapeutic treatment of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof during radiation therapy, making intensive treatment of prostate cancer is possible. In some embodiments, once-daily administration of oral formulations of the present invention occurs before and during radiation therapy, and administration may be suspended after radiation therapy. In some embodiments, once-daily administration of oral formulations of the present invention may be suspended during radiation therapy. In some embodiments, once-daily administration of oral formulations of the present invention may be withheld because the subject requires an increase in serum testosterone levels due to radiation therapy for at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks. weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 36 weeks, about 48 weeks or about 52 weeks. In some embodiments, once-daily administration of oral formulations of the present invention is not resumed after administration has been suspended before, after, or during radiation therapy. In some such embodiments, once daily dosing is not resumed after dosing has been suspended following radiation therapy. In some embodiments, once daily dosing may be resumed when an increase in PSA nadir+2 ng/mL is observed following radiation therapy. In some embodiments, once daily dosing may be resumed after radiation therapy when the subject's PSA level is >3, >10, >20, or >30 ng/mL.

In some embodiments, once daily administration may be suspended during intercurrent illness or when the subject is on bed rest. In some embodiments, once daily administration may be withheld following an intercurrent illness. In some embodiments, once-daily administration of oral formulations of the present invention may be withheld because the subject requires an increase in serum testosterone levels due to an intercurrent illness, presex

- 35 043716 estimated recovery time of at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 36 weeks, about 48 weeks or about 52 weeks. In some such embodiments, the recovery time is about 2 weeks. In some embodiments, once-daily administration of oral formulations of the present invention is not resumed after administration has been suspended following or during an intercurrent illness. In some such embodiments, once daily dosing is not resumed after dosing has been suspended following an intercurrent illness. In some embodiments, the once daily oral formulations of the present invention may be suspended due to an intercurrent illness, wherein the illness is a stroke or cerebral hemorrhage. In some embodiments, once daily dosing may be suspended due to an intercurrent disease, the disease being myocardial infarction or congestive heart failure. In some embodiments, once daily dosing is suspended following an accident or injury requiring prolonged recovery. In some embodiments, once daily dosing is stopped following a stroke, cerebral hemorrhage, myocardial infarction, congestive heart failure, hip fracture, or other condition resulting in limited mobility and requiring prolonged recovery.

In some embodiments, once-daily administration of the oral formulations of the present invention may be withheld because the subject requires an increase in serum testosterone levels due to injury, with an expected recovery time of at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 36 weeks, about 48 weeks or about 52 weeks. In some such embodiments, the recovery time is about 2 weeks. In some embodiments, administration of the once daily oral formulations of the present invention may be interrupted due to injury, wherein the injury is a fracture. In some embodiments, once daily administration may be interrupted due to injury, wherein the injury is a hip fracture. In some embodiments, the administration of once daily oral formulations of the present invention may be interrupted due to injury, wherein the injury is a knee injury.

The formulations of this invention may provide an increase in serum testosterone levels as medically necessary. Stopping the once-daily oral formulations of this invention containing Compound 1 or a pharmaceutically acceptable salt thereof may reduce the catabolic effect of intercurrent/acute illness and bed rest in men with prostate cancer, thereby allowing serum testosterone levels to increase to help restore strength and mobility after intercurrent/acute illness. Such benefit cannot be achieved with depot forms of GnRH agonists/antagonists. Such intermittent anti-androgen therapy may minimize the adverse events associated with continuous anti-androgen therapy while providing comparable efficacy to patients with prostate cancer.

The duration of the suspension period should be such as to have minimal adverse effect on treatment due to the temporary interruption of the once daily oral formulations of the present invention. In some embodiments, the suspension period is from 4 weeks or less to 12 weeks or more. Longer periods of suspension are possible as long as the subject's PSA levels remain low, such as <4 or <0.2 ng/mL. In some embodiments, once daily dosing may be resumed when there is an increase in PSA nadir of +2 ng/mL during the suspension period. In some embodiments, once daily dosing may be resumed when the subject's PSA level increases to >3, >10, >20, or >30 ng/mL during the suspension period. In some embodiments, the suspension period may be up to 60 weeks. In some embodiments, the suspension period may be up to 52 weeks. In some embodiments, the suspension period may be up to 48 weeks. In some embodiments, the suspension period may be up to 36 weeks. In some embodiments, the suspension period may be up to 24 weeks. In some embodiments, the suspension period may be up to 20 weeks. In some embodiments, the suspension period may be up to 16 weeks. In some embodiments, the suspension period may be up to 12 weeks. In some embodiments, the suspension period may be up to 4 weeks. In some embodiments, the suspension period may be up to 8 weeks.

The duration of the suspension period may be modified depending on one or more of the following factors: severity of symptoms, subject's age, weight, and sensitivity. In some embodiments, as long as the PSA level is <4 or <0.2 ng/mL, the subject may not receive therapy. In some embodiments, the suspension period is terminated when the subject's prostate-specific antigen (PSA) level is >20% of the nadir of the subject's PSA level during treatment. In some embodiments, the suspension period is terminated when the subject's PSA level is >50% of the subject's pre-treatment PSA level. In some embodiments, the suspension period is interrupted when the subject's PSA level is greater than the subject's PSA level at the beginning of the suspension period. In some embodiments, the suspension period is interrupted when the subject experiences a return of prostate cancer symptoms. In some embodiments, the suspension period is interrupted when the subject's PSA level is >3 ng/mL. In other embodiments, the suspension period is terminated when the subject's PSA level is >10 ng/mL. In some embodiments, the suspension period is terminated when the subject's PSA level is >20 ng/mL. In other embodiments, the suspension period is terminated when the subject's PSA level is >30 ng/mL.

In some embodiments, the length of time that a subject may use the suspension period during the treatment period should be such as to have minimal adverse impact on treatment due to the suspension period. In some embodiments, before using the suspension period, the subject must have completed treatment for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks, at least 24 consecutive weeks, at least 36 consecutive weeks, at least 48 consecutive weeks, at least 52 consecutive weeks, at least 72 consecutive weeks, or at least 96 consecutive weeks. In some embodiments, the subject must have completed at least 24 consecutive weeks of treatment before using the suspension period. In some embodiments, the subject must have completed at least 48 consecutive weeks of treatment before using the suspension period. The duration of the suspension period may be modified depending on one or more of the following factors: severity of symptoms, subject's age, weight, and sensitivity.

Relative to the onset of disease, within about 4 days to about 8 days of the first once-daily administration of an oral formulation of the present invention, or a loading dose of an oral formulation of the present invention, and a maintenance dose of an oral formulation of this invention after a period of suspension, the subject's serum testosterone levels may be at or below the level of therapeutic castration. In some embodiments, within 4 days of the first once-daily administration of an oral formulation of this invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention, the subject's serum testosterone levels may be at or below the level of therapeutic castration. In some embodiments, within 5 days of the first once-daily administration of an oral formulation of this invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention, the subject's serum testosterone levels may be at or below the level of therapeutic castration. In some embodiments, within 6 days of the first once-daily administration of an oral formulation of the present invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention, the subject's serum testosterone levels may be at or below the level of therapeutic castration. In some embodiments, within 7 days of the first once-daily administration of an oral formulation of this invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention, the subject's serum testosterone levels may be at or below the level of therapeutic castration. . In some embodiments, within 8 days of the first once-daily administration of an oral formulation of the present invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention, the subject's serum testosterone levels may be at or below the level of therapeutic castration. In some embodiments, within 3 days of the first once-daily administration of an oral formulation of this invention or a loading dose of an oral formulation and a maintenance dose of an oral formulation of this invention, the subject's serum testosterone levels may be at or below the level of therapeutic castration.

Additionally, regarding the onset of disease, in some embodiments, after administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the beginning of treatment and administration of a once daily maintenance dose of an oral formulation of this invention, starting as follows: days after administration of the last loading dose of the oral formulation and continuing for the indicated

- 37 043716 treatment period (for example, at least 4 consecutive weeks or more, at least 8 consecutive weeks or more, at least 12 consecutive weeks or more, at least 16 consecutive weeks or more, at least 20 consecutive weeks or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, at least 72 consecutive weeks or more or less at least 96 consecutive weeks or more), therapeutic castration levels less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone may be achieved within 24 to 48 hours from the start of administration and maintained until the end of administration . In some embodiments, following administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation, and continuing during the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 3 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 4 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation, and continuing during the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 5 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 6 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 1 week from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 2 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 3 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation, and continuing for the designated treatment period, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 4 weeks from the start of administration and maintained until the end of administration.

Additionally, regarding the onset of disease manifestation, as described in this document, according to

- 38 043716 following once daily administration of an oral formulation containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, within 24 to 48 hours from the start of administration, therapeutic castration levels less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone. In some embodiments, following once daily administration of an oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 3 days with start of administration. In some embodiments, following once daily administration of an oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 4 days with start of administration. In some embodiments, following once daily administration of an oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 5 days with start of administration. In some embodiments, following once daily administration of an oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 6 days with start of administration. In some embodiments, following once daily administration of an oral formulation of this invention containing about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 1 week with start of administration.

Additionally, regarding the onset of disease, as described herein, following once-daily administration of an oral formulation containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, for 24 to 48 hours from the onset administration, therapeutic castration-like levels less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone may be achieved. In some embodiments, following once-daily administration of an oral formulation of this invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration within 3 days from the start of administration. In some embodiments, following once-daily administration of an oral formulation of this invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration within 4 days from the start of administration. In some embodiments, following once-daily administration of an oral formulation of this invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration within 5 days from the start of administration. In some embodiments, following once-daily administration of an oral formulation of this invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration within 6 days from the start of administration. In some embodiments, following once-daily administration of an oral formulation of this invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration within 1 week from the start of administration.

Additionally, relative to the onset of disease, as described herein, following once daily administration of an oral formulation containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, levels of as in therapeutic castration, less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone. In some embodiments, following once daily administration of an oral formulation of this invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 3 days with start of administration. In some embodiments, following once daily administration of an oral formulation of this invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of

- 39 043716 for therapeutic castration within 4 days from the start of administration. In some embodiments, following once daily administration of an oral formulation of this invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 5 days with start of administration. In some embodiments, following once daily administration of an oral formulation of this invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 6 days with start of administration. In some embodiments, following once-daily administration of an oral formulation of this invention containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, the subject's serum testosterone levels may be at or below the level of therapeutic castration for 1 week with start of administration.

Additionally, regarding the onset of disease manifestation, in some embodiments, after administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of one once daily maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, starting the next day after the last loading dose of the oral formulation, and continuing for the designated treatment period (e.g. at least 4 consecutive weeks or more, at least 8 consecutive weeks or more, at least 12 consecutive weeks or more, at least 16 consecutive weeks or more, at least 20 consecutive weeks or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, at least 72 consecutive weeks or more, or at least 96 consecutive weeks or more), in Within 24 to 48 hours from the start of administration and maintained until the end of administration, therapeutic castration levels less than or equal to 50 ng/dL (1.73 nmol/L) of serum testosterone can be achieved. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level during therapeutic castration within 3 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level during therapeutic castration within 4 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level during therapeutic castration within 5 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level during therapeutic castration within 6 days from the beginning of injection

- 40 043716 deniya and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1 to 3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of therapeutic castration within 1 week from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1 to 3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of therapeutic castration for 2 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the therapeutic castration level for 3 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the therapeutic castration level for 4 weeks from the start of administration and maintained until the end of administration.

Additionally, regarding the onset of disease manifestation, in some embodiments, after administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of one once daily maintenance dose of an oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, starting the next day after the last loading dose of the oral formulation, and continuing for the designated treatment period (e.g. at least 4 consecutive weeks or more, at least 8 consecutive weeks or more, at least 12 consecutive weeks or more, at least 16 consecutive weeks or more, at least 20 consecutive weeks or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, at least 72 consecutive weeks or more, or at least 96 consecutive weeks or more), may therapeutic castration levels less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone should be achieved within 24 to 48 hours of the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level during therapeutic castration within 3 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for

- 41 043716 1-3 days at the beginning of treatment and administration of a once daily maintenance dose of an oral formulation according to this invention containing 120 mg of compound 1 or the corresponding amount of its pharmaceutically acceptable salt, starting from the next day after the administration of the last dose of the oral loading dose formulation, and continued during the designated treatment period, the subject's serum testosterone levels may be at or below those of therapeutic castration for 4 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1 to 3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level during therapeutic castration within 5 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level during therapeutic castration within 6 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1 to 3 days at the start of treatment, and administration of a once daily maintenance dose oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be or be below the therapeutic castration level for 1 week from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of therapeutic castration for 2 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the therapeutic castration level for 3 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the therapeutic castration level for 4 weeks from the start of administration and maintained until the end of administration.

Additionally, regarding the onset of disease manifestation, in some embodiments, after administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof,

- 42 043716 once a day for 1-3 days at the beginning of treatment and administration of a once daily maintenance dose of an oral formulation according to this invention containing 120 mg of compound 1 or the corresponding amount of its pharmaceutically acceptable salt, starting from the next day after administration last dose of the loading dose of the oral formulation, and continuing for the designated treatment period (e.g., at least 4 consecutive weeks or more, at least 8 consecutive weeks or more, at least 12 consecutive weeks or more, at least 16 weeks consecutive or more, at least 20 consecutive weeks or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, by at least 72 consecutive weeks or more or at least 96 consecutive weeks or more), complete castration levels less than or equal to 20 ng/dL (1.73 nmol/L) serum testosterone may be achieved within 24 to 48 h from the beginning of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of complete castration within 3 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of complete castration within 4 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of complete castration within 5 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of complete castration within 6 days from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of complete castration within 1 week from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of the present invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be lower

- 43 043716 level of complete castration within 2 weeks from the beginning of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of complete castration within 3 weeks from the start of administration and maintained until the end of administration. In some embodiments, following administration of a loading dose of an oral formulation of this invention containing 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, once daily for 1-3 days at the start of treatment and administration of a once daily maintenance dose of oral formulation of this invention containing 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning the next day after administration of the last loading dose of the oral formulation and continuing for the designated treatment period, the subject's serum testosterone levels may be at or be below the level of complete castration within 4 weeks from the start of administration and maintained until the end of administration.

In some embodiments of the methods and uses described herein, PSA can be reduced in a subject to a level of less than or equal to 4 ng/ml or less than or equal to 2 ng/ml.

During the treatment period (eg, at least 4 consecutive weeks or more, at least 8 consecutive weeks or more, at least 12 consecutive weeks or more, at least 16 consecutive weeks or more, at least 20 consecutive weeks, or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, at least 72 consecutive weeks or more or at least 96 consecutive weeks or more) with once-daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof, the median time from administration of the first oral formulation to the PSA nadir may be less than 5 weeks, less than 6 weeks, less than 7 weeks, less than 8 weeks, less than 9 weeks, less than 10 weeks, less than 11 weeks, less than 12 weeks, less than 13 weeks, less than 14 weeks, less than 15 weeks, less than 16 weeks, less than 17 weeks, less than 18 weeks, less than 19 weeks, less than 20 weeks, less than 21 weeks, less than 22 weeks, less than 23 weeks, less than 24 weeks or less than 25 weeks. In some embodiments, during the treatment period of once-daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof, the median time from administration of the first oral formulation to the PSA nadir may be from about 5 weeks to about 10 weeks, from about 5 weeks to about 15 weeks, from about 5 weeks to about 20 weeks, from about 5 weeks to about 25 weeks, from about 10 weeks to about 15 weeks, from about 10 weeks to about 20 weeks, from about 10 weeks to about 25 weeks or from about 15 weeks to about 20 weeks. In some embodiments, during the treatment period of once-daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof, the median time from administration of the first oral formulation to the PSA nadir may be from about 10 weeks to about 20 weeks. In some embodiments, following once-daily administration of oral formulations of this invention for 4 weeks, serum PSA levels decrease by greater than or about 5%, greater than or about 10%, greater than, or about 20% greater than. more than or about 30%, more than or about 40%, more than or about 50%, more than or about 60%, more than or about 70%, more than or about 80%, or more than at or about 90% of the subject's pre-treatment serum PSA levels. In some embodiments, following once-daily administration of oral formulations of the present invention for 4 weeks, serum PSA levels are reduced by more than or about 50% of the subject's pre-treatment serum PSA levels.

In some embodiments, following a once-daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment and a once-daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation and continued for the designated treatment period, the median time from the start of treatment to the PSA nadir may be less than 5 weeks, less than 6 weeks, less than 7 weeks, less than 8 weeks, less than 9 weeks, less less than 10 weeks, less than 11 weeks, less than 12 weeks, less than 13 weeks, less than 14 weeks, less than 15 weeks, less than 16 weeks, less than 17 weeks, less than 18 weeks, less than 19 weeks, less less than 20 weeks, less than 21 weeks, less than 22 weeks, less than 23 weeks, less than 24 weeks or less than 25 weeks. In neko

- 44 043716 in other embodiments, after administration of a once daily loading dose of an oral formulation according to this invention for 1-3 days at the beginning of treatment and administration of a once daily maintenance dose of an oral formulation according to this invention, starting the next day after administration the last loading dose of the oral formulation and continuing for the designated treatment period, the median time from the start of treatment to the PSA nadir may be from about 5 weeks to about 10 weeks, from about 5 weeks to about 15 weeks, from about 5 weeks to about 20 weeks, from about 5 weeks to about 25 weeks, from about 10 weeks to about 15 weeks, from about 10 weeks to about 20 weeks, from about 10 weeks to about 25 weeks, or from about 15 weeks to about 20 weeks. In some embodiments, following a once-daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment and a once-daily maintenance dose of an oral formulation of this invention beginning on the next day after the last dose. loading dose of the oral formulation and continued for the designated treatment period, the median time from the start of treatment to the PSA nadir can range from about 10 weeks to about 20 weeks. In some embodiments, 4 weeks from the start of a once-daily loading dose of an oral formulation of this invention for 1-3 days and a once-daily maintenance dose of an oral formulation of this invention starting the next day after the last loading dose. dose of oral formulation, serum PSA levels decrease by more than or about 5%, more than or about 10%, more than or about 20%, more than or about 30%, more than or about 40%, more than at or about 50%, greater than or about 60%, greater than or about 70%, greater than or about 80%, or greater than or about 90% of the subject's pre-treatment serum PSA levels. In some embodiments, 4 weeks from the start of a once-daily loading dose of an oral formulation of this invention for 1-3 days and a once-daily maintenance dose of an oral formulation of this invention starting the next day after the last loading dose. dose of the oral formulation decreases serum PSA levels by more than or about 50% of the subject's pre-treatment serum PSA levels.

Following once-daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for 1 week, 4 weeks, 12 weeks, 24 weeks, or 48 weeks, serum FSH levels may be less than or about 7.2 mIU. ml, about 4.8 mIU/ml, about 2.4 mIU/ml, or about 1.2 mIU/ml. In some such embodiments, once daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may result in a continuous decrease in serum FSH levels. Normal FSH levels in adult men typically range from 1.5 to 12.4 mIU/mL but are elevated in patients with prostate cancer. In some embodiments, following once-daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for 1 week, serum FSH levels may be less than or equal to about 7.2 mIU/mL, about 4.8 mIU /ml, about 2.4 mIU/ml or about 1.2 mIU/ml. In some embodiments, once-daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for 1 week, 4 weeks, 12 weeks, 24 weeks, or 48 weeks can reduce serum FSH levels by more than or about 80 %, or about 90%, of the subject's pre-treatment serum FSH levels.

In some embodiments, after administering a once-daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment and administering a once-daily maintenance dose of an oral formulation of this invention beginning on the next day after the last loading dose, dose of oral formulation, serum FSH levels may be less than or equal to about 7.2 mIU/mL, about 4.8 mIU/mL, about 2.4 mIU/mL, or about 1.2 mIU/mL after 1 week, 4 weeks, 12 weeks, 24 weeks or 48 weeks from the start of treatment. In some such embodiments, once daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may result in a continuous decrease in serum FSH levels. In some embodiments, after administering a once-daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment and administering a once-daily maintenance dose of an oral formulation of this invention beginning on the next day after the last loading dose, dose of oral formulation, serum FSH levels may be less than or equal to about 7.2 mIU/mL, about 4.8 mIU/mL, about 2.4 mIU/mL, or about 1.2 mIU/mL after one week of onset treatment. In some embodiments, after administering a once-daily loading dose of an oral formulation of this invention for 1-3 days at the start of treatment and administering a once-daily maintenance dose of an oral formulation of this invention beginning on the next day after the last loading dose, dose of the oral formulation, serum FSH levels may be reduced by more than or about 80%, or about 90% of the subject's pretreatment serum FSH levels after one week, 4 weeks, 12 weeks, 24 weeks, or 48 weeks. after starting treatment.

The present invention also provides oral formulations containing from about 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject in need thereof.

The present invention provides oral formulations containing from about 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject in need thereof, comprising administering to the subject once a day day of oral ready-made form;

suspending administration of the oral formulation for a period of suspension to allow serum testosterone levels to rise; and resuming administration of the once daily oral formulation to the subject at the end of the suspension period.

The present invention also provides the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of prostate cancer. In some such embodiments, the prostate cancer is hormone-sensitive prostate cancer, advanced prostate cancer, metastatic, non-metastatic, localized advanced prostate cancer, advanced hormone-sensitive cancer, advanced castration-resistant cancer, recurrent, castration-resistant castration-resistant metastatic prostate cancer, castration-resistant non-metastatic prostate cancer, hormone-sensitive metastatic prostate cancer, or hormone-sensitive non-metastatic prostate cancer. In some embodiments, the drug contains from 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

The methods and uses described herein may provide reductions in androgen levels in prostate cancer without increasing the risk of hyperglycemia and diabetes compared to GnRH agonists (eg, Lupron). Unlike other GnRH antagonists (eg, degarelix), the oral formulations of this invention provide reduction in androgen levels without the need for injection.

The methods and uses described herein may delay the progression of castration-resistant disease. In particular, Compound 1 or a pharmaceutically acceptable salt thereof may provide improved disease control compared to a GnRH agonist in terms of better reduction of FSH levels and PSA progression-free survival.

The methods and uses described herein can be used to achieve anti-androgen withdrawal syndrome. Antiandrogen can refer to any drug or substance that reduces the levels or activity of androgens. Antiandrogens tend to inhibit the production, activity or action of male sex hormone or prevent androgens such as testosterone or dihydrotestosterone from mediating their biological effects in the body. Anti-androgen withdrawal syndrome is a well-known phenomenon in prostate cancer. It is widely accepted that a subgroup of patients will benefit from antiandrogen or steroid hormone withdrawal from hormone therapy, demonstrating a decrease in PSA values and clinical improvement.

The methods and uses described herein can be used to provide cardiac benefits. The cardiac benefit may be due to better reduction of FSH levels compared with agonists. The methods and uses described herein can be used to provide AATs with lower rates of cardiovascular side effects compared to agonists. Additionally, the formulations of the present invention may be useful in gender reassignment/transition protocols. In addition, the formulations of the present invention may be useful for preserving fertility during chemotherapy.

Dosing and administration.

Although GnRH agonists and antagonists are typically administered either subcutaneously, intramuscularly, or intranasally, including via depot formulations, Compound 1 or a pharmaceutically acceptable salt thereof can be administered orally and once daily, making dosing easier and more convenient.

For the treatment of prostate cancer, Compound 1 or a pharmaceutically acceptable salt thereof can be administered orally once daily and formulated with a pharmaceutically acceptable carrier or excipient. In some embodiments, the dosage form is a solid preparation, such as a tablet, capsule, granule, or powder, for oral administration.

In some embodiments, oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof have a rapid release curve. However, the oral formulation may have other release profiles including, for example, sustained release, controlled release, delayed release, and extended release.

In some embodiments, the periods of once-daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof in the methods and uses described herein are at least 4 consecutive weeks or more, at least 8 consecutive weeks, or more, at least 12 consecutive weeks or more, at least 16 consecutive weeks or more, at least 20 consecutive weeks or more, at least 24 consecutive weeks or more, at least 36 consecutive weeks or more, at least 48 consecutive weeks or more, at least 52 consecutive weeks or more, at least 72 consecutive weeks or more, or at least 96 consecutive weeks or more. In some embodiments, once daily dosing periods are 4 consecutive weeks or longer. In some embodiments, once-daily dosing periods are 8 consecutive weeks or longer. In some embodiments, once-daily dosing periods are 12 consecutive weeks or longer. In some embodiments, once daily dosing periods are 16 consecutive weeks or more. In some embodiments, once daily dosing periods are 20 consecutive weeks or more. In some embodiments, once-daily dosing periods are 24 consecutive weeks or longer. In some embodiments, once-daily dosing periods are 36 consecutive weeks or longer. In some embodiments, once daily dosing periods are 48 consecutive weeks or longer. In some embodiments, once daily dosing periods are 52 consecutive weeks or more. In some embodiments, once-daily dosing periods are 72 consecutive weeks or more. In some embodiments, once daily dosing periods are 96 consecutive weeks or greater.

The methods and uses described herein involve chronic administration. For example, periods of treatment using oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for treating prostate cancer in a subject, and reducing the levels of PSA and/or one or more sex hormones in the subject, including testosterone, LH and FSH , may be extended periods, for example, once daily administration for periods of consecutive days of 48 weeks or more, once daily administration for periods of consecutive days of 52 weeks or more, once daily administration for for periods of consecutive days of 72 weeks or more, administration once daily for periods of consecutive days of 76 weeks or more, administration once daily for periods of consecutive days of 96 weeks or more, administration of one once daily for periods of consecutive days of 104 weeks or more, administered once daily for periods of consecutive days of 128 weeks or more. In some such embodiments, the treatment period is once daily administration for periods of consecutive days of 48 weeks or more.

The methods and uses described herein include once-daily administration of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof for the treatment of prostate cancer. In some such embodiments, the oral formulation contains at least about 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains about 80 mg, about 120 mg, about 160 mg, about 180 mg, or about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains from about 80 mg to about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains about 80 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains about 120 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains about 180 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation contains about 240 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

The present invention provides once daily administration of oral formulations, for example a loading dose of an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof, and a maintenance dose of an oral formulation containing Compound 1

- 47 043716 or a pharmaceutically acceptable salt thereof, to a subject in need of treatment for prostate cancer. In some embodiments, the oral loading dosage formulation is a tablet or capsule, and the oral maintenance dosage formulation is a tablet or capsule. In some embodiments, the loading dose of the oral formulation has an immediate release profile. However, the loading dose of the oral formulation may have other release profiles, including, for example, sustained release, controlled release, delayed release, and extended release. In some embodiments, the maintenance dose of the oral formulation has an immediate release profile. However, the maintenance dose of the oral formulation may have other release profiles, including, for example, sustained release, controlled release, delayed release, and extended release. In some embodiments, both the loading and maintenance oral formulations are immediate release formulations.

In some embodiments, a loading dose of an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered once daily to initiate treatment for prostate cancer, and the duration of administration is from 1 to 3 days. In some embodiments, a loading dose of an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered once daily to initiate treatment for prostate cancer, and the duration of administration is 1 day. In some embodiments, a loading dose of an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered once daily to initiate treatment for prostate cancer, and the duration of administration is 2 days. In some embodiments, a loading dose of an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered once daily to initiate treatment for prostate cancer, and the duration of administration is 3 days.

Loading doses of the oral formulation may contain from about 240 mg to about 480 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, for example from about 320 mg to about 400 mg. In some embodiments, a loading dose of the oral formulation contains about 240 mg, about 320 mg, about 360 mg, or about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of the oral formulation contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of the oral formulation contains about 240 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of the oral formulation contains about 320 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of the oral formulation contains about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

After this, and sometimes in combination with a loading dose of the oral formulation, a maintenance dose of the oral formulation is administered once a day. In some embodiments, administration of the maintenance dose of the oral formulation begins the day after administration of the last loading dose of the oral formulation. In some embodiments, a maintenance dose of an oral formulation of this invention contains from about 80 mg to about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, such as from about 100 to about 140 mg. In some embodiments, a maintenance dose of the oral formulation contains about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a maintenance dose of the oral formulation contains about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, the maintenance dose of the oral formulation contains about 80 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a maintenance dose of the oral formulation contains about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1 to 3 days at the start of treatment, and each dose contains from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, for example, from about 320 mg to about 400 mg. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1 to 3 days at the start of treatment, and each dose contains about 240 mg, about 320 mg, about 360 mg, or about 480 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of the oral formulation of this invention may be administered once daily for 1-3 days at the start of treatment and each

- 48 043716 dose contains about 360 mg of compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1-3 days at the start of treatment, and each dose contains about 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1-3 days at the start of treatment, and each dose contains about 320 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1-3 days at the start of treatment, and each dose contains about 480 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof.

In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1 day at the start of treatment, and each dose contains from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, such as about 320 mg to about 400 mg. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1 day at the start of treatment, and each dose contains about 240 mg, about 320 mg, about 360 mg, or about 480 mg of Compound 1 or an appropriate amount thereof. pharmaceutically acceptable salt. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1 day at the start of treatment, and each dose contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1 day at the start of treatment, and each dose contains about 240 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1 day at the start of treatment, and each dose contains about 320 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 1 day at the start of treatment, and each dose contains about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 2 days at the start of treatment, and each dose contains from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, e.g. about 320 mg to about 400 mg. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 2 days at the start of treatment, and each dose contains about 240 mg, about 320 mg, about 360 mg, or about 480 mg of Compound 1 or an appropriate amount thereof. pharmaceutically acceptable salt. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 2 days at the start of treatment, and each dose contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 2 days at the start of treatment, and each dose contains about 240 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 2 days at the start of treatment, and each dose contains about 320 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 2 days at the start of treatment, and each dose contains about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 3 days at the start of treatment and each dose contains from about 240 mg to about 480 mg of Compound 1, such as from about 320 mg to about 400 mg, or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 3 days at the start of treatment, and each dose contains about 240 mg, about 320 mg, about 360 mg, or about 480 mg of Compound 1 or an appropriate amount thereof. pharmaceutically acceptable salt. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 3 days at the start of treatment, and each dose contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 3 days at the start of treatment, and each dose contains

- 49 043716 about 240 mg of compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 3 days at the start of treatment, and each dose contains about 320 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for 3 days at the start of treatment, and each dose contains about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, a maintenance dose of an oral formulation of the present invention may be administered once daily and contains from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, such as from about 100 mg to about 140 mg. In some embodiments, a maintenance dose of an oral formulation of this invention may be administered once daily and contains about 120 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a maintenance dose of an oral formulation of this invention may be administered once daily and contains about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a maintenance dose of an oral formulation of this invention may be administered once daily and contains about 80 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some embodiments, a maintenance dose of an oral formulation of this invention may be administered once daily and contains about 180 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 4 consecutive weeks or more, 8 consecutive weeks or more, 12 consecutive weeks or more, 16 consecutive weeks or more, 20 consecutive weeks or more, 24 consecutive weeks or more, 36 consecutive weeks or more, 48 consecutive weeks or more, 52 consecutive weeks or more, 72 consecutive weeks or more, or 96 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 4 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 8 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 12 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 16 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 20 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 24 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 36 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 48 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 52 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 72 consecutive weeks or more. In some embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for 96 consecutive weeks or more. For chronic administration, maintenance doses of oral formulations may be administered once daily for: 48 weeks or more consecutive days of 52 weeks or more of consecutive days of 72 weeks or more of 76 consecutive days weeks or more periods of consecutive days being 96 weeks or more periods of consecutive days being 104 weeks or more periods of consecutive days being 128 weeks or more periods of consecutive days. In some such embodiments, maintenance doses of the oral formulations of this invention may be administered once daily for periods of consecutive days of 48 weeks or more.

In some embodiments, a loading dose of the oral formulation of this invention contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and can be administered once per day 1 of treatment, and a maintenance dose of the oral formulation of this invention contains about 120 mg of Compound 1 or an appropriate amount of its pharmaceutically acceptable salt and can be administered once daily starting from day 2 of the treatment period. In some such embodiments, daily maintenance

- 50 043716 doses of oral formulations may be administered once daily for 12 consecutive weeks or for a longer treatment period. In some embodiments, daily maintenance oral dosages of the formulations of this invention may be administered once daily for 48 consecutive weeks or a longer treatment period.

In some embodiments, a loading dose of the oral formulation of this invention contains about 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof and may be administered once per day 1 of treatment, and a maintenance dose of the oral formulation of this invention contains about 120 mg of Compound 1 or an appropriate amount of its pharmaceutically acceptable salt and can be administered once a day starting from day 2 of the treatment period. In some such embodiments, daily maintenance doses of oral formulations may be administered once daily for 12 consecutive weeks or a longer treatment period. In some embodiments, daily maintenance oral dosages of the formulations of this invention may be administered once daily for 48 consecutive weeks or a longer treatment period.

In some embodiments, a loading dose of an oral formulation of this invention contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and may be administered once daily for the first treatment period, and a maintenance dose of an oral formulation of this invention contains about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof and may be administered once daily beginning on day 1 or day 2 of the second treatment period. In some such embodiments, daily maintenance doses of oral formulations may be administered once daily for 12 consecutive weeks or a longer treatment period. In some embodiments, daily maintenance oral dosages of the formulations of this invention may be administered once daily for 48 consecutive weeks or a longer treatment period.

In some embodiments, a loading dose of the oral formulation of this invention contains about 240 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof and may be administered once daily 1 of the first treatment period, and a maintenance dose of the oral formulation of this invention contains about 120 mg compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, and may be administered once daily beginning on day 1 or day 2 of the second treatment period. In some such embodiments, daily maintenance doses of oral formulations may be administered once daily for 12 consecutive weeks or a longer treatment period. In some embodiments, daily maintenance oral dosages of the formulations of this invention may be administered once daily for 48 consecutive weeks or a longer treatment period.

The present invention further provides that the administration of once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof can be suspended for a period of suspension, thereby allowing the subject's serum testosterone levels to increase. Increased serum testosterone levels during the suspension period may allow subjects to control their lifestyle and quality of life (eg, maintaining sexual activity). In some embodiments, the suspension occurs after the oral formulation of this invention has been administered once daily for 4 consecutive weeks or more. In some embodiments, the suspension occurs after an oral formulation of this invention has been administered once daily for 8 consecutive weeks or more. In some embodiments, the suspension occurs after an oral formulation of this invention has been administered once daily for 12 consecutive weeks or more. In some embodiments, the suspension occurs after the oral formulation of this invention has been administered once daily for 16 consecutive weeks or more. In some embodiments, the suspension occurs after the oral formulation of this invention has been administered once daily for 20 consecutive weeks or more. In some embodiments, the suspension occurs after an oral formulation of this invention has been administered once daily for 24 consecutive weeks or more. In some embodiments, the suspension occurs after an oral formulation of this invention has been administered once daily for 36 consecutive weeks or more. In some embodiments, the suspension occurs after the oral formulation of this invention has been administered once daily for 48 consecutive weeks or more. In some embodiments, the suspension occurs after the oral formulation of this invention has been administered once daily for 52 consecutive weeks or more. In some embodiments, the suspension occurs after the oral formulation of this invention has been administered once daily for 72 consecutive weeks or more. In some embodiments, the suspension occurs after the oral formulation of this invention has been administered once daily for 96 consecutive weeks or more. In some embodiments, administration of an oral formulation

- 51 043716 forms according to this invention are suspended after at least 24 consecutive weeks of once-daily administration. In some embodiments, administration of the oral formulation of this invention is discontinued after at least 48 consecutive weeks of once daily administration.

The suspension period may last until the desired increase in serum testosterone levels is achieved, or may last as long as needed. In some embodiments, the suspension period may last until the PSA begins to rise. In some embodiments, once daily dosing may be resumed when there is a rise in PSA nadir of +2 ng/mL. In some embodiments, once daily dosing may be resumed when the subject's PSA level is >3, >10, >20, or >30 ng/mL. In some embodiments, the suspension period may be up to 60 weeks. In some embodiments, the suspension period may be up to 52 weeks. In some embodiments, the suspension period may be up to 48 weeks. In some embodiments, the suspension period may be up to 36 weeks. In some embodiments, the suspension period may be up to 24 weeks. In some embodiments, the suspension period may be up to 20 weeks. In some embodiments, the suspension period may be up to 16 weeks. In some embodiments, the suspension period may be up to 12 weeks. In some embodiments, the suspension period may be up to 4 weeks. In some embodiments, the suspension period may be up to 8 weeks.

In some embodiments, once daily oral formulations of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period of 4 weeks or less after at least 24 consecutive weeks of once-daily administration. In some embodiments, once-daily administration of oral formulations of this invention containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period of 4 weeks or less to 8 weeks. weeks or more, after at least 24 consecutive weeks of once-daily administration. In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period ranging from 4 weeks or less to 12 weeks or more. , after at least 24 consecutive weeks of once-daily administration. In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period ranging from 4 weeks or less to 16 weeks or more. , after at least 24 consecutive weeks of once-daily administration. In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period ranging from 4 weeks or less to 20 weeks or more. , after at least 24 consecutive weeks of once-daily administration. In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period ranging from 4 weeks or less to 24 weeks or more. , after at least 24 consecutive weeks of once-daily administration. In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period ranging from 4 weeks or less to 36 weeks or more. , after at least 24 consecutive weeks of once-daily administration. In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period ranging from 4 weeks or less to 48 weeks or more. , after at least 24 consecutive weeks of once-daily administration. In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period ranging from 4 weeks or less to 52 weeks or more. , after at least 24 consecutive weeks of once-daily administration. In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for all methods and uses disclosed herein may be suspended for a period ranging from 4 weeks or less to 60 weeks or more , after at least 24 consecutive weeks of once-daily administration.

The present invention provides for the resumption of once daily administration of oral formulations of the present invention after a period of suspension. In some embodiments, once-daily administration of oral formulations of this invention containing from about 80 mg to about 480 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof is resumed at the end of the suspension period.

The present invention also provides for the administration of a once daily loading dose of the oral formulation after a period of suspension. In some embodiments, a loading dose of an oral formulation of this invention containing from about 240 mg to about 480 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof may be administered once daily for 1 to 3 days at the beginning of the treatment period after the period suspension. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily on day 1 after a suspension period. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for two days following the suspension period. In some embodiments, a loading dose of an oral formulation of this invention may be administered once daily for three days following the suspension period.

After a period of suspension, the present invention provides for once-daily administration of a maintenance dose of an oral formulation of the present invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, beginning after the last loading dose of the oral formulation. according to this invention. In some embodiments, after a period of suspension, administration of a once-daily maintenance dose of an oral formulation of this invention containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof begins on the next day after the last loading dose. dosage of the oral formulation according to this invention.

In some intermittent administration embodiments comprising separate treatment periods, a loading dose of the oral formulation of this invention may be administered once daily for 1-3 days at the beginning of each treatment period. In some embodiments with intermittent administration comprising separate treatment periods, a maintenance dose of the oral formulation of the present invention may be administered once daily at the beginning of each treatment period.

Upon resumption of administration of the oral formulations or maintenance doses of oral formulations according to this invention after a period of suspension, the oral formulations or maintenance doses of oral formulations may be administered once daily for 4 consecutive weeks or more, 8 consecutive weeks or more, 12 weeks consecutive weeks or more, 16 consecutive weeks or more, 20 consecutive weeks or more, 24 consecutive weeks or more, 36 consecutive weeks or more, 48 consecutive weeks or more, 52 consecutive weeks or more, 72 consecutive weeks or more, or 96 consecutive weeks or more. In some embodiments, the oral formulations or maintenance doses of the oral formulations of this invention may be administered once daily for 4 consecutive weeks or more. In some embodiments, oral formulations or maintenance doses of oral formulations of this invention may be administered once daily for 8 consecutive weeks or more. In some embodiments, oral formulations or maintenance doses of oral formulations of this invention may be administered once daily for 12 consecutive weeks or more. In some embodiments, the oral formulations or maintenance doses of the oral formulations of this invention may be administered once daily for 16 consecutive weeks or more. In some embodiments, the oral formulations or maintenance doses of the oral formulations of this invention may be administered once daily for 20 consecutive weeks or more. In some embodiments, the oral formulations or maintenance doses of the oral formulations of this invention may be administered once daily for 24 consecutive weeks or more. In some embodiments, the oral formulations or maintenance doses of the oral formulations of this invention may be administered once daily for 36 consecutive weeks or more. In some embodiments, oral formulations or maintenance doses of oral formulations of this invention may be administered once daily for 48 consecutive weeks or more. In some embodiments, oral formulations or maintenance doses of oral formulations of this invention may be administered once daily for 52 consecutive weeks or more. In some embodiments, the oral formulations or maintenance doses of the oral formulations of this invention may be administered once daily for 72 consecutive weeks or more. In some embodiments, oral formulations or maintenance doses of oral formulations of this invention may be administered once daily for 96 consecutive weeks or more. For continuous administration after a period of suspension, oral formulations or maintenance doses of oral formulations may be administered once daily for consecutive weeks or more periods of 52 weeks or more consecutive days of 72 weeks or more. more periods of consecutive days being 76 weeks or more periods of consecutive days being 96 weeks or more periods of consecutive days being 104 weeks or more periods of consecutive days being 128 weeks or more periods of consecutive days. In some such embodiments, the oral formulations or maintenance doses of the oral formulations of this invention may be administered once daily for periods of consecutive days of 48 weeks or more.

In some embodiments, once daily oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof are suspended for a subsequent suspension period after completion of the first suspension and resumption period. In some such embodiments, the subsequent suspension period occurs at least 12 weeks after resuming the once-daily oral formulation containing from about 80 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

The present invention also provides for no resumption of administration after it has been suspended. For example, in some embodiments, administration may be suspended after completion of radiation therapy and not resumed. In some embodiments, administration after completion of radiation therapy will not be resumed until the PSA increases. In some embodiments, once daily dosing may be resumed when an increase in PSA nadir+2 ng/mL is observed following radiation therapy. In some embodiments, once daily dosing may be resumed after radiation therapy when the subject's PSA level is >3, >10, >20, or >30 ng/mL.

In some embodiments, administration of the oral formulations of this invention is meal dependent. In some such embodiments, administration is preferably prior to any meal. In some embodiments, an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered before meals. In some embodiments, administration is at least 1 hour before a meal or at least 2 hours after a meal. In other embodiments, administration may also be at least 30 minutes before a meal or on an empty stomach. In some embodiments, administration occurs about 2 hours before a meal or 1 hour after a meal. In some embodiments, administration is at least 30 minutes before a meal, 1 hour before a meal, or 2 hours before a meal. In some embodiments, administration is at least 30 minutes after a meal, 1 hour after a meal, or 2 hours after a meal.

In some embodiments, administration of the oral formulations of this invention occurs without the need for any fasting or dietary regimen. In some embodiments, administration occurs without the need for any fasting. In some such embodiments, administration of the oral formulation may be independent of food intake. In some embodiments, administration may occur during a meal.

The present invention provides that administration for all methods and uses described herein is such that there is no stimulation of sex hormones and thus exacerbation is prevented or minimized in subjects.

Depending on one or more of the following factors: severity of symptoms, subject's age, weight and sensitivity, as well as risk factors such as smoking and prescribed medications, the duration and intervals of administration may be altered.

Dosage forms according to this invention.

As used herein, oral formulations of this invention may include, but are not limited to, tablets, capsules, capsule tablets, pills, oral films, lozenges, gums, granules, and powders. In some embodiments, the oral formulation is a tablet or capsule.

In some embodiments, the oral formulations, including the loading and maintenance oral formulations disclosed herein, have a rapid release profile. However, oral formulations may have other release profiles, including, for example, sustained release, controlled release, delayed release, and extended release. In some embodiments, the oral formulations disclosed herein have a sustained release profile. In some embodiments, the oral formulations disclosed herein have a controlled release profile. In some embodiments, the oral formulations disclosed herein have a sustained release profile. In some embodiments, the oral formulations disclosed herein have an extended release profile.

The excipients for the oral formulations of this invention are a combination of excipients and amounts that help optimize the effectiveness of the formulation. The following components are the main excipients and include various organic or inorganic excipients or carrier substances, including, but not limited to, one or more fillers or diluents, lubricants, binders, surfactants, pH adjusters, sweeteners , flavorings and raising agents. There may be a film coating with pharmaceutical additives, including, but not limited to, one or more film formers, coating bases, base additives, plasticizers, organic acids, pigments or antioxidants, light blocking agents, flow enhancing or glazing agents, and dyes.

Diluents or excipients for use in this disclosure include organic materials and inorganic materials, including, but not limited to, dextrose, lactose, mannitol, D-mannitol (for example, PEARLITOL 50C, PEARLITOL 100SD, PEARLITOL 200SD, PEARLITOL 300 DC , and PEARLITOL 400DC), sodium starch, sucrose, calcium phosphate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium sulfate, calcium carbonate, calcium silicate, sorbitol, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch and calcium carbonate starch. In some embodiments, the diluent is mannitol. Diluents or excipients for use in this disclosure include organic materials and inorganic materials, also including, but not limited to, hydroxypropyl cellulose, crystalline cellulose (for example, CEOLUS KG-802 (Class: KG-802) and CEOLUS PH -302 (class: PH-302)), crystalline cellulose (particles), crystalline cellulose (fine particles), microcrystalline cellulose, hydroxypropyl methylcellulose (e.g. hydroxypropyl methylcellulose 2910), starch, gelatin, sucrose, dextrin, lactose, povidone (polyvinylpyrrolidone), copolyvidone, acrylic ester, copolyvidone, gum, sodium alginate and carboxymethylcellulose. In some embodiments, the diluent is D-mannitol. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is lactose.

Binders for use in this disclosure include, but are not limited to, hydroxypropyl cellulose, crystalline cellulose (e.g., CEOLUS KG-802 (Grade: KG-802) and CEOLUS PH-302 (Grade: PH-302)), crystalline cellulose (particles), crystalline cellulose (fine particles), microcrystalline cellulose, hydroxypropyl methylcellulose (eg hypromellose 2910), starch, gelatin, sucrose, dextrin, lactose, povidone (polyvinylpyrrolidone) and copolyvidone. Natural and synthetic resins that can be used as binders include, but are not limited to, gum, sodium alginate, and carboxymethylcellulose. In some embodiments, the binder is hydroxypropyl methylcellulose. In some embodiments, the binder is hydroxypropylcellulose.

Disintegrants for use in this disclosure include, but are not limited to, cross-linked polymers such as cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked sodium carmellose, microcrystalline cellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch and sodium starch glycolate. Additional disintegrants for use in this disclosure include, but are not limited to, corn starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl starch, and magnesium aluminosilicate metasilicate. In some embodiments, the leavening agent is sodium starch glycolate. In some embodiments, the disintegrant is cross-linked sodium carboxymethylcellulose.

Lubricants for use in this disclosure include, but are not limited to, magnesium stearate; stearic acid; sodium stearyl fumarate; triethyl citrate; inorganic lubricants, namely talc, colloidal silica and fumed silica; polymeric lubricants such as polyethylene glycol, PEG 4000 and PEG 6000; mineral oils; and hydrogenated vegetable oils. However, other compounds can be used, such as fatty acids and their metal salts, fatty acid esters and their salts, organic waxes, polymers and inorganic substances. Healthy fatty acids include, but are not limited to, lauric acid, palmitic acid and stearic acid. Beneficial metal salts include, but are not limited to, calcium, magnesium and zinc salts. Beneficial fatty acid esters include, but are not limited to, glyceride esters such as glyceryl monostearate, glyceryl tribehenate, glyceryl palmitostearate, and glyceryl dibehenate. Suitable Sugar Esters include, but are not limited to, sucrose fatty acid esters, sorbitan monostearate and sucrose monopalmitate. Their beneficial salts include, but are not limited to, sodium oleate, sodium benzoate, sodium acetate, magnesium lauryl sulfate and sodium lauryl sulfate. In some embodiments, lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica. In some embodiments, the lubricant is magnesium stearate. As used herein, polyethylene glycol is a general term for compounds represented by the formula H(OCH ₂ CH ₂ ) _n OH, where n is a natural number (a compound where n is not less than 2000 is sometimes called polyethylene oxide).

Examples of coloring agents used in the formulations of this invention include, but are not limited to, food coloring such as Yellow No. 5 food coloring, Red No. 2 food coloring, Blue No. 2 food coloring, etc. glaze paints, red iron oxide and yellow iron oxide.

Examples of pH adjusters used in the formulations of this invention include, but are not limited to, citric acid or a salt thereof, phosphoric acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, fumaric acid or its salt. salt, acetic acid or a salt thereof, and an amino acid or a salt thereof.

Examples of surfactants used in the formulations of this invention include, but are not limited to, sodium lauryl sulfate, polysorbate 80 and polyoxyethylene (160), polyoxypropylene (30) glycol.

Examples of sweeteners used in the formulations of this invention include, but are not limited to, aspartame (trade name), acesulfame potassium, sucralose, thaumatin, sodium saccharin and dipotassium glycyrrhizinate.

Examples of flavoring agents used in the formulations of this invention include, but are not limited to, menthol, peppermint oil, lemon oil, and vanillin.

In some embodiments, pigments for use herein include, but are not limited to, titanium dioxide.

In some embodiments, the film-forming agent/film coating base is a sugar-based coating. Sugar-based coatings for use herein include, but are not limited to, sucrose in combination with one or more of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, or carnauba wax.

In some embodiments, the film-forming agent/film coating base is a water-soluble film coating base. Water-soluble film coating bases for use herein include, but are not limited to, cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose (eg, hydroxypropylmethylcellulose 2910, TC-5), hydroxyethylcellulose, methylhydroxyethylcellulose, and the like; synthetic polymers such as polyvinylacetaldiethylaminoacetate, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone and the like; and polysaccharides such as pullulan and the like. In some embodiments, the water-soluble film coating base is hydroxypropyl methylcellulose (eg, hypromellose 2910, TC-5). In some embodiments, the film-forming agent/film coating base is hydroxypropyl methylcellulose (HPMC). In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2910.

In some embodiments, the film-forming agent/film coating base comprises cellulose polymers such as hydroxypropyl methylcellulose phthalate, ethylcellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, and the like; acrylic acid polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer slurry and the like; and naturally occurring substances such as shellac, etc.

In some embodiments, the flow/glaze agent is carnauba wax. In some embodiments, the flow/glaze agent is talc.

In some embodiments, colorants for use herein include, but are not limited to, iron oxide. In some embodiments, the dye is red iron oxide. In some embodiments, the dye is yellow iron oxide. In some embodiments, the dye is a combination of yellow iron oxide and red iron oxide.

In some embodiments, plasticizers for use herein are

- 56 043716 include, but are not limited to, polyethylene glycol (eg macrogol 6000), triethyl citrate, castor oil, polysorbates and the like.

In some embodiments, organic acids for use herein include, but are not limited to, citric acid, tartaric acid, malic acid, ascorbic acid, and the like.

In some embodiments, the formulations of this invention, including an oral loading dose formulation and an oral maintenance dose formulation, contain at least one excipient that improves stability while maintaining capacity. It has been found that the oral formulations of the present invention for the treatment of prostate cancer, which contain sodium starch glycolate, have improved stability and greater capacity of Compound 1 or a pharmaceutically acceptable salt thereof, such that an amount of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof can be as large as about 360 mg in a loading dose of an oral formulation and about 120 mg in a maintenance dose of an oral formulation.

The present invention provides oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer. In some such embodiments, the oral formulations contain about 80 mg, or about 120 mg, or about 160 mg, or about 180 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and essential excipients, such as one or more diluents, one or more binders, one or more disintegrants, one or more lubricants, or combinations thereof. In some such embodiments, the diluent contains mannitol, the binder contains hydroxypropyl cellulose, the disintegrant contains sodium starch glycolate, and the lubricant contains hydroxypropyl cellulose. In some embodiments, the oral formulations further comprise one or more film formers/film coating bases, one or more pigments, one or more dyes, one or more flow agents/glazing agents, or combinations thereof. In some such embodiments, the film-forming agent/film coating base comprises hypromellose 2910, the pigment contains titanium dioxide, the colorant contains iron (III) oxide, and the flow agent/glazing agent contains carnauba wax.

In some such embodiments, the oral formulations of this invention contain from about 240 mg to about 480 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, such as about 360 mg or about 240 mg, and basic excipients, such as one or more diluents , one or more binders, one or more disintegrants, one or more lubricants, or combinations thereof. In some such embodiments, the diluent contains mannitol, the binder contains hydroxypropyl cellulose, the disintegrant contains sodium starch glycolate, and the lubricant contains hydroxypropyl cellulose. In some embodiments, the oral formulations of the present invention further comprise one or more film formers/film coating bases, one or more pigments, one or more dyes, one or more flow agents/glazing agents, or combinations thereof. In some such embodiments, the film-forming agent/film coating base comprises hypromellose 2910, the pigment contains titanium dioxide, the colorant contains iron (III) oxide, and the flow agent/glazing agent contains carnauba wax.

In some embodiments, the present invention provides oral formulations containing about 80 mg, or about 120 mg, or about 160 mg, or about 180 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and essential excipients, namely from 51 to 244 mg mannitol, 3 to 12 mg hydroxypropyl cellulose, 10 to 20 mg sodium starch glycolate and 2 to 4 mg magnesium stearate. In some embodiments, the oral formulations of this invention may contain 80, or 120, or 160 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and essential excipients, namely, 51 to 244 mg of mannitol, 3 to 12 mg of hydroxypropylcellulose, 10 to 20 mg sodium starch glycolate and 2 to 4 mg magnesium stearate. Still according to the present invention, it is also further provided that such oral formulations contain a film coating containing film excipients, namely from 7.12 to 14.24 mg of hypromellose 2910 (i.e. hydroxypropyl methylcellulose), from 0.8 to 1.6 mg of titanium dioxide, a sufficient amount of carnauba wax and 0.08 to 0.16 mg of iron oxide.

In some embodiments, the oral formulations of this invention contain 80, or 120, or 160 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and essential excipients, namely, 102 to 204 mg of mannitol, 6 to 12 mg of hydroxypropylcellulose, 10 to 20 mg sodium starch glycolate and 2 to 4 mg magnesium stearate. It is also further provided according to the present invention that such oral formulations contain a film coating containing film excipients, namely from 7.12 to 14.24 mg of hypromellose 2910 (i.e. hydroxypropyl methylcellulose), from 0.8 up to 1.6 mg of titanium dioxide, a sufficient amount of carnauba wax and from 0.08 to 0.16 mg of iron oxide.

In some embodiments, the oral formulations of this invention contain from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. Additionally, in some such embodiments, the oral formulations of this invention may contain from 306 to 612 mg of mannitol (including D-mannitol); from 30 to 60 mg sodium starch glycolate; 18 to 36 mg hydroxypropylcellulose; and 6 to 12 mg magnesium stearate as primary excipients; and also from 21.36 to 42.72 mg of hypromellose 2910; from 2.4 to 4.8 mg titanium dioxide; 0.24 to 0.48 mg iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, the oral formulations of this invention contain from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. Additionally, in some such embodiments, the oral formulations of this invention may contain from 306 to 612 mg of mannitol (including D-mannitol); from 30 to 60 mg sodium starch glycolate; 18 to 36 mg hydroxypropylcellulose; and 6 to 12 mg magnesium stearate. In some such embodiments, the oral formulations of this invention further contain from 21.36 to 42.72 mg of hypromellose 2910; from 2.4 to 4.8 mg titanium dioxide; 0.24 to 0.48 mg iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, loading doses of the oral formulations contain about 240 mg, about 320 mg, about 360 mg, or about 480 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and can be administered once daily. In some embodiments, loading doses of the oral formulations contain about 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. About 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof is used as it optimizes the stability of the composition as well as maintaining the effectiveness of the loading dose. In some embodiments, maintenance doses of the oral formulations of this invention contain about 80 mg, about 120 mg, about 160 mg, or about 180 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and can be administered once daily. In some embodiments, maintenance doses of the oral formulations contain about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. About 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof is used as it optimizes the stability of the composition as well as maintaining the effectiveness of the loading dose.

Maintenance doses of oral formulations of this invention containing Compound 1 or a pharmaceutically acceptable salt thereof can be used for the treatment of prostate cancer. In some such embodiments, the oral maintenance dosage formulations of this invention contain from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, such as about 120 mg, and essential excipients, such as one or more diluents, one or more binders, one or more disintegrants, one or more lubricants, or combinations thereof. In some such embodiments, the diluent contains mannitol, the binder contains hydroxypropyl cellulose, the disintegrant contains sodium starch glycolate, and the lubricant contains hydroxypropyl cellulose. In some embodiments, the oral maintenance dosage formulations further comprise one or more film formers/film coating bases, one or more pigments, one or more dyes, one or more flow agents/glazing agents, or combinations thereof. In some such embodiments, the film-forming agent/film coating base comprises hypromellose 2910, the pigment contains titanium dioxide, the colorant contains iron (III) oxide, and the flow agent/glazing agent contains carnauba wax. Additionally, in some embodiments, oral maintenance dosage formulations of this invention may contain from 244 to 488 mg of mannitol (including D-mannitol); 80 to 160 mg microcrystalline cellulose; 12 to 24 mg hydroxypropylcellulose; and 20 to 40 mg croscarmellose sodium; 4 to 8 mg magnesium stearate; from 14.24 to 28.48 mg hypromellose 2910; from 1.6 to 3.2 mg titanium dioxide; from 0.16 to 0.32 mg of iron oxide. With this and other oral formulations of this invention, water is removed during the manufacture of a maintenance dose of the oral formulation.

In some embodiments, the maintenance dose of the oral formulation of this invention contains 17.54% by weight of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 53.51 wt.% mannitol; 17.54 wt.% microcrystalline cellulose;

- 58 043716

2.63 wt.% hydroxypropylcellulose; 4.39 wt.% croscarmellose sodium and 0.88 wt.% magnesium stearate as main excipients. In some such embodiments, the maintenance dose of the oral formulation of this invention also contains the following other excipients: 3.12% by weight hypromellose 2910; 0.35 wt.% titanium dioxide; and 0.04 wt.% iron oxide.

In some embodiments, maintenance doses of the oral formulations provided herein contain from about 80 mg to about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. Additionally, in some such embodiments, the oral maintenance dosage formulations of this invention may contain from 102 to 204 mg of mannitol (including D-mannitol); from 10 to 20 mg sodium starch glycolate; 6 to 12 mg hydroxypropylcellulose; and 2 to 4 mg magnesium stearate; from 7.12 to 14.24 mg hypromellose 2910; from 0.8 to 1.6 mg titanium dioxide; 0.08 to 0.16 mg iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, maintenance doses of the oral formulation provided herein contain from about 80 mg to about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. Additionally, in some such embodiments, the oral maintenance dosage formulations of this invention may contain from 102 to 204 mg of mannitol (including D-mannitol); from 10 to 20 mg sodium starch glycolate; 6 to 12 mg hydroxypropylcellulose; and 2 to 4 mg magnesium stearate. In some such embodiments, the oral maintenance dosage formulations of this invention further contain from 7.12 to 14.24 mg of hypromellose 2910; from 0.8 to 1.6 mg titanium dioxide; 0.08 to 0.16 mg iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, the oral maintenance dosage formulations of this invention contain 38.46% by weight of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof; 49.04 wt.% mannitol; 4.81 wt.% sodium starch glycolate (type A); 2.88 wt.% hydroxypropylcellulose; and 0.96 wt.% magnesium stearate, as the main fillers. In some such embodiments, the oral maintenance dosage formulations of this invention also contain the following other excipients: 3.42% by weight hypromellose 2910; 0.38 wt.% titanium dioxide; and 0.04 wt.% iron oxide, and a sufficient amount of carnauba wax.

In some embodiments, the oral maintenance dosage formulations of this invention contain 80 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 244 mg mannitol; 80 mg microcrystalline cellulose; 12 mg hydroxypropylcellulose; 20 mg croscarmellose sodium and 4 mg magnesium stearate, as main excipients. In some such embodiments, the oral maintenance dosage formulations of this invention also comprise a film coating containing 14.24 mg of hypromellose 2910; 1.6 mg titanium dioxide; and 0.16 mg iron oxide.

In some embodiments, the oral maintenance dosage formulations of this invention contain: 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof; 366 mg mannitol (excipient/diluent); 120 mg microcrystalline cellulose (excipient/diluent); 18 mg hydroxypropylcellulose (binder); 30 mg croscarmellose sodium (raising agent), and 6 mg magnesium stearate (lubricant), as main excipients. In some such embodiments, the oral maintenance dosage formulations of this invention also contain the following other excipients: 21.36 mg of hypromellose 2910 (film coating base); 2.4 mg titanium dioxide (pigment); and 0.24 mg iron oxide (dye).

In some embodiments, the oral maintenance dosage formulations of this invention contain 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 488 mg mannitol; 160 mg microcrystalline cellulose; 24 mg hydroxypropylcellulose; 40 mg croscarmellose sodium and 8 mg magnesium stearate, as main excipients. In some such embodiments, the oral maintenance dosage formulations of this invention also contain 28.48 mg of hypromellose 2910 as a film coating; 3.2 mg titanium dioxide; and 0.32 mg iron oxide.

In some embodiments, the oral maintenance dosage formulations provided by this invention contain 80 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 102 mg mannitol; 10 mg sodium starch glycolate; 6 mg hydroxypropylcellulose; 2 mg magnesium stearate; 7.12 mg hypromellose 2910; and 0.8 mg titanium dioxide; 0.08 iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, the oral maintenance dosage formulations provided by this invention contain 120 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 153 mg mannitol (excipient/diluent); 15 mg sodium starch glycolate (raising agent); 9 mg hydroxypropylcellulose (binder); 3 mg magnesium stearate (lubricant); 10.68 mg hypromellose 2910 (film coating base); And

- 59 043716

1.2 mg titanium dioxide (pigment); 0.12 iron oxide (dye); and a sufficient amount of carnauba wax (flow agent/glazing agent for tablets).

In some embodiments, the oral maintenance dosage formulations provided by this invention contain 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 204 mg mannitol; 20 mg sodium starch glycolate; 12 mg hydroxypropylcellulose; 4 mg magnesium stearate; 14.24 mg hypromellose 2910; and 1.6 mg titanium dioxide; 0.16 iron oxide; and a sufficient amount of carnauba wax.

The present invention provides loading doses of an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer. In some such embodiments, the oral loading dose formulations of this invention contain from about 240 mg to about 480 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, such as about 360 or 240 mg, and essential excipients, such as one or more diluents , one or more binders, one or more disintegrants, one or more lubricants, or combinations thereof. In some such embodiments, the diluent contains mannitol, the binder contains hydroxypropyl cellulose, the disintegrant contains sodium starch glycolate, and the lubricant contains hydroxypropyl cellulose. In some embodiments, the oral loading dose formulations of the present invention further comprise one or more film formers/film coating bases, one or more pigments, one or more dyes, one or more flow agents/glazing agents, or combinations thereof. . In some such embodiments, the film-forming agent/film coating base comprises hypromellose 2910, the pigment contains titanium dioxide, the colorant contains iron (III) oxide, and the flow agent/glazing agent contains carnauba wax. Additionally, in some embodiments, the oral loading dose formulations of this invention may contain from 732 to 1464 mg of mannitol (including D-mannitol); 240 to 480 mg microcrystalline cellulose; 36 to 72 mg hydroxypropylcellulose; 60 to 120 mg croscarmellose sodium; 12 to 24 mg magnesium stearate; from 42.72 to 85.44 mg of hypromellose 2910; from 4.8 to 9.6 mg titanium dioxide; from 0.48 to 0.96 mg of iron oxide. For these and other oral formulations, water is removed during the manufacturing of the loading dose of the oral formulation.

In some embodiments, the oral dosage formulations of this invention contain 17.54% by weight of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 53.51 wt.% mannitol; 17.54 wt.% microcrystalline cellulose; 2.63 wt.% hydroxypropylcellulose; 4.39 wt.% croscarmellose sodium and 0.88 wt.% magnesium stearate as main excipients. In some such embodiments, the oral loading dose formulations of this invention also contain the following other excipients: 3.12% by weight hypromellose 2910; 0.35 wt.% titanium dioxide; and 0.04 wt.% iron oxide.

In some embodiments, loading doses of the oral formulation of this invention contain from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some such embodiments, the oral loading dose formulations of this invention may contain from 306 to 612 mg of mannitol (including D-mannitol); from 30 to 60 mg sodium starch glycolate; 18 to 36 mg hydroxypropylcellulose; and 6 to 12 mg magnesium stearate, as primary excipients; and also from 21.36 to 42.72 mg of hypromellose 2910; from 2.4 to 4.8 mg titanium dioxide; 0.24 to 0.48 mg iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, loading doses of the oral formulation of this invention contain from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some such embodiments, the oral loading dose formulations of this invention may contain: 306 to 612 mg of mannitol (including D-mannitol); from 30 to 60 mg sodium starch glycolate; 18 to 36 mg hydroxypropylcellulose; and 6 to 12 mg magnesium stearate. In some such embodiments, the oral loading dose formulations of this invention further contain from 21.36 to 42.72 mg of hypromellose 2910; from 2.4 to 4.8 mg titanium dioxide; 0.24 to 0.48 mg iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, the oral loading dose formulations of this invention contain 38.46% by weight of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof; 49.04 wt.% mannitol; 4.81 wt.% sodium starch glycolate (type A); 2.88 wt.% hydroxypropylcellulose; and 0.96 wt.% magnesium stearate, as the main fillers. In some such embodiments, the oral loading dose formulations of this invention also contain the following other excipients: 3.42% by weight hypromellose 2910; 0.38 wt.% titanium dioxide; and 0.04 wt.% iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, the oral loading dose formulations of the present invention contain 240 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 732 mg mannitol; 240 mg microcrystalline cellulose; 36 mg hydroxypropylcellulose; 60 mg croscarmellose sodium; 12 mg magnesium stearate, 42.72 mg hypromellose 2910; 4.8 mg titanium dioxide; and 0.48 mg iron oxide.

In some embodiments, the oral loading dose formulations of this invention contain 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 1098 mg mannitol (excipient/diluent); 360 mg microcrystalline cellulose (excipient/diluent); 54 mg hydroxypropylcellulose (binder); 90 mg croscarmellose sodium (raising agent); and 18 mg magnesium stearate (lubricant) as primary excipients. In some such embodiments, the oral loading dose formulations of this invention also contain the following other excipients: 64.08 mg of hypromellose 2910 (film coating base); 7.2 mg titanium dioxide (pigment); and 0.72 mg iron oxide (color).

In some embodiments, a loading dose of an oral formulation of this invention contains 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 1464 mg mannitol; 480 mg microcrystalline cellulose; 72 mg hydroxypropylcellulose; 120 mg croscarmellose sodium; 24 mg magnesium stearate, 85.44 mg hypromellose 2910; 9.6 mg titanium dioxide; and 0.96 mg iron oxide.

In some embodiments, the oral loading dose formulations provided by this invention contain 240 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 306 mg mannitol; 30 mg sodium starch glycolate; 18 mg hydroxypropylcellulose; 6 mg magnesium stearate; 21.36 mg hypromellose 2910; 2.4 mg titanium dioxide; 0.24 iron oxide; and a sufficient amount of carnauba wax.

In some embodiments, the oral loading dose formulations provided by this invention contain 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 459 mg mannitol (excipient/diluent); 45 mg sodium starch glycolate (raising agent); 27 mg hydroxypropylcellulose (binder); 9 mg magnesium stearate (lubricant); 32.04 mg hypromellose 2910 (film coating base); and 3.6 mg titanium dioxide (pigment); 0.36 iron oxide (dye); and a sufficient amount of carnauba wax (flow agent/glazing agent for tablets).

In some embodiments, the oral loading dose formulations provided by this invention contain 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; 612 mg mannitol; 60 mg sodium starch glycolate; 36 mg hydroxypropylcellulose; 12 mg magnesium stearate; 42.72 mg hypromellose 2910; 4.8 mg titanium dioxide; 0.48 iron oxide; and a sufficient amount of carnauba wax.

Dose packages according to this invention.

The present invention provides dose packages containing loading and maintenance doses of the formulation disclosed herein. The dose package of this invention contains a loading dose of the oral formulation separated from a maintenance dose of the oral formulation. In some such embodiments, the dosage package is used to treat prostate cancer. In some embodiments, the loading dose of the oral formulation in the dose package is a different color, shape, and/or size than the maintenance dose of the oral formulation.

In some embodiments, a dosage package provided by this invention comprises a loading dose of an oral formulation containing excipients and from about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; and a maintenance dose of an oral formulation containing excipients and from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof. In some such embodiments, booster and maintenance doses of the oral formulation independently contain excipients such as one or more diluents, one or more binders, one or more disintegrants, one or more lubricants, or combinations thereof. In some such embodiments, the diluent contains mannitol, the binder contains hydroxypropyl cellulose, the disintegrant contains sodium starch glycolate, and the lubricant contains hydroxypropyl cellulose. In some embodiments, the booster and maintenance doses of the oral formulation independently further comprise one or more film formers/film coating bases, one or more pigments, one or more dyes, one or more flow agents/glazing agents, or combinations thereof. . In some such embodiments, the film-forming agent/film coating base comprises hypromellose 2910, the pigment contains titanium dioxide, the colorant contains iron (III) oxide, and the flow agent/glazing agent contains carnauba wax.

In some embodiments, a loading dose of an oral formulation in a dose package

- 61 043716 according to this invention contains from 306 to 612 mg of mannitol, from 18 to 36 mg of hydroxypropylcellulose, from 30 to 60 mg of sodium starch glycolate and from 6 to 12 mg of magnesium stearate.

In some embodiments, the loading dose of the oral formulation in the dose package of this invention further contains 21.36 to 42.72 mg of hypromellose 2910, 2.4 to 4.8 mg of titanium dioxide, 0.24 to 0.48 mg iron oxide and a sufficient amount of carnauba wax.

In some embodiments, a maintenance dose of an oral formulation in a dosage package of this invention contains 102 to 204 mg of mannitol, 6 to 12 mg of hydroxypropylcellulose, 10 to 20 mg of sodium starch glycolate, and 2 to 4 mg of magnesium stearate.

In some embodiments, the maintenance dose of the oral formulation in the dosage package of this invention further contains 7.12 to 14.24 mg of hypromellose 2910, 0.8 to 1.6 mg of titanium dioxide, 0.08 to 0.16 mg iron oxide and a sufficient amount of carnauba wax.

In some aspects of the present invention, the loading dose of the oral formulation and the maintenance dose of the oral formulation in the dose package contain at least one excipient that improves stability while maintaining capacity. In some embodiments, sodium starch glycolate in a loading dose oral formulation and a maintenance dose oral formulation in a dose package according to this invention improves the stability and quantity capacity of Compound 1, or a pharmaceutically acceptable salt thereof, in a loading dose oral formulation and a maintenance dose oral formulation .

In some embodiments, a loading dose of the oral dosage formulation contains about 240 mg, about 320 mg, about 360 mg, or about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation in a dosage package of this invention contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a loading dose of an oral formulation in a dosage package of this invention contains about 240 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, the maintenance dose of the oral formulation per dose package contains about 80 mg, about 120 mg, or about 160 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, a maintenance dose of an oral formulation in a dosage package of this invention contains about 120 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, a loading dose of an oral formulation in a dose package of this invention contains about 360 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a maintenance dose of an oral formulation contains about 120 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, a loading dose of an oral formulation in a dose package of this invention contains about 240 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, and a maintenance dose of an oral formulation contains about 120 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

In some embodiments, the loading dose of the oral formulation and the maintenance dose of the oral formulation in the dosage package of the present invention are tablets.

In some embodiments, the loading dose of the oral formulation and the maintenance dose of the oral formulation in a dosage package of the present invention have an immediate release profile.

In some embodiments, the dose package of the present invention further contains at least one of an anti-androgen inhibitor or a CYP17 lyase inhibitor. In some such embodiments, the anti-androgen includes enzalutamide, bicalutamide, enzalutamide, or flutamide, and the CYP17 lyase inhibitor includes abiraterone.

Combination therapy.

The method of administration of oral formulations according to the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof and a concomitant drug may, for example, be

1) simultaneous administration of one oral formulation obtained by preparing compound 1 or a pharmaceutically acceptable salt thereof and a concomitant drug;

2) simultaneous administration, in the same route, of two oral formulations obtained by separately preparing compound 1 or a pharmaceutically acceptable salt thereof and a concomitant drug;

3) sequential and intermittent administration by the same route of two oral formulations obtained by separate preparation of compound 1 or a pharmaceutically acceptable salt thereof,

- 62 043716 and related medicinal products.

In accordance with the present invention, methods and uses involving the administration of oral formulations of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof may further include radiation therapy.

In accordance with the present invention, methods and uses involving the administration of oral formulations of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof may further include chemotherapy. Chemotherapy can refer to the category of treatment using agents/drugs that are destructive to tumor cells and certain tissues. Examples of such agents/drugs include small molecule compounds and biological drugs such as an antibody or polypeptide. Chemotherapy drugs that can be used with the methods and applications described herein include, but are not limited to, alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, corticosteroids, differentiation agents, proteasome inhibitors, immunotherapeutic and hormonal drugs. Chemotherapy drugs may include, but are not limited to, abiraterone acetate with or without prednisone, enzalutamide, docetaxel, cabazitaxel, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, and polyadenosine diphosphate ribose polymerase (PARP) enzyme inhibitors.

In accordance with the present invention, the oral formulations of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof can be administered daily along with an anti-androgen. An antiandrogen may be given and discontinued throughout treatment to benefit from anti-androgen withdrawal. Alternatively, oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered and discontinued throughout the treatment cycle to induce anti-androgen withdrawal. To facilitate the treatment of clinical exacerbation in subjects with prostate cancer, the anti-androgen can be administered together with an oral formulation of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof. Exemplary anti-androgens include, but are not limited to, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutadimide, and fluridutidim (fluoridemide). ). Such anti-androgens are usually administered during the first 2-4 weeks of treatment. An exemplary dosage is an oral formulation containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof and 160 mg of enzalutamide.

In some embodiments, an oral formulation of this invention containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered with a CYP17 lyase inhibitor. In some embodiments, the CYP17 lysase inhibitor is abiraterone or salts thereof, galeterone or salts thereof, ketoconazole or salts thereof, or seviteronel or salts thereof. In some such embodiments, the CYP17 lyase inhibitor includes abiraterone or salts thereof. In some embodiments, a CYP17 lyase inhibitor and an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered with a glucocorticoid. In some such embodiments, the glucocorticoid is prednisone. An exemplary administration regimen is daily administration of abiraterone acetate in combination with prednisone. In some such embodiments, 1000 mg of abiraterone acetate is administered orally once daily in combination with 5 mg of prednisone administered orally twice daily. In some embodiments, the CYP17 lyase inhibitor and oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof may be administered in the absence of a glucocorticoid.

According to the treatment methods and uses of the present invention, if the prostate cancer is growth hormone dependent, the oral formulation of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof can be administered in combination with a growth hormone (receptor) antagonist or antagonist prolactin receptor (prolactin receptor) or other drugs that can reduce the amount of growth hormone or IGF-1.

Another benefit of the present invention is that the oral formulation of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof can be administered to a subject in combination with one or more measures that mitigate or help avoid side effects typically associated with GnRH antagonist, such as loss of bone mineral density (BMD). Measures include lifestyle changes and pharmacological measures. Such lifestyle changes include, but are not limited to, exercise, abstaining from smoking, and abstaining from alcohol. Such pharmacological measures include, but are not limited to, calcium supplements, vitamin D supplements, bisphosphonates, denosumab, calcitonin, SERM and strontium.

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In some embodiments, the methods and uses provided herein do not involve administering Compound 1, or a pharmaceutically acceptable salt thereof, within 6 hours of administration of a P-glycoprotein (P-gp) inhibitor, CYP3A inducer, or P-gp inducer , or any combination thereof. P-gp mediates the export of drugs from certain cells, such as cells located in the small intestine, blood-brain barrier, hepatocytes and the proximal tube of the kidney. P-gp can be affected by P-gp inducers or inhibitors, which reduce P-gp-mediated uptake or export or enhance P-gp activity, respectively. CYP3A is a subfamily of monooxygenases that may be involved in drug metabolism. Inducers of P-gp or CYP3A may include carbamazepine, rifampin, St. John's wort, bosentan, efavirenz, mitotane, modafinil, or nafcillin. P-GP inhibitors may include amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conavepen, cyclosporine, diltiazem, dronedarone, eliglustat, erythromycin, felodipine, itraconazole, ketoconazole, lapatinib, lopinavir/ritonavir, propafenone, quercetin, quinidine, reserpine, ranolazine, saquinavir, telaprevir, tipranavir, ticagrelor, tacrolimus and verapamil. A discussion of the P-gp transport system can be found in J.D. Wesslery, et al. JACC (2013) 61(25): 2495-502. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at least 6 hours, at least 8 hours, at least 10 hours, or at least 12 hours before administration of the P-gp inhibitor, CYP3A inducer, or a P-gp inducer, or any combination thereof. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered no less than 6 hours, no less than 8 hours, no less than 10 hours, or no less than 12 hours after administration of the P-gp inhibitor, CYP3A inducer, or P-gp inducer. gp, or any combination thereof. In some embodiments, for example, when treatment involving administration of Compound 1 or a pharmaceutically acceptable salt thereof is initiated, Compound 1 or a pharmaceutically acceptable salt thereof is administered at least 16 hours before, at least 20 hours before, or at least 24 hours before before administration of a P-gp inhibitor, a CYP3A inducer, or a P-gp inducer, or any combination thereof. In other embodiments, for example, when treatment involving administration of Compound 1 or a pharmaceutically acceptable salt thereof is initiated, Compound 1 or a pharmaceutically acceptable salt thereof is administered no less than 16 hours, no less than 20 hours, or no less than 24 hours after administration a P-gp inhibitor, a CYP3A inducer, or a P-gp inducer, or any combination thereof.

Pharmacokinetics.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is formulated to achieve a desired PK profile, eg, effective plasma levels for once-daily treatment with a low dose of Compound 1 or a pharmaceutically acceptable salt thereof. Pharmacokinetic properties were determined in healthy subjects after single or repeated dosing (once daily until a steady-state pharmacokinetic state was achieved for at least 5 half-lives). The effect of food or meals was determined after a single dose, with the pharmacokinetics of Compound 1 before/during/after meals compared with administration in a fasted state (without eating for at least 8 hours before administration and for 4 hours after administration). . Following administration of Compound 1, blood samples were collected at predetermined intervals, plasma was collected, and the concentration of Compound 1 was determined using analytical methods such as high performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters (such as _Cmax , AUC and half-life) were determined from plasma concentration data over time for each individual subject using non-compartmental analysis methods as implemented in software such as Phoenix WinNonlin. These parameters can then be summarized or compared using statistical methods.

In some embodiments, a highly bioavailable formulation dosage form containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, taken orally before dinner, can provide a plasma concentration of at least about 22.68 ng/mL after 1 hour after dosing. In some embodiments, it may provide a plasma concentration of about 48.6 ng/mL 1 hour after dosing. In some embodiments, it may provide a plasma concentration of about 84 ng/mL 1 hour after dosing. In some embodiments, a highly bioavailable formulation may have a lower dose of Compound 1 or a pharmaceutically acceptable salt thereof while still achieving the same average drug exposure in subjects.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be formulated to achieve low variability in pharmacokinetic and pharmacodynamic effects across subjects. In some embodiments, a low variability formulation dosage form containing about 40 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, taken orally before dinner, may provide pharmacodynamic effects that are less susceptible to variation among subjects, yet may achieve the same average effect drug in subjects as in other variants

- 64 043716 implementations described in this document.

In some embodiments, a loading dose of an oral tablet formulation containing from about 240 mg to about 480 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, and a maintenance dose of an oral tablet formulation containing from about 80 mg to about 160 mg of the compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, is formulated so that both have high bioavailability, are independent of food intake, and can provide pharmacokinetic and pharmacodynamic effects that are less subject to variation within subjects.

In some embodiments, a loading dose of an oral tablet formulation containing about 360 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof and a maintenance dose of an oral tablet formulation containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof are formulated such that both have high bioavailability, are independent of food intake, and can provide pharmacokinetic and pharmacodynamic effects that are less susceptible to variation among subjects.

In some embodiments, the patient may take an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof before or after a meal, which requires minimal impact of food intake on mean plasma AUC compared to the fasted state. In some embodiments, a meal-independent formulation of an oral maintenance dosage formulation containing about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof administered orally may have a ratio of mean plasma AUC for administration in a fed state relative to administration in a fed state. fasting [ _mean plasma AUC/mean _plasma AUC] which is 0.9 to 1.1, such as 0.95 to 1.05, or 1. In some embodiments, the mean AUC( Plasma _satiety /mean plasma AUC( _fasting ) ranges from 0.8 to 1.25.

The present invention provides a method or use for treating prostate cancer, which includes administering to a subject, at least once daily for 24 consecutive weeks or more during the treatment period, a dosage form containing at least about 80 mg Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, in a dosage formulation that can produce _a pharmacokinetic (PK) profile in which the area under the plasma drug concentration-time curve (AUC( _0.tau )) is increased by at least 1.5 times, or 2 times, or more, when measured from the first to the last day of the treatment period. In some such embodiments, AUQo-tau) may increase by at least 1.5 times when measurements are taken from the first to the last day of the treatment period. In some such embodiments, AUC( _{0_tau} ) may increase by at least a factor of 2 or more when measurements are taken from the first to _the last day of the treatment period.

The present invention also provides a method or use for treating prostate cancer in a subject, comprising administering to the subject, at least one day during the first treatment period, a loading dose of an oral formulation containing from about 240 mg to about 480 mg of Compound 1 or the corresponding the amount of a pharmaceutically acceptable salt thereof; and administering to the subject at least once daily for 24 consecutive weeks or more during the second treatment period a maintenance dose of an oral formulation containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, and a maintenance dose oral formulation has a PK profile in which the mean plasma AUC( _{0_tau} ) may increase by at least 1.5-fold, or 2-fold, or more when measured from the first day of _the first treatment period to the last day of the second treatment period . In some such embodiments, the maintenance dose of the oral formulation has a PK profile in which the mean plasma AUC( _{0_tau} ) may increase by at least 2-fold or more when measured from the first to the last day of _the treatment period.

The present invention further provides a method or use for reducing the levels of one or more sex hormones in a subject having prostate cancer, which includes administering to the subject at least once daily for 24 consecutive weeks, or more, for treatment period, an oral formulation containing at least about 80 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, in a dosage form that can produce a PK profile in which the _average (AUC( _{0_tau} )) in plasma may increase by at least 1.5 times, or 2 times, or more, when measured from the first to the last day of the treatment period. In some such embodiments, the AUC( ₀ - _tau ) may increase by at least 1.5 times when measurements are taken from the first to the last day of the treatment period. In some such embodiments, the AUC( ₀ - _tau ) may increase by at least 2-fold or more when measurements are taken from the first to the last day of the treatment period.

The present invention provides a method or use for reducing the levels of one or more sex hormones in a subject having prostate cancer, comprising administering to the subject at least one day during the first treatment period a loading dose of an oral formulation containing from about 240 mg to about 480 mg of compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; and administering to the subject at least once daily for 24 consecutive weeks or more during the second treatment period a maintenance dose of an oral formulation containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, and a maintenance dose oral formulation has a PK profile in which the mean plasma AUC( _{0_tau} ) may increase by at least 1.5-fold, or 2-fold, or more when measured from the first day of _the first treatment period to the last day of the second treatment period .

In some such embodiments, AUC( _{0_tau} ) may increase by at least a factor of 2 or more when measurements are taken from the first to _the last day of the treatment period.

The present invention further provides a method or use for treating prostate cancer, which includes administering to a subject at least once daily for 24 consecutive weeks or more during the treatment period, an oral formulation containing at least about 80 mg of Compound 1, or an appropriate amount of a pharmaceutically acceptable salt thereof, in dosage form to obtain a PK profile in which the average C _max may increase by at least 2-fold when measured from the first to the last day of the treatment period.

The present invention further provides a method or use for treating prostate cancer, which includes administering to a subject, at least one day during the first treatment period, an oral formulation containing from about 240 mg to about 480 mg of Compound 1 or a corresponding amount thereof a pharmaceutically acceptable salt; and administering to the subject at least once daily for 24 consecutive weeks or more during the second treatment period a maintenance dose of an oral formulation containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, and a maintenance dose oral formulation has a PK profile in which the average _Cmax can increase by at least 2 times when measurements are taken from the first day of the first treatment period to the last day of the second treatment period.

The present invention also provides a method or use for reducing the levels of one or more sex hormones in a subject having prostate cancer, which includes administering to the subject at least once daily for 24 consecutive weeks or more during the treatment period of an oral formulation containing at least about 80 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, in a dosage form to obtain a PK profile in which the average _Cmax may increase by at least 2-fold when measurements are taken from the first to the last day of the treatment period.

The present invention further provides a method or use for reducing the levels of one or more sex hormones in a subject having prostate cancer, which includes administering to the subject, at least one day during the first treatment period, a loading dose of an oral formulation containing: about 240 mg to about 480 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof; and administering to the subject at least once daily for 24 consecutive weeks or more during the second treatment period a maintenance dose of an oral formulation containing from about 80 mg to about 160 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof, and a maintenance dose oral formulation has a PK profile in which the average _Cmax can increase by at least 2 times when measurements are taken from the first day of the first treatment period to the last day of the second treatment period.

In some embodiments, certain beneficial effects may result from administration of an oral formulation containing Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof before a meal. In some embodiments, the average _Cmax may be higher when administered before a meal than when administered after a meal. In addition, the mean plasma AUC( _{0_tau} ) may be higher when administered before a meal than when administered after a meal at _least 30 minutes later.

Certain beneficial effects may result from treating prostate cancer by administering oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In some embodiments, the average Cmax may be achieved between 1 and 2 hours ( _Tmax ) after the start of treatment. The average _half- life of plasma can range from 30 to 70 hours, as measured on the 14th day after the start of treatment. A steady state can be achieved within 10 days after the start of treatment. Less than 4% of compound 1 can be derived from

- 66 043716 organism unchanged in the subject's urine, as measured 14 days after the start of treatment. Levels similar to therapeutic castration that are less than or equal to 50 ng/dL (1.73 nmol/L) of serum testosterone can be achieved and maintained from days 14 to 28 after the start of treatment.

Additional beneficial effects that may result from treating prostate cancer by administering oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof to a subject include, for example, mean plasma AUC( ₀ - _tau ) which may increase by 1 .5-2.5 times (from 150 to 250%) from 1 to 14 days after the start of treatment. In some embodiments, the average C _max may increase 1.5 to 2.5 times (150 to 250%) from days 1 to 14 after initiation of treatment.

Additional beneficial effects that may result from treating prostate cancer by administering oral formulations _containing Compound 1 or a pharmaceutically acceptable salt thereof to a subject include, for example, mean plasma AUC( _{0_tau} ), which may increase by 1 .5-2.5 times (from 150 to 250%) from 1 to 14 days after the start of treatment. In some embodiments, the average C _max may increase 1.5 to 2.5 times (150 to 250%) from days 1 to 14 after initiation of treatment.

In accordance with this disclosure, the average T _1/2 in plasma of compound 1 may be at least 15 hours, at least about 30 hours, or at least about 35 hours, as measured at the end of the treatment period. In some embodiments, the average T _1/2 in plasma of compound 1 may be from about 35 to about 45 hours, such as from about 37 to about 42 hours, as measured at the end of the treatment period.

Following administration of maintenance doses of an oral formulation containing about 80 mg or about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof once daily for 25 consecutive weeks, the composition, mean residual plasma concentration ( _Cmin ) of unchanged Compound 1 may be in the range between 1.0 and 9.0 ng/ml, in particular between 2.0 and 8.0 ng/ml and more particularly between 2.5 and 7.5 ng/ml for a dose of 80 mg and between 2, 0 and 14.0 ng/ml, in particular between 4.0 and 12.0 ng/ml and more particularly between 4.5 and 11.5 ng/ml for the 120 mg dose.

In some embodiments, C _min may be maintained constant during the treatment period.

As described herein, in some embodiments, the plasma absorption of Compound 1 can be reduced and delayed following a single dose administered 30 minutes after the start of a standard FDA high-calorie, high-fat breakfast ( approximately 800-1000 calories, 50% fat) compared to fasting conditions. Median _Tmax may increase during feeding conditions. The mean _Cmax and mean AUC in plasma may be reduced under fed conditions compared to fasted conditions, indicating a clinically significant effect of food on the oral bioavailability of Compound 1. When Compound 1, or a pharmaceutically acceptable salt thereof, can be administered once daily for 30 minutes before consuming a standardized breakfast (approximately 600 calories, 27% fat), the systemic exposure of Compound 1 may be reduced to a lesser extent and there is no apparent change in the rate of absorption compared to fasting conditions. In some embodiments, subjects should take an oral formulation containing Compound 1 or a pharmaceutically acceptable salt thereof upon rising in the morning, on an empty stomach, and begin eating approximately 30 minutes after administration, when possible.

Following administration of maintenance doses of an oral formulation containing about 80 mg or about 120 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof (Compound 1 Formulation), once daily for 13 consecutive weeks, containing the following excipients: 244 or 549 mg of mannitol , 40 or 90 mg microcrystalline cellulose, 12 or 27 mg hydroxypropyl cellulose, 20 or 45 mg croscarmellose sodium, 4 or 10 mg magnesium stearate, 14.24 or 35.6 mg hypromellose 2910, 1.6 or 3.6 mg titanium dioxide and 0.16 or 0.36 mg iron oxide, the change from baseline (ie, the subject's pre-treatment serum PSA level) in mean serum PSA concentration after 13 consecutive weeks (ie, week 13, day 1) may be a decrease from 10.6004 to 1.0823 ng/L (i.e., a decrease of 10.6 times (1060%)) for the 80 mg dose and a decrease from 6.6275 to 0.5849 ng/L (i.e. .decrease by 11.3 times (1130%)) for a dose of 120 mg. The change in the average serum PSA concentration relative to the initial value can be for a dose of 80 mg a decrease from 6.5 to 15.5 times (from 650 to 1550%), in particular from 7.5 to 14.5 times (from 750 to 1450 %) and more specifically from 8.0 to 12 times (800 to 1200%), and for a dose of 120 mg a decrease from 7.5 to 16.5 times (from 750 to 1650%), in particular from 8. 5 to 15.5 times (850 to 1550%) and more specifically 9.0 to 13 times (900 to 1300%). The PSA reduction rates achieved with Compound 1 or its pharmaceutically acceptable salt may be comparable to leuprolide acetate and degarelix, but formulations of Compound 1 or its pharmaceutically acceptable salt provide greater ease of administration.

After administration of maintenance doses of an oral formulation containing about 80 mg or about 180 mg of Compound 1 or an appropriate amount of its pharmaceutically acceptable salt (compound 1 formulation), once daily for 16 consecutive days, the change from baseline (67 043716) i.e. the subject's serum LH level before treatment) the average serum LH concentration at the end of 16 consecutive days, i.e. at the end of treatment, there may be a decrease from 3.90 to 0.23 IU/l (i.e. a decrease of 13.8 times (1380%)) for a dose of 180 mg and a decrease from 4.57 to 0.33 IU/ l (i.e., a decrease of 17 times (1700%)) for a dose of 80 mg. The change in mean serum LH concentration relative to the initial value can be for a dose of 80 mg a decrease of 10 to 18 times (from 1000 to 1800%), in particular from 12 to 16 times (from 1200 to 1600% and more specifically from 12. 5 to 15.5 times (from 1250 to 1550%), and for a dose of 180 mg a decrease of 14 to 20 times (from 1400 to 2000%), in particular from 15 to 19 times (from 1500 to 1900%) and more specifically, 15.5 to 18.5 times (1550 to 1850%).

Following administration of maintenance doses of an oral formulation containing about 80 mg or about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof (Compound 1 Formulation) once daily for 16 consecutive days, the change from baseline (i.e. subject's pre-treatment serum testosterone level) mean serum testosterone concentration at the end of 16 consecutive days may be a decrease from 10.40 to 0.3565 nmol/L (i.e., a 29-fold (2900%) decrease) for the 80 mg dose and a decrease from 10.40 to 0.4320 nmol/l (i.e., a 24-fold decrease (2400%)) for a dose of 180 mg. The change in mean serum testosterone concentration relative to the initial value can be for a dose of 80 mg a decrease of 25 to 33 times (from 2500 to 3300%), in particular from 27 to 31 times (from 2700 to 3100%) and more specifically from 27 .5 to 30.5 times (from 2750 to 3050%), and for a dose of 180 mg a decrease of 20 to 28 times (from 2000 to 2800%), in particular from 22 to 26 times (from 2200 to 2600%) and more specifically 22.5 to 25.5 times (2250 to 2550%). The testosterone reduction rates achieved with Compound 1 or a pharmaceutically acceptable salt thereof may be comparable to leuprolide acetate and degarelix, but formulations of Compound 1 or a pharmaceutically acceptable salt thereof provide greater ease of administration.

After administration of maintenance doses of an oral formulation containing about 80 mg or about 180 mg of Compound 1 or an appropriate amount of its pharmaceutically acceptable salt (Compound 1 Formulation) once daily for 16 consecutive days, the change from baseline in mean serum FSH concentration in at the end of 16 consecutive days, there may be a decrease from 6.07 to 0.67 IU/l (i.e. a decrease of 9.1 times (910%)) for a dose of 80 mg and a decrease from 3.88 to 0.33 IU /l (i.e., a decrease of 11.8 times (1180%)) for a dose of 180 mg. The change in mean serum FSH concentration relative to the initial value can be for a dose of 80 mg a decrease of 5 to 13 times (from 500 to 1300%), in particular from 7 to 11 times (from 700 to 1100%), and more specifically from 7 .5 to 10.5 times (from 750 to 1050%), and for a dose of 180 mg a decrease from 8 to 16 times (from 800 to 1600%), in particular from 10 to 14 times (from 1000 to 1400%) and more specifically 10.5 to 13.5 times (1050 to 1350%).

Following administration of maintenance doses of an oral formulation containing about 80 mg or about 180 mg of Compound 1 or an appropriate amount of a pharmaceutically acceptable salt thereof (Compound 1 Formulation) once daily for 16 consecutive days, the change from baseline (i.e. subject's pretreatment serum DHT level) mean serum DHT concentration at the end of 16 consecutive days may be a decrease from 1.883 to 1.095 nmol/L (i.e., a 1.7-fold (170%) decrease) for the 80 mg dose and a decrease from 1.882 to 0.865 nmol/l (i.e., a decrease of 2.2 times (220%)) for a dose of 180 mg. The change in the average serum concentration of DHT relative to the initial value can be for a dose of 80 mg a decrease of 1.1 to 5 times (from 110 to 500%), in particular from 1.1 to 3 times (from 110 to 300%) or more specifically from 1.1 to 2.5 times (from 110 to 250%), and for a dose of 180 mg a decrease from 1.1 to 6 times (from 110 to 600%), in particular from 1.1 to 4 times (110 to 400%) and more specifically 1.1 to 3.5 times (110 to 350%).

The following non-limiting examples are provided to illustrate the invention.

Examples

Example 1. Preparation of compound 1.

N-(4-(1-(2,6-difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-5-((methylamino)methyl)-2,4-dioxo-1,2,3,4tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea (150 mg, 0.259 mmol) was dissolved in DMF (dimethylformamide) (4 ml) and methyl iodide (0.010 ml, 0.164 mmol) was added. . The reaction mixture was stirred at room temperature for 1 hour, combined with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified

- 68 043716 column chromatography on silica gel (eluent: ethyl acetate/methanol=40/1) and recrystallized from dichloromethane/methanol/diethyl ether to give the title compound (17.3 mg,

17%) in the form of colorless crystals.

¹ H-NMR (CDCl ₃ ) δ 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5 .35 (2H), 6.92 (2H, t, J=8.2 Hz), 7.12 (1H, d, J=8.8 Hz), 7.2-7.65 (7H, m) , 7.69 (1H, s).

Example 2. Production of film-coated tablets of compound 1.

Film-coated tablets were prepared using the compound obtained in Example 1 (120 mg), mannitol (366 mg), microcrystalline cellulose (120 mg), hydroxypropyl cellulose (18 mg), croscarmellose sodium (30 mg), magnesium stearate (6 mg) and a sufficient amount of purified water. Water was removed during production. In a fluid bed dryer granulator (LAB-1, Powrex Corporation), the compound prepared in Example 1, mannitol, particularly D-mannitol, and microcrystalline cellulose were preheated and mixed, an aqueous solution of hydroxypropyl cellulose was sprayed, and the mixture was dried to obtain a granulated powder . Croscarmellose sodium and magnesium stearate were added to the resulting granular powder and mixed in a chamber to obtain a mixed powder. The mixed powder was tableted using a rotary tableting machine (Compact Tableting Machine 10, Kikusui Seisakusho Ltd.) with a 6.0 mmφ presser to obtain a tablet base. The tablet base was placed in a film coating machine (DRC-200, Powrex Corporation), a film coating solution containing a composition of hypromellose 2910 (21.36 mg), titanium dioxide (2.4 mg) and red iron oxide (0.24 mg) was sprayed to obtain film-coated tablets. The resulting film-coated tablets were placed in a glass bottle, which was tightly closed and stored at 60°C for 2 weeks.

Example 3. Production of film-coated tablets of compound 1.

Film-coated tablets were prepared using the compound obtained in Example 1 (360 mg), mannitol (1098 mg), microcrystalline cellulose (360 mg), hydroxypropyl cellulose (54 mg), croscarmellose sodium (90 mg), magnesium stearate (18 mg) and a sufficient amount of purified water. Water was removed during production. In a fluid bed dryer granulator (LAB-1, Powrex Corporation), the compound prepared in Example 1, mannitol, particularly D-mannitol, and microcrystalline cellulose were preheated and mixed, an aqueous solution of hydroxypropyl cellulose was sprayed, and the mixture was dried to obtain a granulated powder . Croscarmellose sodium and magnesium stearate were added to the resulting granular powder, and they were mixed in a chamber to obtain a mixed powder. The mixed powder was tableted using a rotary tableting machine (Compact Tableting Machine 10, Kikusui Seisakusho Ltd.) with a 6.0 mmφ presser to obtain a tablet base. The tablet base was placed in a film coating machine (DRC-200, Powrex Corporation), a film coating solution containing a composition of hypromellose 2910 (64.08 mg), titanium dioxide (7.2 mg) and red iron oxide (0.72 mg) was sprayed to obtain film-coated tablets. The resulting film-coated tablets were placed in a glass bottle, which was tightly closed and stored at 60°C for 2 weeks.

Example 4. Production of film-coated tablets of compound 1.

Film-coated tablets were prepared using the compound obtained in Example 1 (120 mg), mannitol (153 mg), sodium starch glycolate (type A) (15 mg), hydroxypropylcellulose (9 mg), magnesium stearate (3 mg) and sufficient amount of purified water. As before, water was removed during production. In a fluid bed dryer granulator (LAB-1, Powrex Corporation), the compound obtained in Example 1, D-mannitol and sodium starch glycolate were preheated and mixed, an aqueous solution of hydroxypropylcellulose was sprayed, and the mixture was dried to obtain a granular powder. Magnesium stearate was added to the resulting granular powder, and they were mixed in a chamber to obtain a mixed powder. The mixed powder was tableted using a rotary tableting machine (Compact Tableting Machine 10, Kikusui Seisakusho Ltd.) with a 6.0 mmφ presser to obtain a tablet base. The tablet base was placed in a film coating machine (DRC-200, Powrex Corporation), a film coating solution containing a composition of hypromellose 2910 (10.68 mg), titanium dioxide (1.2 mg), iron oxide (0.12 mg), was sprayed. and a sufficient amount of carnauba wax to obtain film-coated tablets. The resulting film-coated tablets were placed in a glass bottle, which was tightly closed and stored at 60°C for 2 weeks.

Example 5. Production of film-coated tablets of compound 1.

Film-coated tablets were prepared using the compound obtained in Example 1 (360 mg), mannitol (459 mg), sodium starch glycolate (type A) (45 mg), hydroxypropyl cellulose (27 mg), magnesium stearate (9 mg) and sufficient amount of purified water. As before, water was removed during production. In a fluid bed dryer granulator (LAB-1, Powrex Corporation), the compound obtained in Example 1, D-mannitol, and sodium starch glycolate were preheated and mixed, an aqueous solution of hydroxypropyl cellulose was sprayed, and the mixture was dried to obtain a granular powder. Magnesium stearate was added to the resulting granular powder and mixed into

- 69 043716 chamber, to obtain mixed powder. The mixed powder was tableted using a rotary tableting machine (Compact Tableting Machine 10, Kikusui Seisakusho Ltd.) with a 6.0 mmφ presser to obtain a tablet base. The tablet base was placed in a film coating machine (DRC-200, Powrex Corporation) and a film coating solution containing a composition of hypromellose 2910 (32.04 mg), titanium dioxide (3.6 mg), iron oxide (0.36 mg) and sufficient amount of carnauba wax to obtain film-coated tablets. The resulting film-coated tablets were placed in a glass bottle, which was tightly closed and stored at 60°C for 2 weeks.

Example 6 Study to evaluate the effects of Compound 1 on pharmacokinetics and pharmacodynamics in men with non-metastatic prostate cancer.

This study consisted of two parts: Part A, dose escalation phase, and Part B, expansion phase. Whether or not the study would continue into the next arm or Part B was determined by assessing tolerability at the current dose based on the incidence of adverse events during the evaluation period.

Compound 1 formulation was administered orally once daily for 28 days. The 120 mg formulation of Compound 1 contained a tablet base of Compound 1 (120 mg), mannitol (366 mg), microcrystalline cellulose (60 mg), hydroxypropylcellulose (18 mg), croscarmellose sodium (30 mg) and magnesium stearate (6 mg). The tablet base was coated with a film coating containing hypromellose 2910 (21.36 mg), titanium dioxide (2.4 mg) and red iron oxide (0.06 mg). The amounts of excipients in the tablet base and film coating were adjusted accordingly depending on the amount of Compound 1 in the tablet base (e.g., for a 360 mg tablet, the amount of excipient added to the tablet base and film coating was three times greater than the amount added in the 120 mg tablet). mg tablet).

Subjects in group 1 received a loading dose of 320 mg and a maintenance dose of 80 mg; subjects in group 2 received a loading dose of 320 mg and a maintenance dose of 120 mg; subjects in group 3 received a loading dose of 320 mg and a maintenance dose of 160 mg; and subjects in group 4 received a loading dose of 360 mg and a maintenance dose of 120 mg. Subjects who are switched to treatment with a GnRH agonist (e.g., leuprolide acetate) or GnRH antagonist (e.g., degarelix) undergo a 1-week observation period after receiving their last dose of Compound 1 formulation.

If tolerability was confirmed in arm 2, then the study continued simultaneously in arm 3 and part B. However, if tolerability was not confirmed in arm 2, an additional arm was introduced in which subjects received a loading or loading dose of 320 mg of compound 1 and a maintenance dose of 40 mg. Group 4 was used after confirmation of tolerability in group 3.

In Part B, subjects were randomized 1:1 (15 patients each) to either the 80 mg group (320 mg loading dose of Compound 1 and 80 mg maintenance dose, PO once daily) or the 120 mg group (320 mg loading dose of compound 1). mg of compound 1 and a maintenance dose of 120 mg, PO once daily) to evaluate the safety of formulation of compound 1. In addition to the safety assessments, efficacy assessments were also performed according to the study schedule, and formulation of compound 1 was administered until each subject did not meet discontinuation criteria.

Serum testosterone concentrations and other pharmacodynamic parameters involved in the testosterone synthesis pathway, such as LH, FSH, DHT and SPGH, were measured during the 28-day treatment period in part A and up to 96 weeks in part B. Methods for the analysis of serum testosterone, LH and FSH - chemiluminescent immunoassay (CLIA) (lower limits of quantitation [LOQ] were 0.04 ng/ml, 0.10 and 0.10 mIU/ml, respectively), DHT - ammonium sulfate salting-out radioimmunoassay (RIA) (LOQ was 0. 02 ng/ml), and SPGG by bilateral CLIA (LOL was 2.0 nmol/L).

For Part A, the average serum testosterone concentration for each dose level of Compound 1 is shown in FIG. 1, and individual changes in serum testosterone concentrations for each study drug dose level are presented in FIG. 2. Serum testosterone concentrations decreased rapidly after the first dose at all dose levels (maintenance dose 80, 120, or 160 mg). Mean serum testosterone concentrations fell below therapeutic castration levels (i.e., below 50 ng/dL) during the first 3 days of administration. Serum testosterone concentrations reached therapeutic castration levels between Day 2 and Day 14 and were thereafter maintained until 3 days after the last dose on Day 28 in all subjects.

For Part A, the mean serum concentrations of LH, FSH, DHT, and SPGG for each study drug dose level are shown graphically in FIG. 3-6 respectively. Serum concentrations of LH, FSH, and DHT decreased rapidly, similar to serum testosterone concentrations, at all dose levels. There were no significant differences between baseline (i.e., subject's serum hormone levels before treatment) and post-dose serum concentrations of SPGG.

For Part B, the mean serum testosterone concentration for each study drug dose level is shown in FIG. 7, and changes in the concentration of whey dough

- 70 043716 sterone for each study drug dose level are shown in FIG. 8A and 8B, and summary statistics of serum testosterone concentrations are shown in FIG. 2. Serum testosterone concentrations decreased rapidly after the first dose at all dose levels (maintenance dose 80 or 120 mg). Mean serum testosterone concentrations were reduced below therapeutic castration levels (ie, below 50 ng/dL) during the first 4 days after administration. In all subjects, serum testosterone concentrations reached levels similar to therapeutic castration between days 2 and 3. Therapeutic castration levels were maintained in all subjects during the evaluation period.

For Part B, the mean serum concentrations of LH, FSH, DHT, and SPHT for each study drug dose level are shown graphically in FIG. 9-12 respectively. Serum concentrations of LH, FSH, and DHT decreased rapidly, similar to serum testosterone concentrations, at all dose levels. There were no significant differences between baseline and postdose serum concentrations of SGT.

To evaluate the clinical efficacy of Compound 1 in prostate cancer, serum PSA concentrations, a common diagnostic marker for prostate cancer, were measured throughout the 28-day treatment period in Part A and up to 96 weeks in Part B. The method for assessing PSA is the chemiluminescent enzyme-linked immunosorbent assay (CLEIA). ), and the LLOQ was 0.008 ng/ml.

For part A, on day 28, the mean and median percentage changes in serum PSA concentration compared to baseline were -76.37 and -77.50%, respectively, in group 1, -60.10 and -72.30%, respectively, in group 2 and -32.10 and -50.50%, respectively, in Group 3. For Part A, summary statistics for serum PSA and PSA change from baseline are tabulated in FIG. 13.

For Part B, the mean and median percentage changes from baseline in serum PSA concentration at day 1 week 13 (LOCF) were -89.47 and -97.20%, respectively, in the 80 mg group and -93.11 and -95.80 % respectively in the 120 mg group. For Part B, summary statistics for serum PSA and PSA change from baseline are tabulated in FIG. 14.

After continued administration until Day 1 of Week 13 in Part B, the change in mean serum PSA concentration from baseline on Day 1 of Week 13 was a 10.6-fold decrease (1060%) for the 80 mg dose (decrease from 10.6004 to 1 .0823 ng/l) and a decrease of 11.3 times (1130%) for a dose of 180 mg (decrease from 6.6275 to 0.5849 ng/l).

To preliminarily evaluate the pharmacokinetics of Compound 1, plasma concentrations of unchanged Compound 1 were measured by a validated LC-MS/MS method (LOL: 0.01 ng/mL) in prostate cancer patients when the study drug was rechallenged.

For Part A, the formulation of Compound 1 was administered once daily for 28 days. The plasma concentration profiles of Compound 1 - time on day 1 (loading dose) and days 14 and 28 (maintenance dose) - are shown in FIG. 15A-15C, and preliminary pharmacokinetic parameters are summarized in FIGS. 16.

One loading dose of 320 mg was administered orally per day. Plasma concentrations of unchanged compound 1 increased rapidly after administration in different dose cohorts. The median time to maximum drug concentration ( _Tmx ) was 1.0 or 1.5 hours. There were small differences in mean plasma _Cmax or mean AUC24 between groups. After day 2, a maintenance dose of 80 to 160 mg was repeated once daily. On days 14 and 28, the plasma concentration of unchanged compound 1 increased rapidly in all groups after administration. The median _Tmax was 0.5-2.0 hours. Average _Cmax , Ctrough and median AUC24 in plasma generally increased proportionally to the dose. On day 28, the mean plasma T1 _/2 was 66.5-78.1 hours, and differences between groups were insignificant.

For Part B, a maintenance dose of 80 or 120 mg (starting with a loading dose of 320 mg on day 1 for both) was repeated once daily. The mean residual plasma concentration of unchanged Compound 1 between week 2 and week 25 is shown in FIG. 17A and 17B. The mean residual plasma concentration of unchanged compound 1 ranged from 2.60 to 6.09 ng/ml in the 80 mg group (n=3-15) and from 5.72 to 10.7 ng/ml in the 120 mg group ( n=3-14) and was maintained almost constant over time in both groups.

Example 7: Double-blind, randomized, placebo-controlled study to evaluate the effect of Compound 1 on the pharmacokinetics and pharmacodynamics of testosterone reduction in healthy men.

Objective: To evaluate the PK, PD, safety and tolerability of Compound 1 in healthy men after single and once daily dosing for 2 and 4 weeks.

Main results: FA was dosed proportionally in the range of 80-360 mg. The effect of the meal at the 180 mg dose was similar to that observed at the 40 mg dose, demonstrating that the effect of the meal was independent of dose. The results of the analysis of variance showed that the coefficients C _max and AUC ₀ _ _inf weighted means (90% CI) for the fed state compared to the fasted state

- 71,043,716 were 48.25 (22.62-102.90) and 52.74 (29.99-92.76), respectively. A single dose of 360 mg resulted in castration levels (<50 ng/dL) within 24 hours of dosing. 360 mg per day 1 and 40 mg per day from day 14 resulted in rapid castration rates and sustained castration rates. 320 mg per day 1,

160 mg per day 2 and 40 mg per day 3 to 28 did not maintain castration levels. It took up to 24 hours of 80 mg once daily to reach castration levels.

This was a randomized, double-blind, placebo-controlled, single- and multiple-dose study in healthy men to evaluate the safety, tolerability, pharmacokinetics, and testosterone-lowering efficacy of Compound 1, an oral GnRH antagonist. The study consisted of 4 parts: Part 1 (hospital) included a single administration of the formulation of Compound 1 to all 4 dose groups plus placebo and included fed/fasted groups; part 2 (hospital) included repeated administration of the finished form of compound 1 for 14 days to all 5 dose groups plus placebo; and parts 3 and 4 (outpatient) included repeated once-daily (daily) administration of a formulation of compound 1 for 28 days in two dose groups (a total of 4 dose levels) plus placebo.

The formulation of Compound 1 was provided as light red colored, film-coated tablets, each containing the active compound 1. The 120 mg formulation of Compound 1 contained a tablet base of Compound 1 (120 mg), mannitol (366 mg), microcrystalline cellulose (60 mg), hydroxypropylcellulose (18 mg), croscarmellose sodium (30 mg) and magnesium stearate (6 mg). The tablet base was coated with a film coating containing hypromellose 2910 (21.36 mg), titanium dioxide (2.4 mg) and red iron oxide (0.06 mg). The amounts of excipients in the tablet base and film coating were adjusted accordingly depending on the amount of Compound 1 in the tablet base (e.g., for a 360 mg tablet, the amount of excipient added to the tablet base and film coating was three times greater than the amount added in the 120 mg tablet). mg tablet).

In part 1, a single dose of 80, 120, 180 and 360 mg of the prepared form of compound 1 was administered orally. In part 2, 80, 180, 40 and 20 mg of the prepared form of compound 1 were administered for 14 days. A dose of 40 mg was administered once a day with a single loading dose of 360 mg per day, 1 of 14 days of treatment. For the 20 mg doses, one 20 mg dose was administered with loading doses of 320 mg on day 1, 240 mg on day 2, and 160 mg on day 3, and another 20 mg dose was administered with loading doses of 320 mg on day 1 and 160 mg on day 2. day. In parts 3 and 4 of the study, 40 or 160 mg and 60 or 80 mg of the finished form of compound 1 were administered once daily for 28 days. A dose of 40 mg was administered with loading doses of 320 and 160 mg on days 1 and 2 of treatment, respectively. .

Part 1 included a single oral dose; part 2 included 14 days of daily treatment; and parts 3 and 4 included 28 days of daily treatment.

Blood (approximately 4 ml) and urine samples were collected to determine the concentrations of Compound 1 in plasma (parts 1-4) and urine (parts 1 and 2). Samples were analyzed using validated liquid chromatography tandem mass spectrometry (LC/MS/MS) methods. The LLOQ was 0.0100 ng/mL in plasma and 0.500 ng/mL in urine.

Key pharmacodynamic variables included serum concentrations of LH and testosterone measured at regular intervals after single and multiple doses of Compound 1 formulation in Parts 1-4. FSH, DHT, and insulin-like growth factor 1 (IGF-1; parts 3 and 4 only) were measured in a subset of samples. Serum testosterone levels were analyzed using a conventional screening immunoassay (LOL = 0.4 nmol/L). A validated LC/MS/MS method with an LLOQ of 0.173 nmol/L and an ULLO (upper limit) of 10.425 nmol/L was used for all subsequent measurements of baseline values (i.e., hormone levels in the subject's serum before treatment) and post-dose values.

Selected plasma and urinary concentration-time data for Compound 1 obtained in parts 1 and 2 were analyzed using non-commercial methods (WinNonlin Enterprise version 5.2) to characterize the pharmacokinetics of single and multiple dose formulations of Compound 1 and assess the effects of food on pharmacokinetics of Compound 1 formulation. Individual plasma and/or urinary concentrations and PK parameters of single and multiple dose formulations of Compound 1 were listed and statistically summarized by study part, study day, and dose level. The dose proportionality of the PK parameters of the formulation of compound 1 after single and multiple administrations was first examined graphically by plotting individual dose-normalized exposure parameters: observed mean dose-adjusted C _max /D, mean plasma AUC ₀ _ _tlqc /D adjusted for dose and mean dose-adjusted plasma AUC ₀ _ tau /D or dose-adjusted mean plasma AUC ₀ _ _tau /D over the entire dosing interval as a function of dose. Formal evaluation was then conducted using both analysis of variance (ANOVA) techniques and powerful modeling approaches. In part 1 (group 3), ANOVA was performed with ln-transformed PK parameters [mean plasma AUC _{0.ti qc} , mean plasma AUC _0.0 and mean _Cmax ] of compound 1 to evaluate the effect of food intake on oral bioavailability compound 1. In part 2, the achievement of steady state was determined based on visual inspection of the average observed plasma concentration before dosing at

- 72 043716 repeated dose administration (C _trough ) depending on the time profiles at each dose level. Analysis of data from parts 3 and 4 using a tubeless model was not planned given the limited number of post-dose samples collected from each subject on days 1 and 28.

Pharmacodynamic measurements included serum concentrations of testosterone, DHT, LH, and FSH. Part 2 tabulated the number and percentage of subjects with mean serum testosterone levels less than 0.69 nmol/L occurring during the second week of administration. Parts 3 and 4 tabulated the number and percentage of subjects with serum testosterone levels that were consistently below 0.69 nmol/L from days 14 to 28.

In Part 1, the single-dose pharmacokinetics of Compound 1 were assessed in healthy men at 4 dose levels (80, 120, 180, and 360 mg) under fasted conditions and for 1 dose level (180 mg) 30 min after dosing at a standard FDA-recommended high fat content, high-calorie breakfast (in conditions of satiety). The mean plasma concentration profiles of Compound 1 over time are presented in FIG. 18A, 18B and 19. A summary of relevant PK parameters in plasma and urine is shown in FIGS. 20.

In Part 2, the pharmacokinetics of repeated dosing of Compound 1 were assessed in healthy men for 4 dosing schedules (20, 40, 80 and 180 mg) administered once daily for 14 days; of these doses, three included a loading dose administered over the first 1, 2, or 3 days. The mean plasma concentration profiles of Compound 1 over time on days 1 and 14 are plotted in FIG. 21A and 21B. Summary statistics for all relevant PK parameters in plasma and urine obtained on days 1 and 14 are presented in Fig. 22 and 23 respectively.

On days 1 and 14, compound 1 was administered to healthy adult men 30 minutes before a standardized breakfast, which was readily absorbed into plasma. Peak concentrations observed generally occurred within 1 to 2 hours after dosing. When comparing the absorption profiles of a single 180 mg dose in the fasted state (part 1) or 30 minutes before a standardized meal (part 2, day 1), it was noted that the average AUC value _{of 0} - ₂₄ in plasma decreased to a lesser extent (by approximately 28%), while no changes in the absorption rate (average _Cmax and _Tmax ) of compound 1 were observed.

Compound 1 was readily absorbed into plasma after single and multiple oral administrations. The phase of absorption was somewhat variable, with individual first-time _Tmax values ranging from 0.5 to 12 hours post-dose (average approximately 2 hours) for all doses tested. Coadministration with food decreased _{mean Cmax} and mean plasma AUC by approximately 50% and delayed absorption (median _Tmax 5 hours) compared with fasting conditions. When administered 30 minutes before a standardized meal, the rate of absorption was unaffected, whereas systemic exposure of Compound 1 (mean plasma AUC) was reduced by an average of approximately 28%.

Absorption of Compound 1 into plasma was reduced and delayed following a single 180 mg dose administered 30 min after the start of a standard US FDA high-fat, high-calorie breakfast (approximately 800-1000 calories, 50% fat) compared to fasting conditions. Median _Tmax increased from 1.75 to 5.00 h under fed conditions. The ratios of mean plasma _Cmax and mean AUC^ (and corresponding 90% CI) weighted means for the fed versus fasted state were 48.25% (22.62, 102.90%) and 52.74% (29, 99, 92.76%) respectively, indicating a clinically significant effect of food intake on the oral bioavailability of compound 1. In the 14-day inpatient multiple dose part 2, the formulation of compound 1 was administered once daily 30 min before dosing standard breakfast (about 600 calories, 27% fat). Under these conditions, systemic exposure to Compound 1 was reduced to a lesser extent (on average by approximately 28%), and no obvious changes in absorption rate were observed compared to fasting conditions. Therefore, in the 28-day multiple-dose outpatient portions 3 and 4, subjects were instructed to take the formulation of Compound 1 upon waking in the morning, on an empty stomach, and to begin eating approximately 30 minutes after dosing when possible.

In general, approximate dose-dependent increases in mean plasma _Cmax and mean AUC were observed following single doses of ₈₀ to 360 mg. At steady state, mean plasma AUC _{0_tau} increased dose proportionally following repeated dosing of Compound 1 over the dose range from 20 to 180 mg once daily, whereas _{mean Cmax} increased slightly more than dose proportionally. It was noted that there was moderate to large interindividual variability between systemic exposures to Compound 1 across all parts of the study.

After reaching the mean _Cmax , plasma concentrations of Compound 1 decreased in a multi-exponential manner with mean plasma half _- life ranging from 19.1 to 21.7 hours after a single dose, and from 35.8 (180 mg once daily) to 64.5 hours (20 mg once daily) after repeated dosing. Steady state was achieved within 11-14 days from the start of once-daily dosing. The observed accumulation _index based on mean plasma AUC _{0_tau} was 1.92 and

- 73 043716

2.16 for dosage regimens of 80 and 180 mg once daily, respectively.

Less than 4% of Compound 1 was excreted unchanged in urine from the body after single and repeated dosing. The average renal clearance of Compound 1 represented a small fraction of its total clearance, indicating that renal excretion plays a minor role in the elimination of Compound 1.

It was noted that a clinically significant decrease in mean serum testosterone levels occurred 4-6 hours after single doses of 80, 120, 180 and 360 mg of Compound 1, and this was maintained for 36 hours after dosing. Mean serum LH concentration profiles were similar to testosterone for these 4 doses. The mean serum LH concentration over time (IU/L) for the treatment period (Part 1) is presented in FIG. 24. The average reduction in serum testosterone levels after a single dose of Compound 1 (Part 1) is graphically shown in FIG. 25. Mean serum testosterone concentrations over time (nmol/L) for the treatment period (Part 1) are presented in FIG. 26.

Mean serum FSH concentrations over time (IU/L) for the treatment period (Part 1) are presented in FIG. 27. The profile of mean serum FSH concentrations was similar in the respective dose groups at the corresponding time points for the 80, 120, 180 and 360 mg groups. Mean serum FSH concentrations decreased 2 hours after dosing to low levels by 48 hours.

Mean serum DHT concentrations over time (nmol/L) for the treatment period (Part 1) are presented in FIG. 28. The profile of mean serum DHT concentrations was similar in the respective dose groups at the corresponding time points for the 80, 120, 180 and 360 mg groups. Mean serum DHT concentrations began to decrease 2 hours after dosing. The reduction in DHT levels was more pronounced in the 180 and 360 mg dose groups, with minor and further variable reductions occurring after 12 hours.

After 14 days of once-daily dosing, mean serum LH and testosterone values and concentration profiles were similar for the 80, 180 and 40 mg dose groups of Compound 1. Concentrations decreased from 2 to 6 hours post-dose for 14 days. Either 1- to 3-day loading dose regimens or 180 mg once daily doses resulted in a rapid decrease in serum testosterone concentrations within the first 48 hours of dosing. However, once-daily maintenance dosing was the primary determinant of sustained reduction in serum testosterone levels. The threshold for complete castration (defined for this study as mean serum testosterone levels <0.69 nmol/L) was achieved with repeated dosing over 14 days for the 40, 80, and 180 mg doses; however, 20 mg once daily was not sufficient to maintain adequate reductions in LH and serum testosterone concentrations during the second week.

With increasing dose of compound 1, no increase in the incidence of side effects (AE) was observed. The most common treatment-emergent adverse events (TEAEs) observed across all dose groups were bradycardia, hot flashes, and headache. The most common drug-related TEAE was hot flush. There were no deaths, serious adverse events (SAEs), or severe AEs following single-dose treatment or multiple-dose treatment with Compound 1 for 14 or 28 days.

The results of the safety testing showed that single and multiple doses of the administered formulation of Compound 1 were safe and well tolerated.

Compound 1 was readily absorbed into plasma after single and multiple oral administrations. After reaching the mean _Cmax , typically occurring within 1-2 hours after repeated dosing, plasma concentrations of Compound 1 decreased in a multi-exponential manner with mean disposition time. The average T1 _/2 in plasma was approximately 36 to 65 hours for the dose range from 20 to 180 mg when administered once daily. Moderate to large inter-individual variability was evident in systemic exposure to Compound 1 in all parts of the study.

At steady state, mean plasma AUC _{0_tau} increased dose proportionally following repeated dosing of Compound 1 over a dose range of 20 to 180 mg once daily, whereas _{mean Cmax} increased slightly more than dose proportionally. Steady-state conditions were reached within 10-14 days, and systemic exposure of Compound 1 increased approximately 2-fold (200%) following once-daily dosing.

Coadministration with food decreased the systemic exposure of Compound 1 (mean plasma _Cmax and _mean AUC) by approximately 50% and delayed absorption compared to fasting conditions.

Effective therapeutic castration was gradually achieved with maintenance doses of 80, 160 and 180 mg once daily. Only loading doses of 180 mg or greater resulted in serum testosterone levels below the therapeutic castration limit of 1.73 nmol/L over 24-48 hours. While greater variability in the pharmacodynamic response was evident between groups, higher doses of compound 1 caused greater decrease in serum testosterone levels. The recommended safe and effective administration regimen based on this study is

- 74 043716 is >80 mg of compound 1 once daily for sustained castration during the treatment period.

Consistent with the mechanism of action of GnRH antagonists, compound 1 caused an immediate and effective decrease in gonadotropins (LH, FSH) and serum testosterone levels through competitive binding to pituitary GnRH receptors.

The mean serum LH concentration (IU/L) over time for the treatment period (Part 2) is presented in FIG. 29. The average reduction in serum testosterone levels following repeated oral dosing of Compound 1 (Part 2) is graphically shown in FIG. 30. Mean serum testosterone concentrations (nmol/L) over time for the treatment period (Part 2) are presented in FIG. 31A and 31B.

Mean serum FSH concentrations over time (IU/L) for the treatment period (Part 2) are presented in FIG. 32. The profiles of mean serum FSH concentrations were similar in the respective dose groups at the corresponding time points for the 80, 180, 40 and 20 mg groups, in which they decreased post-dose after 24 hours until day 14 (end of administration).

Mean serum DHT concentrations (nmol/L) over time for the treatment period (Part 2) are presented in FIG. 33. Mean serum DHT concentration profiles were generally consistent with those of serum testosterone.

After administration of 80 and 180 mg of the finished form of compound 1 for 16 days in part 2, the change compared with the initial value of the average serum concentration of LH at the end of 16 days of treatment was a decrease of 13.8 times (1380%) for a dose of 80 mg (reduction from 4.57 to 0.33 IU/l) and a decrease of 17 times (1700%) for a dose of 180 mg (decrease from 3.90 to 0.23 IU/l).

After administration for 16 days in part 2, the change from baseline in mean serum testosterone concentration at the end of 16 days of treatment was a 29-fold decrease (2900%) for the 80 mg dose (decrease from 10.40 to 0.3565 nmol/ l) and a decrease of 24 times (2400%) for a dose of 180 mg (decrease from 10.40 to 0.4320 nmol/l).

After administration for 16 days in part 2, the change compared to the initial value of the average serum concentration of FSH at the end of 16 days of treatment was a decrease of 9.1 times (910%) for a dose of 80 mg (decrease from 6.07 to 0.67 IU/l) and a decrease of 11.8 times (1180%) for a dose of 180 mg (decrease from 3.88 to 0.33 IU/l).

After administration for 16 days in Part 2, the change from baseline in mean serum dihydrotestosterone concentration at the end of 16 days of treatment was a 1.7-fold decrease (170%) for the 80 mg dose (decrease from 1.883 to 1.095 nmol/L) and a decrease of 2.2 times (220%) for a dose of 180 mg (decrease from 1.882 to 0.865 nmol/l).

In healthy elderly men in parts 3 and 4 of the study, effective therapeutic castration was gradually achieved over days 14 and 28 of once-daily doses of 40 to 180 mg (14 days) and 80 to 160 mg (28 days). Use of a loading dose up to 3 days (or daily doses of 160 mg or higher) resulted in a decrease in serum testosterone below castration levels (50 ng/dL or 1.73 nmol/L) within 24 to 48 hours.

The mean serum LH concentration (IU/L) over time for the treatment period (Part 3) is presented in FIG. 34 and for the treatment period (part 4) in FIG. 39. The average decrease in serum testosterone levels over time following repeated oral dosing of Compound 1 (Part 3) is shown in FIG. 35, and dosing of Compound 1 (Part 4) is shown in FIG. 40. Mean serum testosterone concentration (nmol/L) over time for the treatment period (Part 3) is presented in FIG. 36 and for the treatment period (part 4) in FIG. 41.

The mean serum FSH concentration (IU/L) over time for the treatment period (Part 3) is presented in FIG. 37 and for the treatment period (part 4) are presented in FIG. 42.

Data on mean serum testosterone dihydrogen concentration (nmol/L) over time for the treatment period (Part 3) are presented in FIG. 38 and for the treatment period (part 4) are presented in FIG. 43.

When administered over 28 days, both 160 mg (Part 3) and 80 mg (Part 4) were effective in achieving therapeutic (<1.73 nmol/L) and complete <0.69 nmol/L) castration during the third and fourth weeks of repeated administration. However, a dose of 40 mg once daily was ineffective in maintaining castration between days 14 and 28. Results for 60 mg once daily were moderate compared with 40 and 80 mg, and suggest that the likely minimum, fully effective maintenance dose for therapeutic castration would be 80 mg once daily or higher.

Consistent with the observed dose-dependent reduction in serum testosterone for the dose range tested from 20 to 180 mg once daily, the magnitude of the serum testosterone reduction response correlated with individual trough plasma concentrations of Compound 1; the higher the systemic exposure to compound 1, the more subjects achieved and maintained therapeutic castration throughout the treatment period. Median residual concentrations of Compound 1 greater than 4 ng/mL that resulted from maintenance doses of 80 mg or greater reduced serum testosterone below therapeutic castration levels of 1.73 nmol/L in all subjects, most of whom had serum testosterone testosterone

- 75 043716 decreased below the threshold value for complete castration of 0.69 nmol/l, after 28 days of treatment with the finished form of compound 1.

The decrease in serum testosterone levels after treatment (Part 2) with Compound 1 in healthy men for 14 days is shown in FIG. 44A-44D. The correlation between decreases in serum testosterone levels and steady-state exposure to Compound 1 in healthy men (Part 2) is shown in FIG. 45 and in healthy men (parts 3 and 4) is shown in FIG. 48. The decrease in serum testosterone levels over time after treatment (parts 3 and 4) with Compound 1 in healthy men for 28 days is shown in FIG. 46A-46D. The percentage of subjects achieving serum testosterone levels below castration levels after 28 days of treatment (parts 3 and 4) with Compound 1 is shown in FIG. 47A and 47B.

Compound 1 was well tolerated, with no symptomatic side effects unless they were directly related to the effects of acute therapeutic castration. Mild to moderate elevations in transaminases were observed without symptoms or changes in total bilirubin. Changes in QT/QTc intervals were consistent with those described in the literature for other therapeutic castration agents.

Example 8 Study to evaluate the effect of Compound 1 on testosterone reduction and PSA response in men with advanced prostate cancer.

In this study, patients with advanced prostate cancer requiring first-line anti-androgen therapy (AAT) received either 80 or 120 mg once daily oral formulation of Compound 1 (with a loading dose of 320 mg on day 1) or 22.5 mg leuprolide acetate subcutaneously. The 120 mg formulation of Compound 1 contained a tablet base of Compound 1 (120 mg), mannitol (366 mg), microcrystalline cellulose (60 mg), hydroxypropylcellulose (18 mg), croscarmellose sodium (30 mg) and magnesium stearate (6 mg). The tablet base was coated with a film coating containing hypromellose 2910 (21.36 mg), titanium dioxide (2.4 mg) and red iron oxide (0.06 mg). The amounts of excipients in the tablet base and film coating were adjusted accordingly depending on the amount of Compound 1 in the tablet base (e.g., for a 360 mg tablet, the amount of excipient added to the tablet base and film coating was three times greater than the amount added in the 120 mg tablet). mg tablet).

Compound 1 formulation or conventional leuprolide acetate was administered for up to 48 weeks. For Compound 1 treatment, study visits occurred at baseline (week 1), day 1 of weeks 2, 3, and 5, and then every 4 weeks until week 49 (end of the 48-week primary study period). All patients who completed >12 weeks of Compound 1 therapy received a 12-week break with assessments at weeks 4 (end of treatment, CL), 8 (follow-up visits), and 12 (end of study, CT). For patients receiving leuprolide acetate (leuprolide), treatment visits occurred at baseline (day 1, week 1), day 1 of weeks 2, 3, and 5, and then every 4 weeks until week 25 and then at 12 weeks. intervals (weeks 37 and 49). Patients on leuprorelin received their last injection on day 1 of week 37, and day 1 of week 49 was considered the end of leuprorelin exposure. Patients received leuprorelin at visits 16 (CL), 20 (follow-up visits), and 24 (CI) weeks after the last leuprorelin injection.

Eligible men were aged >18 years with a histologically confirmed diagnosis of adenocarcinoma of the prostate, and were candidates for AAT for the treatment of hormone-sensitive prostate cancer with one of the following clinical disease states: localized advanced disease not suitable for primary surgery or radiation therapy; evidence of biochemical or clinical PSA recurrence after primary surgery or radiation therapy for curative intent; or newly diagnosed metastatic disease that was asymptomatic and without visceral involvement. Additional screening inclusion criteria included healthy testicular serum testosterone levels >150 ng/dL (5.2 nmol/L); serum PSA concentration >2 ng/mL (or, if applicable, >0.2 ng/mL after radical prostatectomy or >2 ng/mL above nadir after radiotherapy); body mass index >18.0 at screening and/or baseline (i.e., subject's pre-treatment BMI); and performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG). Patients with advanced stage, local M0N1 or M1 disease with clinically significant symptoms or visceral involvement who required immediate GnRH therapy, chemotherapy or radiotherapy were not eligible to participate in the study.

The timing and intensity of the decrease in serum testosterone levels observed in patients in this study receiving formulation of Compound 1 were similar to those observed in the study of healthy elderly men in Example 7. Serum testosterone levels were measured at each visit. On average, in patients receiving formulation 1, serum testosterone levels fell below the therapeutic castration threshold of 50 ng/dL (1.73 nmol/L) at visit day 4 (end of day 3) and below threshold complete castration value of 20 ng/dl (0.69 nmol/l) by visit on day 1 of week 5. On the contrary, in

- 76 043716 patients receiving leuprolide acetate, serum testosterone levels increased during the first 1-2 weeks of therapy and then decreased to castration levels by day 1 of week 5. In the Compound 1 groups, the median serum testosterone value was reduced to below the threshold value complete castration (<20 ng/dL) within 5-49 weeks. The most common adverse effect was hot flash in 31 (55%), 35 (65%) and 15 (63%) patients in the 80 mg Compound 1, 120 mg Compound 1, leuprorelin groups, respectively.

Quality of life (QoL) was assessed throughout the study and follow-up period. The 25-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PR25) prostate cancer questionnaire was completed at day 1 screening at weeks 5, 13, 25, 37 and 49, and, if applicable, at follow-up visits. ), the Aged Men's Questionnaire (AMS), and the core 30-item EORTC Quality of Life Questionnaire (EORTC QLQ-C30).

PSA levels were measured at each visit. On average, in patients receiving the formulation of compound 1, PSA levels decreased to less than 0.4 ng/mL by day 1 visit week 13 and to less than 0.2 ng/mL by day 1 visit week 21. After initiation treatment, the PSA response was more rapid in patients receiving compound 1 compared to leuprorelin (Fig. 52). Patients treated with compound 1 also reached PSA nadir more quickly than patients treated with leuprolide acetate (Table 1). 83% of patients treated with compound 1 had a >50% decrease in serum PSA after 4 weeks of treatment compared with only 20% of patients treated with leuprolide. 8% treated with compound 1 had a >90% decrease in serum PSA after 4 weeks of treatment compared to 0% of patients treated with leuprolide.

Table 1

Median time from first dose to PSA nadir

Compound 1 80 mg once daily (N = 56) Compound 1 120 mg once daily (N = 54) Leuprolide P12H (N = 24) Median time from first dose to 16.1 (1.60-24.70) 12.3 (2.00 - 24.60) 20.5 (8.00-24.60) PSA nadir weeks (range)

FSH levels were also measured at each visit. Compound 1 caused a greater decrease in FSH compared to leuprolide (leuprolide acetate). This was seen at both 80 mg and 120 mg doses of compound 1 (Table 2). The median FSH value was approximately 4.2 mIU/mL with leuprolide (agonist) after 48 weeks of treatment. Although FSH did fall with leuprolide, it was not a sustained decrease. However, with compound 1 (antagonist), the average FSH was 1.62 mIU/ml after 48 weeks of treatment, and this was much more stable over 48 weeks. FSH fell from >10 mIU/mL at baseline to a range of 0.6-1.6 mIU/mL for compound 1, 120 mg dose, over the 48-week course.

table 2

FSH levels (IU/L) over time

Connection 1

80 mg once a day 120 mg once a day Total Leuprorelin Initial value (b) day (Ν=56) n (%) day (N=54) n (%) (N=110) n(%) Р12Н (N=24) n (%) η 56 54 110 24 Mean (SD) 14,729 (14.3473) 15,830 (12.8724) 15,269 (13.5920) 19,688 (19.1894) Median 9,550 11,050 9,850 14,500 Min., Max. Week 2, Day 2.80, 77.60 2.80, 68.60 2.80, 77.60 2.00, 79.40 η 52 52 104 22 Mean (SD) 3.112(3.0612) 3.183 (2.8956) 3.147 (2.9653) 7.650 (5.4542) Median 2,100 2,300 2,150 5,150 Min., Max. 0.30, 13.90 0.30, 16.10 0.30, 16.10 0.60, 18.80

Week 5, Day 1

- 77 043716

η 54 52 106 24 Mean (SD) 1.248 (2.6737) 1.035 (1.0479) 1.143 (2.0379) 2.946 (1.4428) Median 0.400 0.600 0.550 2,550 Min., Max. Week 13, Day 1 0.30, 17.40 0.30, 5.70 0.30, 17.40 0.90, 6.30 η 52 50 102 24 Mean (SD) 1.137(2.4242) 0.908 (0.8104) 1.025 (1.8164) 4.625 (2.5594) Median 0.500 0.600 0.500 3,600 Min., Max. Week 25, Day 1 0.30, 16.90 0.30.3.10 0.30, 16.90 0.40, 11.50 η 49 48 97 23 Mean (SD) 1.090 (0.9932) 1.344 (0.9675) 1.215 (0.9838) 5.043 (2.8221) Median 0.800 1,200 0.900 4,400 Min., Max. Week 49, Day 1 0.30, 6.10 0.30, 4.00 0.30, 6.10 1.90, 14.50 η 46 42 88 20 Mean (SD) 1.802 (1.3956) 1.938 (1.2169) 1.867 (1.3077) 5.145 (2.8201) Median 1,450 1,600 1,500 4,250 Min., Max. 0.30, 8.00 0.30, 4.60 0.30, 8.00 2.10, 10.70

LDL=lower limit of definition.

Max=max.

Min=minimum

P12H = once every 12 weeks. r/s = once a day.

SD=standard deviation.

(a) The baseline value was defined as the value obtained shortly but before the start of study drug administration. A value of <0.1 mIU/ml (NPO) was taken as 0.1 mIU/ml.

(b) The baseline value was defined as the value obtained shortly but before the start of study drug administration. A value of <0.3 IU/L (NLO) was taken as 0.3 IU/L.

The results of this study indicate that the timing and intensity of the decrease in serum testosterone levels observed in patients receiving the formulation of Compound 1 were similar to those observed in the study of healthy elderly men in Example 7. On average, in patients receiving the formulation form of compound 1, serum testosterone levels had fallen below the therapeutic castration threshold of 50 ng/dL (1.7 nmol/L) at visit day 4 (end of day 3) and below the complete castration threshold of 20 ng /dL (0.7 nmol/L) at visit day 1 of week 5. In contrast, in patients receiving leuprolide acetate, serum testosterone levels increased during the first 1-2 weeks of therapy and then decreased to castration levels by day 1 weeks 5. After initiation of treatment with Compound 1, there was no surge in serum testosterone or resulting transient worsening of cancer symptoms. The more rapid decline in PSA during the first 2 weeks with Compound 1 compared to the delayed PSA response with leuprorelin illustrates the rapid onset of action and therapeutic effect of Compound 1-mediated GnRH antagonism. Available data at the end of 24 weeks of administration showed that the PSA response rate was greater than 90% in the majority of patients.

Median CL serum testosterone levels (4 weeks post-treatment) were 72.9 ng/dL for 120 mg Compound 1, compared to 9.8 ng/dL for leuprorelin (Tables 3 and 4). At follow-up visits 8 weeks after discontinuation of treatment, median serum testosterone levels were 329.8 ng/dL for 120 mg of Compound 1 compared with 9.8 ng/dL for leuprorelin. In the CT, 12 weeks after discontinuation of treatment, median serum testosterone levels were 322.8 ng/dL for 120 mg of Compound 1 compared with 13.5 ng/dL for leuprorelin. Serum testosterone levels after cessation of treatment with Compound 1 were higher than levels during therapeutic castration (50 ng/dL or 1.7 nmol/L) 4 weeks after the end of treatment.

- 78 043716

Table 3

Testosterone levels at follow-up visits

Median testosterone ng/dL (range) Connection 1 Leuprorelin R12H η 80 mg once daily η 120 mg once daily η CI 14 90 0(10-9-929-4) 21 72-9 (4-3-362-9) 18 9-8(3-5-108) Observation visits 8 3797 (17-9-480 7) eleven 329-8(21-9-646-6) 15 9-8 (4-3-265 0) KL 15 153-8 (2-9-490-8) 15 322-8 (3-7-602-5) 14 13-5 (4-3-332-9)

C=day.

CI=end of study.

CL = end of treatment.

P12H = once every 12 weeks.

r/s = once a day.

Table 4

Testosterone values (nmol/l) during follow-up

Connection 1

80 mg once a day 120 mg once a day Total Leuprorelin day day (Ν=110) Р12Н (Ν=56) (Ν=54) n (%) (N=24) P(%) P(%) n(%) Initial value (b) η 55 54 109 24 Mean (SD) 13.755 (4.7256) 15.139 (5.4871) 14.441 (5.1404) 11.363 (5.0204) Median 12,700 14,350 13,600 11,120 Min., Max. Week 49, Day 1 5.03, 27.20 4.51.27.03 4,51,27,20 4.30, 24.01 η 44 38 82 20 Mean (SD) 0.526 (0.4621) 0.443 (0.2745) 0.487 (0.3867) 0.478(0.6313) Median 0.380 0.365 0.380 0.300 Min., Max. End of treatment 0.11.2.08 0.10, 1.42 0.10, 2.08 0.10.3.05 η 14 21 35 18 Mean (SD) Median 7.211 (9.2178) 3.125 3.592 (3.7809) 2,530 5.039 (6.6432) 2,530 0.641θ (0.9616) Min., Max. Observation 0.38, 32.27 0.15, 12.60 0.15,32.27 0.12.3.75 η 8 eleven 19 15 Mean (SD) 11.004 (5.9971) 12.886 (6.1331) 12.094 (5.9829) 0.992 (2.2948) Median 13,185 11,450 11,970 0.340 Min., Max. End of study 0.62, 16.69 0.76, 22.45 0.62, 22.45 0,15,9,20 η 15 15 thirty 14 Mean (SD) 6.933 (6.4298) 9.565 (7.6479) 8.249 (7.0702) 1.695(3.0345) Median 5,340 11,210 7.425 0.470 Min., Max. 0.10, 17.04 0.13,20.92 0.10, 20.92 0.15, 11.56

LDL=lower limit of definition.

Max=max.

Min=minimum

P12H = once every 12 weeks.

r/s = once a day.

SD=standard deviation.

(a) The baseline value was defined as the value obtained shortly but before the start of study drug administration. A value of <0.10 nmol/L (NLO) was taken as 0.10 nmol/L.

In patients with 12 weeks of recovery data after stopping 48 weeks of treatment with Compound 1, according to testosterone recovery data, QoL such as AMS (Tables 5 and 6, lower AMS score is better) and sexual activity scores from the EORTC QLQ -PR25 seems to improve more in the compound 1 group than in the leuprolide group.

- 79 043716

AMS Total Score - in treatment time Table 5 Connection 1 Mean (95% CI) 80 mg once daily 120 mg once daily Leuprorelin R12H (N=56) (N=54) (N=24) AMS Total Score Initial value* 55 29-8 (27 1-32-6) 53 29-9 (27-6-32-3) 24 28-3 (24-2-32-3) Percentage change by compared to the original meaning N5, D1 54 3-9 (-2-8-10-6) 52 10-9(2-6-19-1) 24 101(-1-4-21-6) N13, D1 52 14-8(8-1-21-5) 51 17-3 (7-7-26-8) 24 21-9(6-5-37-3) N25, D1 49 20-3 (10-1-30-4) 48 20-4(10-4-30-3) 23 47 0(23-1-70-9) N37, D1 47 21 1 (14-2-34-1) 46 24-5 (13-9-35-1) 22 49-4(22-3-76-5) N49, D1 46 30-1 (18-8-41-4) 41 24-4(13-8-35-0) 21 60-0(32-5-87-4)

Table 6

Total AMS score - after treatment

Average (95% Connection 1 Leuprorelin R12H 80 mg once daily 120 mg once daily DI) (N=56) (N=54) (N=24) KL** 13 30-5 (-2-4-63-3) 16 39-2(21-8-56-5) 13 61 1 (22-7-99-2) Observation 5 31-8(-10-2-73-9) 8 25-2(-12-2-62-5) 14 53-8(18-2-89-4) CI 14 21-9(8-9-34-9) 12 25-3 (-6-1-56-7) 16 49-9(21-0-78-7)

AMS=Aged Male Questionnaire.

CI=confidence interval.

C=day.

CI=end of study.

CL = end of treatment.

P12H = once every 12 weeks.

r/s = once a day.

Data are presented as mean (95% CI) change from baseline and percentage change from baseline at the indicated time points for AMS scores. For the total sum of raw AMS scores, a high number indicates a worsening or increasing number of symptoms.

* Baseline value was defined as the value obtained at the time point closest to the administration of the study drug, but before the administration itself.

** CL, follow-up, and CT quality of life assessments include only patients who did not enter the extension phase, or who did not initiate alternative AAT or continue AAT, after the study visit W49D1 (day 1 week 49).

Efficacy and safety analyzes were performed using the safety population (received >1 dose of study drug). The safety population included 56, 54 and 24 patients in the 80 mg Compound 1, 120 mg Compound 1 and leuprorelin groups, respectively. Safety was assessed by documenting the frequency, severity, and type of treatment-emergent adverse events;

by physical examination (including examination of the anterior chamber of the eye using a slit lamp); and by assessing changes from baseline in body weight, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory parameters.

All adverse events and serious adverse events were documented throughout the study period and for 30 days after the last dose of Compound 1 or for 12 weeks plus 30 days after the last leuprolide injection. Adverse events were coded using the Medical Dictionary for Regulatory Activities version 19.0 and classified according to the National Cancer Institute Common Terminology Criteria version 4.03 (Tables 7 and 8). Safety-related hematology, chemistry, and urinalysis measurements were performed at each visit and analyzed at a central laboratory (LabCorp).

Phospholipidosis was assessed as part of the safety assessment. General security profile with

- 80 043716 of Unit 1 was similar to that observed in the smaller leuprolide study group and did not involve off-target or non-AAT side effects that may affect patient compliance or long-term maintenance. An intensive ophthalmic evaluation of patients treated with Compound 1 was performed to evaluate the presence of phospholipidosis, a side effect of Compound 1 treatment observed in rats in non-clinical toxicity studies. Although cataracts occurred in the Compound 1 groups, only patients treated with Compound 1 and not treated with leuprorelin underwent a comprehensive ocular examination, which included slit-lamp evaluation. A small increase in mean adjusted QT interval, of unknown clinical significance, was observed in all treatment groups, confirming previous observations in patients receiving AAT.

Table 7

Summary of treatment-emergent side effects (population for

safety assessments) and most commonly reported (>10%) side effects η (%) Compound 1 80 mg once daily (N=56) Compound 1 120 mg once daily (N=54) Leuprorelin Р12Н (Ν=24) Any side effect 53 (95) 50 (93) 23 (96) Score >3 side effect 5(9) 4(7) 2(8) Drug-related side effect 44 (79) 45 (83) 18 (75) Serious side effect 6(H) 1(2) 2(8) Side effect leading to discontinuation of study drug 2(4) 2(4) 0 Death 1(2) 0(0) 1(4)

Most common side effects, η (%) Score <2 Score >3 Score <2 Score >3 Score <2 Score >3

Patients with any cause

side effect 48 (86) 5(9) 46 (85) 4(7) 21 (88) 2(8) Hot flush 31 (55) 0 35 (65) 0 15 (63) 0 Tired 11 (20) 0(0) 17 (32) 0 7(29) 0 Cataract ⁵ · 5(9) 0 11 (20) 0 ND ND Increased ALT 5(9) 1(2) 3(6) 0 4(17) 0 Arthralgia 5(9) 0 3(6) 1(2) 1(4) 0

ALT=alanine aminotransferase.

ND=not available.

P12H = once every 12 weeks.

r/s = once a day.

A treatment-emergent side effect was defined as any side effect that occurs after the first dose of drug and up to 30 days after the last dose of compound 1, or 12 weeks plus 30 days after the last dose of leuprorelin. The percentage was calculated based on the total number of patients in the population to assess the safety of the 48-week main period.

*Ophthalmological examinations were performed only for patients receiving Compound 1.

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Table 8 Total score >3 adverse events during the 48-week treatment period Compound 1 _______________________________________ Leuprorelin η (%) 80 mg once daily (Ν=56) 120 mg once daily (Ν=54) Р12Н (Ν=24) Patients with at least one assessment >3 for side effects 9(16) 8(15) 2(8) Increased alanine aminotransferase levels 2(4) 0 0 Increased aspartic aminotransferase levels 2(4) 0 0 Death 0 1(2) 0 Sudden death 0 1(2) 0 Acute coronary syndrome 0 1(2) 0 Arthralgia 0 1(2) 0 Atrial flutter 0 1(2) 0 Bladder cancer 1(2) 0 0 Brain hemorrhage 1(2) 0 0 Cerebrovascular accident 1(2) 0 0 Cervical spine fracture 1(2) 0 0 Tired 1(2) 0 0 Increased gammaglutamyltransferase levels 1(2) 0 0 Hypercalcemia 0 1(2) 0 Hypertension 0 1(2) 0 Hypotension 1(2) 0 0 Inguinal hernia 0 1(2) 0 Dislocation of the joint 1(2) 0 0 Bone metastasis 1(2) 0 0 Musculoskeletal pain 0 1(2) 0 Non-cardiac chest pain 0 1(2) 0 Osteoarthritis 0 1(2) 0 Pain during the procedure 0 1(2) 0 Sepsis 1(2) 0 0 Fainting 0 1(2) 0 Transient ischemic attack 1(2) 0 0 Urinary tract infection 1(2) 0 0 Diabetes 0 0 1(4) Myocardial infarction 0 0 1(4)

Example 9 Study to evaluate the effect of Compound 1 in men with prostate cancer requiring AAT as a neoadjuvant and adjuvant before external beam radiation therapy.

External beam radiation therapy (EBRT) is the standard treatment option for intermediate/high risk prostate cancer. The addition of anti-androgen therapy (AAT) as an adjuvant/neoadjuvant, such as gonadotropin-releasing hormone (GnRH) analogues, to EBRT has demonstrated prolonged overall survival. This study examined the efficacy and safety of oral formulations containing Compound 1 or a pharmaceutically acceptable salt thereof.

Eligible male patients were aged >18 years with histologically confirmed

- 82 043716 diagnosed with localized intermediate-risk prostate cancer, who were prescribed 6 months of neoadjuvant and adjuvant anti-androgen therapy (AAT) before external beam radiation therapy (EBRT). Criteria to justify intermediate-risk prostate cancer included the presence of one of the following without any high-risk feature: T2LT2c disease, Gleason score 7, or prostate-specific antigen (PSA) 10-20 ng/mL. Additional entry criteria included: EBRT scheduled to begin >12 weeks after baseline visit; serum testosterone level >150 ng/dL (5.2 nmol/L) at screening; PSA concentration >2 ng/ml at screening; body mass index >18.0 at screening or baseline (i.e., subject's pretreatment BMI); performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) at screening. Based on the discretion of the investigator and clinical assessment of the patient's general medical condition and disease status, participation was permitted in elderly patients at high risk of disease (eg, based on Gleason score or tumor status) who were considered likely to benefit from 6 months of neoadjuvant/ adjuvant AAT. Most patients had intermediate-risk disease. However, several patients, based on Gleason score or tumor, node, and metastasis staging system, were technically above average risk.

Patients were excluded with previous or current use of a gonadotropin-releasing hormone analogue or androgen receptor antagonist as first-line hormonal therapy (excluding cases where the total duration of treatment was <6 months and was completed >1 year before the scheduled baseline visit), history another malignancy within 2 years before the first dose of study drug, or a previous malignancy with evidence of residual disease. Additional exclusion criteria included the presence of an underlying disease with clinical manifestations.

In this study, patients received 120 mg of the oral formulation of the compound once daily (with a loading dose of 320 mg on day 1) or 80 mg of degarelix p-cutaneous. once every 4 weeks (R4W) (with a loading dose of 240 mg on the 1st day). Both treatment groups received treatment for 24 weeks. Patients remained on treatment for at least 12 weeks before the start of external beam radiotherapy (EBRT), which was started for most patients between day 1 of week 13 and day 1 of week 15. EBRT began no later than day 1 of week 17.

The 120 mg formulation of Compound 1 contained a tablet base of Compound 1 (120 mg), mannitol (366 mg), microcrystalline cellulose (60 mg), hydroxypropylcellulose (18 mg), croscarmellose sodium (30 mg) and magnesium stearate (6 mg). The tablet base was coated with a film coating containing hypromellose 2910 (21.36 mg), titanium dioxide (2.4 mg) and red iron oxide (0.06 mg). The amounts of excipients in the tablet base and film coating were adjusted accordingly depending on the amount of Compound 1 in the tablet base (e.g., for a 360 mg tablet, the amount of excipient added to the tablet base and film coating was three times greater than the amount added in the 120 mg tablet). mg tablet).

Patients were assessed every 4 weeks during the treatment period (including day 1 of week 25), at the end of treatment (defined as week 29), during the observation period (week 33) and at the end of the study (EC). The CL visit was defined as week 37, or 12 (compound 1) or 16 (degarelix) weeks after the last dose of study drug, whichever occurred first.

Samples for testosterone, luteinizing hormone (LH), FSH and PSA were taken at screening, on day 1 of week 1 (additionally days 2 and 4 for testosterone and LH) and on day 1 of weeks 2, 3, 5, 9, 13, 17 , 21, 25, 29, 33 and 37 after that. On average, in patients receiving the formulation of Compound 1, PSA levels had decreased to <0.2 ng/mL at Day 1 visit week 13. By Day 4, LH levels were low in both Compound 1 and degaralix treatment groups (Compound 1: 0.462 mIU/ml; degarelix: 0.499 mIU/ml). FSH levels were not available at this time point; however, a decrease from levels before administration of compound 1 or degarelix (compound 1: 11.826 IU/L; degarelix: 11.716 IU/L) was noted on day 1 of week 2 (compound 1: 2.363 IU/L; degarelix: 2.519 IU/L ) for both groups. FSH suppression was less pronounced than that for LH, but consistent with the literature, and was greater than that observed for GnRH agonists. Mean LH and FSH levels remained low before the visit on day 1 of week 25 for both groups (compound 1, LH: 0.325 IU/L; degarelix, LH: 0.342 IU/L; compound 1, FSH: 1.475 IU/L; degarelix, FSH : 1.471 IU/l).

Quality of life (QoL) was assessed using the 30-item core questionnaire, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the 25-item Prostate Cancer Questionnaire, the EORTC Questionnaire (EORTC QLQ-PR25), and the aged men (AMS). Quality of life assessments were performed at screening, on the first day of weeks 1, 5, 13 and 25, and at weeks 29, 33 and 37.

The timing and intensity of the decrease in serum testosterone levels observed in patients in this study receiving the formulation of Compound 1 were similar to those observed

- 83 043716 were given during the study in healthy elderly men in Example 7, and during the study in patients with prostate cancer in Example 8. Serum testosterone levels were measured at each visit. On average, in patients receiving formulation 1, serum testosterone levels fell below the therapeutic castration threshold of 50 ng/dL (1.73 nmol/L) at visit day 4 (end of day 3) and below threshold value for complete castration of 20 ng/dL (0.69 nmol/L) at visit per day 1 week 5.

For this study, the decrease in serum testosterone levels from day 1 to day 15 showed a rapid decrease within the first 24 hours and averaged below therapeutic castration levels of serum testosterone 72 hours (day 4 of week 1) after the start of administration (or loading dose injection). The effect of 120 mg of the compound once daily on reducing serum testosterone over 25 weeks was as consistent as that of the injectable analogue antagonist degarelix. At the end of 8 weeks of administration (before initiation of radiation therapy), in patients with hormone-sensitive cancer in whom the prostate gland and tumor remain in situ, the % PSA responses were less than observed in the study in Example 8, but still exceeded 89% in the majority patients. The PSA responses between the formulation 1 and degarelix treatment groups appear to be similar. The proportion of patients achieving PSA values less than 0.2 ng/mL at the end of 12 weeks was 6 of 30 patients for the formulation 1 group and 1 of 20 patients for the degarelix group.

Rates for therapeutic castration (less than 50 ng/dL) and complete castration (less than 20 ng/dL) were determined over the entire 24-week course for subjects receiving at least 12 weeks of treatment and for subjects receiving at least 12 weeks of treatment. at least 24 weeks. Overall, rates for both therapeutic castration and complete castration at 24 weeks were higher for Compound 1 (95% and 82%, respectively) compared to the degarelix group (89 and 68%, respectively), as shown in FIG. 49. Subjects who completed at least 12 weeks of treatment had generally similar castration rates. In subjects who completed at least 24 weeks of treatment, there continued to be a trend of higher castration rates when treated with Compound 1 (98 and 84% for therapeutic castration and deep castration, respectively) compared to degarelix (86 and 71% for therapeutic castration and deep castration). castration, respectively), as shown in Fig. 49.

The time to serum testosterone levels reaching therapeutic castration (less than 50 ng/dL [1.73 nmol/L] and less than 20 ng/dL [0.69 nmol/L]) and the estimated time to recovery of serum testosterone levels (including estimated percentage of patients who recovered to baseline and percentage of patients who recovered to more than 280 ng/dL within 12 weeks after treatment).

Time to castration was found to be comparable between treatment groups. The median time to therapeutic castration (<50 ng/dL) was 4 days (95% CI: 2-4) for the compound 1 group, and 3 days (95% CI: 2-4) for the degarelix group. The median time to complete castration (<20 ng/dL) was 15 days (95% CI: 8-15) for the compound 1 group and 12 days (95% CI: 8-15) for the degarelix group.

After discontinuation of therapy, mean serum testosterone levels in the degarelix group remained low until the end of the study. For the compound 1 group, serum testosterone levels increased to approximately 10 nmol/L at the control visit and at the end of the study (1.7 nmol/L is the level at therapeutic castration). As shown in FIG. 50, the time to restore serum testosterone to baseline levels or above 280 ng/dL was shorter for Compound 1 compared to the degarelix group. Twelve weeks after treatment, approximately 43% of subjects achieved pre-treatment serum testosterone levels or serum testosterone levels equal to or greater than 280 ng/dL by week 12, compared to only 5.3% for degarelix (Table 9). Results were similar for patients who received treatment for at least 12 weeks or 24 weeks. Based on the achievement of baseline serum testosterone levels or greater than 280 ng/dL serum testosterone concentrations, the compound 1 group showed faster achievement of these levels compared to the degarelix group (Fig. 53).

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Table 9

Testosterone values and time to testosterone recovery (baseline levels or >280 ng/dL [9.72 nmol/L]) for the entire safety cohort

Compound 120 mg once daily (Ν=65) Degarelix 80 mg once daily (N=38) Initial value ⁶ P 65 38 Mean (SD) 14.067 (6.7100) 14.567 (5.5680) Median 12,350 14,020 Min., Max. 5.17, 44.76 4.79, 32.55 Week 25, Day 1 P 64 37 Mean (SD) 0.395 (0.5584) 0.582 (1.5107) Median 0.280 0.310 Min., Max. 0.11.4.34 0.10, 9.47 KL η 61 38 Mean (SD) 5.117 (5.7671) 0.576 (1.2218) Median 3,260 0.335 Min., Max. 0.10, 28.42 0.10, 7.81 Observation η 62 37 Mean (SD) 9.889 (6.3879) 1.206 (1.9330) Median 8,275 0.560 Min., Max. 0.35, 32.24 0,11,9,13 CI P 61 38 Mean (SD) 9.661 (5.4611) 3.038 (4.0224) Median 8,920 1,040 Min., Max. 0.33.29.81 0.13, 13.15 Time to testosterone recovery (day) Number with events, and (%) 34 (52) 6(16) Number of unaccounted for, η (%) 30 (46) 32 (84) 25th percentile (95% CI) 57 (45.62) 100 (87,106) Median (95% CI) 91 (62,127) 100 (100,106) 75th percentile (95% CI) 127 (93.127) 106 (100,106) Min., Max. 7*,127 58.106 Kaplan-Meier estimate ^c (95% CI) 4 weeks after last dose ^a 0.03 (0.00, 0.08) 0.00 (0.00, 0.00) 8 weeks after last dose ^a 0.24 (0.13, 0.34) 0.00 (0.00, 0.00) 12 weeks after last dose ^a 0.45 (0.33, 0.58) 0.06 (0.00, 0.13) Percent recovery (95% CI) ^a 4 weeks after last dose ^a ZD (0.4, 10.7) But 8 weeks after last dose ^a 23.1 (13.5, 35.2) But 12 weeks after last dose ^a 43.1 (30.8, 56.0) 5.3 (0.6, 17.7)

(a) Time to testosterone recovery was defined as the time from day 1 after the last dose of compound 1 or day 1 plus 4 weeks after the last dose of degarelix until testosterone recovery. Testosterone recovery was defined as return to baseline or >280 ng/dL, whichever occurred first. It was censored for patients starting alternative AAT without recovery at the last laboratory testosterone assessment before starting AAT.

(b) The baseline value was defined as the value obtained at the time point closest to the administration of the study drug, but before the administration itself. A value <0.10 nmol/L (LLQ) was arbitrarily designated as 0.10 nmol/L.

(c) Probability of event (n=number of patients at risk).

(d) 4, 8 or 12 weeks from day 1 after the last dose of compound 1 or day 1 plus 4, 8 or 12 weeks after the last dose of degarelix.

A summary of time to serum testosterone recovery based on Kaplan-Meier estimates for the entire safety cohort is presented in FIG. 51. The median (95% CI) number of days to recovery was 91 (62, 127) days for the compound 1 group, and 100 (100, 106) days for the degarelix group. Patients treated with Compound 1 were more likely to achieve serum testosterone recovery throughout

- 85 043716 study compared to patients treated with degarelix, as shown in FIG. 51. For patients treated for at least 12 weeks, results were the same as for the entire safety cohort. For patients treated for at least 24 weeks, results were relatively similar to the overall results for both groups; however, for the compound 1 group, the median (95% CI) number of days to recovery was 86 (58, 93) days, and the percentage of recovery (95% CI) by week 12 after the last dose was 46.0% (31.8, 60, 7%). When serum testosterone recovery was assessed separately as return to baseline or greater than 280 ng/dL, there was a higher likelihood of achieving >280 ng/dL compared with achieving baseline serum testosterone levels for the Compound 1 group.

After discontinuation of therapy at the end of 24 weeks, patients were followed for an additional 12 weeks to assess serum testosterone recovery and associated changes in PSA and quality of life. At the end of the observation period, approximately half of the patients receiving Compound 1 had recovered to either baseline testosterone values or greater than 280 ng/dL, whichever was less, compared with only 6% of patients receiving degarelix. In the degarelix group, there was a relatively small recovery of LH and mean serum testosterone levels remained <50 ng/dL at the end of the study visit; Serum testosterone levels met the definition of recovery in only 6 of 38 patients. Patient-reported outcomes were similar in both treatment groups during the first 12 weeks of treatment, consistent with acute therapeutic castration. In the group treated with Compound 1, there was a trend toward a more rapid improvement in hormonal and sexual symptoms (eg, hot flashes).

Median testosterone at the week 28/CL visit was 93.9 ng/dL (Table 10). This was 4 weeks after stopping Compound 1. Thus, median testosterone 4 weeks after stopping treatment was well above the castration threshold of 50 ng/dL. In comparison, median testosterone was 9.6 ng/dL for degarelix at the same time point (week 28/CL), 16.1 ng/dL 8 weeks without administration (week 32/follow-up), and 30.0 ng/dL 12 weeks without administration (week 36/CT). Thus, for the injectable GnRH antagonist (degarelix), testosterone was still reduced to below the castration threshold 12 weeks after the 24-week study (16 weeks after the last monthly degarelix injection).

Table 10

Recovery of LH and testosterone over time from related PSA levels

Compound 1, 120 mg once daily (N=65) Degarelix, 80 mg P4H (N=38) Median LH value mIU/ml (range) Median testosterone ng/dL (range) Median PSA value, µg/L (range) Median LH value mIU/ml (range) Median testosterone value per ng/dL (range) Median PSA value, µg/L (range) Original value 4-7 (0-8-32-2) 355-7 (148-9-1289-1) 7-3 (2-6-31-5) 4-8 (1-3-42-0) 403-8 (138-0- 937-4) 7-3 (2-5-88-9) Week 24 0-1 (01-3-9) 8-1 (3-2-125-0) 0-07 (0-07-1-6) 0-1 (0-1-3-7) 8-9 (2-9-272-7) 0-1 (0-07-1-9) Week 28/visit KL 3-1 (0-2-15-7) 93-9 (2-9-818-5) 0-07 (0-07-1-5) 0-2 (01-2-8) 9-6 (2-9-224-9) 0-07 (0-07-2-1) Week 32/observation 8-3 (0-1-32-4) 238-3 (10-1-928-5) 0-2 (0-07-3-2) 0-5 (0-1-7-7) 161 (3-2-262-9) 0-07 (0-07-2-2) Week 36/CT 10-7 (0-1-38-7) 256-9 (9-5-858-5) 0-2 (0-07-2-3) 1-4 (0-1-15-7) 30-0 (3-7-378-7) 0-07 (0-07-2-0)

CI=end of study.

CL = end of treatment.

LH=luteinizing hormone.

PSA=prostate specific antigen.

P4H = once every 4 weeks.

r/s = once a day.

From CL to CI, QOL indices such as AMS and sexual activity scores appeared to improve more in the Compound 1 group than in the degarelix group, consistent with the observed pattern of testosterone recovery (Table 11). After discontinuation of study drug treatment at the end of week 24 (or 4 weeks after the last degarelix injection on day 1 of week 21), testosterone recovery and associated changes in PSA were observed for an additional 12 weeks. Nearly half of patients treated with compound 1 recovered to baseline values or >280 ng/dL by week 8 of follow-up, with little apparent recovery during those

- 86 043716 for the next 4 weeks (12 weeks of observation). In contrast, only 6% of patients treated with degarelix recovered by week 12 of follow-up. There were minimal differences in PSA change during the recovery period, with an increase of about 0.2-0.4 ng/mL in patients receiving Compound 1. Based on the relative stability between the 8- and 12-week follow-up period, this recovery could be due to with PSA secretion from residual normal prostate rather than tumor tissue. The results suggest that rapid testosterone recovery in the compound 1 group after 24 weeks of neoadjuvant adjuvant before EBRT for intermediate-risk prostate cancer does not pose a significant risk to long-term treatment outcomes.

Table 11

Change in QoL during treatment (from baseline to week 25) or recovery (from week 25 to week 36)

General health/QoL* Sexual activity Symptoms associated with hormonal treatment** Compound 1, 120 mg once daily (N=65) Degarelix, 80 mg P4H (N=38) Compound 1, 120 mg once daily (N=65) Degarelix, 80 mg P4H (N=38) Compound 1, 120 mg once daily (N=65) Degarel X, 80 mg P4H (N=38) Change from baseline to week 25 (day 1) η 60 38 60 38 60 38 Mean (SD) -101 (18-9) -7-5 (13-7) -19-7 (29-4) -11-8(36-3) 13-4 (121) 12-9 (10-4) Change from week 25 to week 36 η 58 38 58 38 58 38 Mean (SD) 2-3 (16-6) 0-7 (15-5) 121 (21-8) 6-6 (22-8) -50 (10-3) -1-2 (9 1) Change from baseline to week 36 (CT) η 62 38 62 38 62 38 Mean (SD) -7-7(17-8) -6-8(16-0) -7-3 (30-0) -5-3 (34-7) 8.5 (11.3) 11-7 (10-2)

CI=end of study,

Р4Н=once every 4 weeks, r/s=once a day,

QoL=quality of life,

SD=standard deviation.

*Higher scores for general health/QoL and sexual activity reflect better QoL.

* * Higher scores for hormonal treatment-related symptoms reflect worse QoL.

In summary, this study demonstrated a rapid and sustained decrease in serum testosterone levels over 24 weeks of treatment. Importantly, in this study, the recovery of serum testosterone after the last drug dose was more rapid in the Compound 1 group than in the degarelix group.

Example 10: Phase 1, open-label, randomized, three-way crossover study evaluating the relative bioavailability and dietary effects of a tablet formulation of Compound 1 in healthy subjects.

This was an open-label, randomized, three-way, single-dose crossover study designed to evaluate the oral bioavailability of two tablet formulations of Compound 1 (T4 Formulation B and T4 Formulation C) relative to a third tablet formulation of Compound 1 (T2 Formulation) and the effects of food. on the PK of compound 1 after oral administration of T4 formulations B and C. There were five single dose treatment regimens.

Schedule A: compound 1, 120 mg dose of T2 ready-made form under fasting conditions.

Regimen B: compound 1, 120 mg T4 prepared form B under fasting conditions.

Schedule C: Compound 1, 120 mg T4 Formulation B under fed conditions (US Food and Drug Administration [FDA] standard high-fat, high-calorie breakfast).

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Regimen D: compound 1, 120 mg T4 prepared form C under fasting conditions.

Schedule E: Compound 1, 120 mg T4 Preformed Form C under fed conditions (US FDA standard, high fat, high calorie breakfast).

Screening assessments were conducted for 28 days prior to day 1 of Compound 1. After eligibility was confirmed, subjects were randomly assigned to a sequence of one of two treatment groups.

Group 1: T2 ready-made form (scheme A serves as control) and T4 ready-made form B (schemes B and C).

Group 2: T2 ready-made form (scheme A serves as control) and T4 ready-made form C (schemes D and E).

In each study arm, each subject participated in 3 treatment periods with a 10-day washout interval between each dose. Subjects received a single oral dose of 120 mg of compound 1 on day 1, day 11, and day 21 for the assigned group and sequence, followed by serial blood draws for PK assessment at predetermined time points up to 120 hours after administration. During each of the 3 treatment periods, subjects were limited to the clinical center for a total of 4 days. Each eligible subject was screened at the clinical center on the evening of Day 1 and completed a baseline safety assessment.

Subjects were restricted to the clinical center from days 1 to day 4. After blood collection for FC assessment on day 4 (72 hours post-dose), patients were discharged from the clinical center. Subjects were instructed to return to the study clinic on the morning of Day 5 for the 96-hour FC assessment, and on the morning of Day 6 for the 120-hour FC assessment. Subjects were required to return to the study clinic on the evening of day 10 and were limited to being there from days 10 to 14. After blood collection on day 14 (72 hours post-dose), patients were discharged from the clinical center. Subjects were instructed to return to the study clinic on the morning of day 15 for the 96-hour FC assessment, and on the morning of day 16 for the 120-hour FC assessment. Subjects were required to return to the study clinic on the evening of day 20 and were limited to being there from days 20 to 24. After blood collection for FC assessment on day 24 (72 hours post-dose), patients were discharged from the clinical center. Subjects were instructed to return to the study clinic on the morning of Day 25 for the 96-hour FC assessment and on the morning of Day 26 for the 120-hour FC assessment. The study drug was administered in the morning of days 1, 11 and 21 in a fed or fasted state. While at the center, subjects received standardized meals provided at the same time every 24 hours. For each subject, vital sign data, physical examination data, adverse event (AE) scores, laboratory values (chemistry, hematology, and urinalysis), and 12-lead electrocardiograms (ECG) were obtained to assess the safety and tolerability of Compound 1. It was believed that that subjects completed the study if they completed each of the 3 treatment periods and completed the end-of-study (ES) assessment (30 days after the last dose of study drug). Subjects may discontinue participation in the study at any time. Each subject was required to be a healthy adult male between the ages of 18 and 55 years (inclusive) to be included in this study. Table 12 and 13 provide summary data for treatment group 1 and treatment group 2 of the study.

Table 12

Sequence of treatment periods of group 1

Subsequence Period ³ 1 Period ³ 2 Period ³ 3 1 Scheme A ^b Scheme B ^c Scheme C ^d 2 Scheme A: Scheme C: Scheme B: 3 Scheme B: Scheme A: Scheme C: 4 Scheme B: Scheme C: Scheme A: 5 Scheme C: Scheme A: Scheme B: 6 Scheme C: Scheme B: Scheme A:

(a) The duration of each treatment period was 10 days. Subjects received single doses of Compound 1 on the first day of each treatment period (ie, day 1, day 11, and day 21).

(b) Schedule A: Compound 1, 120 mg dose (80+40 mg tablets) T2 formulation under fasting conditions.

(c) Schedule B: Compound 1, 120 mg dose (1x120 mg tablet) T4 formulation B under fasting conditions.

(d) Schedule C: Compound 1, 120 mg (1x120 mg tablet) T4 Formulation B under fed conditions (US FDA standard, high fat, high calorie breakfast).

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Table 13

Sequence of treatment periods of group 2 Subsequence Period ³ 1 Period ³ 2 Period ³ 3 1 Scheme A ^b Scheme D ^e Scheme E ^d 2 Scheme A: Scheme E: Scheme D: 3 Scheme D: Scheme A: Scheme E: 4 Scheme D: Scheme E: Scheme A: 5 Scheme E: Scheme A: Scheme D: 6 Scheme E: Scheme D: Scheme A:

(a) The duration of each treatment period was 10 days. Subjects received single doses of Compound 1 on the first day of each treatment period (ie, day 1, day 11, and day 21).

(b) Schedule A: Compound 1, 120 mg dose (80+40 mg tablets) T2 formulation under fasting conditions.

(c) Schedule D: Compound 1, 120 mg (1x120 mg tablet) T4 Formulation C under fasting conditions.

(d) Schedule E: Compound 1, 120 mg (1x120 mg tablet) T4 formulation C under fed conditions (US FDA standard, high fat, high calorie breakfast).

A total of 54 subjects were enrolled and completed the study. There were 27 subjects in each study group. All 54 subjects were included in the safety population and the PK population. There were no major protocol deviations for any subjects during this study. One subject had a minor protocol deviation related to the dosing interval that occurred more than 30 minutes after the start of breakfast. In Period 3, the subject was administered T4 formulation B under fed conditions; the start time of dosing of Compound 1 after the start of breakfast was 31 minutes and 3 seconds. All PK parameters for a given subject following oral administration of T4 Formulation B under fed conditions were generally similar to the mean PK parameter values in that treatment group; therefore, a given subject's PK parameters were included in the descriptive and statistical analyzes of variance. In table 14 and 15 below provide summary data on some pharmacokinetic parameters after administration of various finished forms.

Table 14

Summary statistics of the pharmacokinetic parameters of Compound 1 in plasma following a single oral administration of 120 mg of Compound 1 tablet formulation T4 B or C compared to tablet formulation T2 under fasted conditions „ .. Group Groups

Statistical a 2* parameter (unit of measurement)

Form T2. Form T4. IN Form T2. Form T4. WITH N 27 26 27 27 tmax ( ^h ) Median 2.01 3.00 3.00 3.00 Min., Max. 0.500, 6.00 0.502, 12.0 0.499, 6.02 0.499, 12.0 Stakh (NG/ML) sg 46.7 42.0 52.0 43.5 sq% 115 153 93.3 147 AUC120 (ng"h/ml) SG 447 440 532 415 sq% 64.7 83.3 55.4 85.1 AUCco (ng"h/ml) SG 476 467 563 440 sq% 63.5 82.8 55.1 84.8 tl/2z (h) Average 36.3 36.1 ^a 34.9 35.5 CO 4.40 4.90 4.13 4.22 Min., Max. 28.8, 46.5 27.4, 44.7 29.2, 44.8 25.4, 46.0

KB=geometric coefficient of variation.

SG=geometric mean.

(a) N=27.

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Table 15

Summary statistics of the pharmacokinetic parameters of compound 1 in plasma after a single oral administration of 120 mg of compound 1 in the form of tablet formulation T4 B or C under food conditions

Statistical parameter (unit) T4 ready form B T4 finished form C N 27 27 tmax (i) Median 3.00 3.00 Min., Max. 0.500, 8.00 1.00, 8.00 Stakh (NG/ML) sg 33.0 41.2 sq% 116 106 AUC120 (ng"h/ml) SG 350 386 sq% 65.0 52.4 AUCco (ng"h/ml) SG 372 409 sq% 64.1 51.8 ti/2z (h) Average 35.1 35.4 CO 4,I 2.97 Min., Max. 29.9, 45.7 29.9, 42.2

CV=geometric coefficient of variation.

SG=geometric mean.

All subjects included in this study were healthy men, the majority of whom were white (81%) and Hispanic or Latino (65%). The overall mean (SD) age of the subjects was 38.9 (10.8) years, with an age range of 19 to 55 years. The overall mean (SD) body weight and BMI of the subjects were 83.4 (12.7) kg and 27.2 (3.2) kg/ ^m2 , respectively. Demographic characteristics were similar for both treatment groups. No subjects were excluded from the population assessed by FC; therefore, the demographics for this population were the same as for the safety population. Composition information for the various formulations used in this example and other exemplary formulations is presented in Table 1. 16.

Table 16 Illustrative ready-made forms

Function 1-20 mg (T1) 40 mg (T2) 40 mg (TZ) 40 mg (T4-B) 120 mg (T4-B) 120 mg (T4-C) Connection 1 Another substance in the medicine 1-20 40 40 40 120 120 Mannitol Thinner 80-61 122 122 51 153 234 Microcrystalline cellulose Thinner 10 20 40 - - thirty Polyethylene ikol 8000 Lubricant - - - - - 1.8 Hydroxypropylcellulose Binder 3 6 6 3 9 P,4 Croscarmello sodium for Baking powder 5 10 10 - - 19.05

-90043716

Sodium starch glycolate Baking powder - - - 5 15 - Magnesium stearate Lubricant 1 2 2 1 3 3.75 Purified water* solvent how many Oh will be required how much do you need I'll bet how much do you need I'll bet how much will it take how much will it take how much is needed From everything (Tablet base) 100 220 220 100 300 420 Hypromellose 2910 Film coating 2.93 7.12 7.12 3.56 10.68 13.5 Polyethylene ikol 8000 plasticizing additive 0.67 - - - - - Titanium dioxide Pigment 0.33 0.8 0.8 0.4 1.2 1.5 Iron oxide, red Dye 0.07 0.02 0.02 0.04 0.12 0.15 Iron oxide, yellow Dye - - 0.06 - - - Purified water* how many Oh will be required How many required how much do you need I'll bet how many Oh will be required how many Oh will be required how much is needed From everything (film coating layer) 4 8 8 4 12 15.15 Total 104 228 228 104 312 435.15 Carnauba wax - - 0.012 0.004 0.008 how much is needed

Example 11 Study to evaluate the safety and efficacy of Compound 1 in patients with advanced androgen-sensitive prostate cancer.

This study is a phase 3, multinational, randomized, open-label, parallel-group study to evaluate the safety and efficacy of Compound 1, or its pharmaceutically acceptable salt, in patients with advanced androgen-sensitive prostate cancer who require at least 1 year of continuous treatment. anti-androgen therapy (Fig. 54). Compound 1 is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that reduces testosterone levels by inhibiting pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Patients with prostate cancer who require anti-androgen therapy will be given 120 mg of the compound orally once daily or 22.5 mg of leuprolide acetate suspension depot (or 11.25 mg in some Asian countries) every 3 months (3- M). This study will evaluate the ability of Compound 1, or a pharmaceutically acceptable salt thereof, to achieve and maintain reductions in serum testosterone at castration levels (<50 ng/dL [1.7 nmol/L]) for 48 weeks in patients with advanced developmental disease. androgen-sensitive prostate cancer.

To be eligible for the study, the patient must be, in the opinion of the investigator, a candidate for at least 1 year of continuous anti-androgen therapy for the treatment of advanced androgen-sensitive prostate cancer and must not be a candidate for

- 91 043716 surgical treatment. Eligible patients include those with evidence of biochemical relapse (rising PSA level) after local primary intervention for curative purposes, newly diagnosed metastatic disease (excluding brain metastases) and/or local advanced disease. Patients may undergo radiation therapy, cryotherapy, or high-frequency ultrasound no sooner than 2 months after starting antiandrogen therapy. Patients could be included if they had not previously received anti-androgen therapy for more than 12 months, and if anti-androgen therapy had been completed at least 12 months before the study baseline. Patients who were previously treated with taxanes or were expected to receive taxanes after initiation of anti-androgen therapy were excluded, as were patients receiving anti-androgen therapy as an adjuvant or neoadjuvant before radiation therapy as primary definitive therapy. Baseline serum testosterone must be >150 ng/dL (5.2 nmol/L) to be included in the study.

Patients enrolled in this study will be randomized 2:1 to receive 120 mg of compound 1 orally once daily after a loading dose of 360 mg daily 1 or 22.5 mg of leuprolide acetate 3-M depot (or 11.25 mg in some Asian countries), plus an anti-androgen for the first 4 weeks or longer if indicated in the investigator's report. Randomization will be stratified by geographic region, presence of metastatic disease, and age.

Approximately 1,125 patients will be enrolled in this study from approximately 200 study sites in the Americas, Europe and Asia-Pacific. The study includes a screening period of up to 28 days, a treatment period of 48 weeks, and an observation period of up to 90 days (with visits at 30 and 60 days after the end of the treatment period). In addition, unscheduled follow-up visits may be arranged for patients with study safety concerns as needed. Eligible patients will receive study treatment for 48 weeks. During this time, testosterone and PSA will be assessed monthly and patient-reported outcomes (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30, European 5-item Quality of Life Questionnaire with 5 levels each [EuroQol EQ-5D -5L]) will be assessed approximately every 3 months during the treatment period and more frequently during the observation period. Additional serum hormonal tests will include LH, FSH, dihydrotestosterone, and sex hormone binding globulin. Compound 1 pharmacokinetic (PK) samples will be collected throughout the study. Full PK profiles will be determined in a subgroup of patients in Asia. Time to testosterone recovery will be measured in approximately 100 patients randomized to Compound 1 and approximately 50 patients randomized to leuprolide acetate who complete 48 weeks of treatment and who do not plan to initiate alternative anti-androgen therapy within the next 12 weeks (or within 24 weeks after the last injection of leuprolide acetate depot 3-M). Safety assessments will include treatment-emergent side effects, vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms (ECGs), and visual acuity tests.

Patients with disease progression during the treatment period in the setting of testosterone levels declining to castration levels (testosterone levels <50 ng/dL [1.7 nmol/L]) should remain on study and may receive additional oral therapy, systemic antineoplastic therapy, and/or or radiation therapy as prescribed by the investigator.

The primary endpoint of the study is the rate of sustained castration, defined as the cumulative probability of a decrease in testosterone levels to >50 ng/dL (1.7 nmol/L) during treatment from day 1 week 5 (day 29 of the study) to day 1 week 49 (day 337 of the study).

Secondary endpoints include castration rate, defined as the cumulative probability of testosterone levels decreasing to >50 ng/dL (1.7 nmol/L) pre-challenge on day 4 of week 1, pre-challenge on week 2, and pre-challenge on week 3;

complete castration rate, defined as the cumulative probability of testosterone levels decreasing to >20 ng/dL (0.7 nmol/L) during study treatment from day 1 week 25 to day 1 week 49;

time to testosterone recovery in the first 100 patients randomized to compound 1, or its pharmaceutically acceptable salt, and in the first 50 patients randomized to leuprolide acetate who completed 48 weeks of treatment and who do not plan to initiate alternative anti-androgen therapy within the next 12 weeks (or within 24 weeks after the last injection of leuprolide acetate 3-M depot);

proportion of patients with a confirmed PSA response according to Working Group 3 Clinical Trials Guidelines for Prostate Cancer at the 2- and 5-week visits;

proportion of patients with PSA concentration <0.2 n/mL (0.2 μg/L) at week 25 visit;

absolute values and changes from baseline in domain general scores

- 92 043716 health EORTC-QLQ-C30, and sexual activity EORTC-QLQ-PR25, and subdomains for symptoms associated with hormonal treatment, at regular intervals during treatment and, if necessary, during observation and/or visit end of treatment;

absolute values and changes from baseline in the remaining EORTC-QLQ-C30 and EORTC-QLQ-PR25 domains, and in the EuroQol EQ-5D-5L at regular intervals during treatment and, if applicable, at follow-up visits ;

frequency of side effects;

frequency of abnormal clinical laboratory data;

hormonal markers of the effects of compound 1 and leuprolide acetate, measured as absolute value and change from baseline for: LH at visits week 2, week 3 and week 5, and then every 4 weeks until the last screening visit; FSH at visits at week 5, week 13, week 25, week 37 and week 49; dihydrotestosterone at visits at week 13, week 25, week 37, and week 49; and sex hormone binding globulin at visits at week 13, week 25, and week 49;

concentration of compound 1 in blood plasma before administration;

PK parameters of compound 1 in plasma for single and repeated dosing, such as maximum plasma concentration ( _Cmax ), area under the concentration-time curve from time 0 to the end of the dosing interval (AUC _0- t), and time to maximum concentration at plasma ( _tmax ) in a subgroup of Asian patients at visit day 1.

Study endpoints include overall survival, defined as the time from randomization to the date of death to the cutoff date; and the presence of polymorphisms in germline genes associated with the hypothalamic-pituitary androgen pathway, prostate cancer risk, or drug-metabolizing enzymes and transport proteins that may be associated with the localization, safety, or efficacy of Compound 1.

Exemplary Embodiments

Some embodiments of the present invention relate to Embodiment I as follows.

Embodiment I-1. A method of treating prostate cancer in a subject in need of increasing serum testosterone levels above 50 ng/dL, comprising administering to the subject once daily an oral formulation containing from about 80 mg to about 480 mg of N-(4-( 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-nurudazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d ]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, wherein when once daily dosing is suspended for the period of suspension, the subject experiences an increase in serum testosterone levels.

Embodiment I-2. A method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a once daily oral formulation containing from about 80 mg to about 480 mg K-(4-(1-(2,6-difluorobenzyl)- 5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)- N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof;

suspending administration of the oral formulation for a period of suspension to allow serum testosterone levels to increase; and resuming administration of the once daily oral formulation to the subject at the end of the suspension period.

Embodiment I-3. Method according to embodiment I-1, characterized in that after a period of suspension, administration is not resumed.

Embodiment I-4. The method according to embodiment I-2, characterized in that the level of serum testosterone is increased above the level during therapeutic castration.

Embodiment I-5. The method of any of the preceding embodiments, wherein the serum testosterone level is increased above about 55 ng/dL.

Embodiment I-6. The method of any of the preceding embodiments, wherein the serum testosterone level is increased above about 350 ng/dL.

Embodiment I-7. The method of any one of embodiments I-1-I-3, wherein the serum testosterone level is increased to from about 300 to about 600 ng/dL.

Embodiment I-8. The method of any of the preceding embodiments, wherein the serum testosterone level is increased to the subject's serum testosterone level prior to administration of the oral formulation.

Embodiment I-9. The method of Embodiment I-8, wherein the serum testosterone level is increased to the subject's serum testosterone level prior to administration of the oral formulation within 7 days of the start of the suspension period.

- 93 043716

Embodiment I-10. The method of Embodiment I-8, wherein the serum testosterone level is increased to the subject's serum testosterone level prior to administration of the oral formulation within 45 days of the start of the suspension period.

Embodiment I-11. The method according to any of the previous embodiments, characterized in that the increase in serum testosterone levels occurs within 7 days after the start of the suspension period.

Embodiment I-12. The method according to any of the previous embodiments, characterized in that the prostate cancer is a hormone-dependent prostate cancer.

Embodiment I-13. The method according to any of the previous embodiments, characterized in that the prostate cancer is a late stage of prostate cancer.

Embodiment I-14. The method of any of the preceding embodiments, wherein the prostate cancer is metastatic, non-metastatic, advanced localized cancer, advanced hormone-sensitive cancer, advanced castration-resistant cancer, or recurrent.

Embodiment I-15. The method of any of the preceding embodiments, wherein said administration comprises administering a once daily loading dose of an oral formulation of about 240 mg to about 480 mg of K-(4-(1-(2,6-difluorobenzyl) -5-((dimethylamino)methyl)3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl )-N'methoxyurea or an appropriate amount of its pharmaceutically acceptable salt for 1-3 days at the beginning of treatment.

Embodiment I-16. The method of any of the preceding embodiments, wherein said administration comprises administering a once daily loading dose of an oral formulation of about 240 mg to about 480 mg of K-(4-(1-(2,6-difluorobenzyl) -5-((dimethylamino)methyl)3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl )-N'methoxyurea or an appropriate amount of its pharmaceutically acceptable salt, for 13 days at the beginning of treatment after a period of suspension.

Embodiment I-17. The method of any of the preceding embodiments, wherein said administration comprises administering a once daily maintenance dose of an oral formulation of about 80 mg to about 160 mg of K-(4-(1-(2,6-difluorobenzyl) -5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin6-yl)phenyl)- K'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-18. The method according to embodiment I-17, characterized in that the administration of the maintenance dose of the oral formulation begins the next day after the administration of the last loading dose of the oral formulation.

Embodiment I-19. The method according to any one of embodiments I-1-I-18, characterized in that said suspension period is up to 52 weeks.

Embodiment I-20. The method according to any one of embodiments I-1-I-18, characterized in that said suspension period is up to 36 weeks.

Embodiment I-21. The method according to any one of embodiments I-1-I-18, characterized in that said suspension period is up to 24 weeks.

Embodiment I-22. The method according to any one of embodiments I-1-I-18, characterized in that said suspension period is up to 12 weeks.

Embodiment I-23. The method according to any one of embodiments I-1-I-18, characterized in that said suspension period is up to 8 weeks.

Embodiment I-24. The method according to any one of embodiments I-1-I-18, characterized in that said suspension period is up to 4 weeks.

Embodiment I-25. The method of any of the preceding embodiments, wherein the suspension period is interrupted when the subject's prostate-specific antigen (PSA) level is >20% of the nadir of the subject's PSA level during treatment.

Embodiment I-26. The method of any of the preceding embodiments, wherein the suspension period is interrupted when the subject's PSA level is >50% of the subject's pre-treatment PSA level.

Embodiment I-27. The method as in any one of the preceding embodiments, wherein the suspension period is interrupted when the subject's PSA level becomes greater than the subject's PSA level at the beginning of the suspension period.

Embodiment I-28. The method of any of the preceding embodiments, wherein the suspension period is interrupted when the subject experiences a return of symptoms of prostate cancer.

- 94 043716

Embodiment I-29. The method of any of the preceding embodiments, wherein the suspension period is interrupted when the subject's PSA level is >3 ng/ml.

Embodiment I-30. The method of any of the preceding embodiments, wherein the suspension period is interrupted when the subject's PSA level is >10 ng/ml.

Embodiment I-31. The method of any of the preceding embodiments, wherein the suspension period is interrupted when the subject's PSA level is >20 ng/ml.

Embodiment I-32. The method of any of the preceding embodiments, wherein the suspension period is interrupted when the subject's PSA level is >30 ng/ml.

Embodiment I-33. The method according to any of the previous embodiments, characterized in that the oral formulation is administered for a consecutive period of 12 weeks or more.

Embodiment I-34. The method according to any of the previous embodiments, characterized in that the oral formulation is administered for a consecutive period of 24 weeks or more.

Embodiment I-35. The method according to any of the previous embodiments, characterized in that the oral formulation is administered for a consecutive period of 48 weeks or more.

Embodiment I-36. The method according to any of the previous embodiments, characterized in that the oral formulation is administered for a consecutive period of 52 weeks or more.

Embodiment I-37. The method according to any of the previous embodiments, characterized in that the oral formulation is administered for a consecutive period of 72 weeks or more.

Embodiment I-38. The method according to any of the previous embodiments, characterized in that the oral formulation is administered for a consecutive period of 96 weeks or more.

Embodiment I-39. The method according to any one of embodiments I-1-I-32, characterized in that the administration is suspended after at least 24 consecutive weeks of treatment.

Embodiment I-40. The method according to embodiment I-39, characterized in that the administration is suspended after at least 36 consecutive weeks of treatment.

Embodiment I-41. The method according to embodiment I-39, characterized in that the administration is suspended after at least 52 consecutive weeks of treatment.

Embodiment I-42. The method of any of the preceding embodiments, wherein the subject requires an increase in serum testosterone levels due to intercurrent illness, radiation therapy, bed rest, previous trauma, previous surgical or invasive procedure, or desire to resume sexual function for a specified period.

Embodiment I-43. The method of any one of embodiments I-1-I-41, wherein the subject requires an increase in serum testosterone levels due to an intercurrent illness or surgical or other invasive procedure with an expected time to complete recovery of at least two weeks.

Embodiment I-44. The method of embodiment I-42 or I-43, wherein administration is suspended before surgery or other invasive procedure, or radiation therapy.

Embodiment I-45. The method of embodiment I-42 or I-43, wherein administration is suspended after surgery or other invasive procedure, trauma, or radiation therapy.

Embodiment I-46. The method according to any one of embodiments I-42-I-45, characterized in that administration is suspended during surgery or other invasive procedure, trauma, or radiation therapy.

Embodiment I-47. The method of embodiment I-42 or I-43, wherein administration is carried out before and during a surgical or other invasive procedure or radiation therapy, and administration is suspended after a surgical or other invasive procedure or radiation therapy.

Embodiment I-48. The method according to any one of embodiments I-42-I-47, characterized in that the surgical procedure is cardiac surgery, knee replacement, hip replacement, abdominal surgery, pelvic surgery, vascular surgery, spine or an emergency procedure due to injury.

Embodiment I-49. The method of any one of embodiments I-42-I-48, wherein the subject is identified as being at risk for acute postoperative weakness.

Embodiment I-50. The method of embodiment I-42 or I-43, wherein administration is suspended during intercurrent illness or when the subject is on bed rest.

Embodiment I-51. The method of any one of embodiments I-43 or I-49, characterized in that administration is resumed after the subject has been cured of the intercurrent

- 95 043716 illness, no longer remains in bed, has resumed normal daily activities, or has regained a normal level of physical activity.

Embodiment I-52. The method according to any of the previous embodiments, characterized in that the serum testosterone level is higher than the levels during therapeutic castration within 7 days of suspension of administration.

Embodiment I-53. The method of any one of embodiments I-15-I-52, wherein the loading dose of the oral formulation contains about 240 mg, about 360 mg, or about 480 mg Na(4-(1-(2,6-difluorobenzyl)- 5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)- N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-54. The method of embodiment I-53, wherein the loading dose of the oral formulation contains about 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-55. The method of any one of embodiments I-17-I-54, wherein the maintenance dose of the oral formulation contains about 80 mg, about 120 mg, or about 160 mg N-(4-(1-(2,6-difluorobenzyl) -5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl) -N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-56. The method of embodiment I-55, wherein the maintenance dose of the oral formulation contains about 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-57. The method according to any of embodiments I-17-I-54, characterized in that the loading dose of the oral formulation contains about 360 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)- 3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate pharmaceutical amount thereof acceptable salt, and is administered once daily for 1 treatment, and the maintenance dose of the oral formulation contains approximately 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6 -methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, and is administered once a day.

Embodiment I-58. The method of any one of embodiments I-1-I-14 or I-19-I-52, wherein the oral formulation contains from about 80 mg to about 160 mg N-(4-(1-(2,6difluorobenzyl )-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl )-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-59. The method according to any of the previous embodiments, characterized in that the administration is carried out before a meal.

Embodiment I-60. The method according to any of the previous embodiments, characterized in that the administration is carried out at least 1 hour before a meal and at least 2 hours after a meal.

Embodiment I-61. The method according to any one of embodiments I-1-I-58, characterized in that the administration is carried out at least 30 minutes before a meal or on an empty stomach.

Embodiment I-62. The method of any of the preceding embodiments, wherein the oral formulation, the loading dose of the oral formulation, and the maintenance dose of the oral formulation are immediate release formulations.

Embodiment I-63. The method according to any one of embodiments I-17-I-52, characterized in that the maintenance dose of the oral formulation contains from 102 to 204 mg of mannitol, from 6 to 12 mg of hydroxypropylcellulose, from 10 to 20 mg of sodium starch glycolate and from 2 to 4 mg magnesium stearate.

Embodiment I-64. The method of any of the preceding embodiments, further comprising administering an anti-androgen.

Embodiment I-65. The method of embodiment I-64, wherein the antiandrogen is selected from the group consisting of flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide (fluridil) and cimetidine.

Embodiment I-66. The method of any of the preceding embodiments, further comprising administering a CYP17 lyase inhibitor.

- 96 043716

Embodiment I-67. The method of embodiment I-66, wherein the CYP17 lyase inhibitor is abiraterone.

Embodiment I-68. The method of any of the preceding embodiments, characterized in that the subject's serum testosterone level is reduced before and after the administration is stopped.

Embodiment I-69. The method according to any one of embodiments I-1-I-63 or I-66-I-68, characterized in that the method does not include the administration of an anti-androgen.

Embodiment I-70. The method according to any of the previous embodiments, characterized in that the method does not include the administration of prednisone.

Embodiment I-71. The method according to any one of embodiments I-1-I-69, characterized in that the method further includes administering prednisone.

Embodiment I-72. The method of any of the preceding embodiments, further comprising the step of suspending administration for a subsequent suspension period after completion of the suspension period and resuming administration.

Embodiment I-73. The method of Embodiment I-72, wherein the subsequent suspension period occurs at least 12 weeks after resuming the once daily oral formulation containing from about 80 mg to about 480 mg N-(4-(1( 2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin- 6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-74. The method according to any of the previous embodiments, wherein the prostate cancer is castration-resistant metastatic prostate cancer.

Embodiment I-75. The method of any of the preceding embodiments, wherein the prostate cancer is castration-resistant, non-metastatic prostate cancer.

Embodiment I-76. The method according to any of the previous embodiments, wherein the prostate cancer is hormone-sensitive metastatic prostate cancer.

Embodiment I-77. The method according to any of the previous embodiments, characterized in that the prostate cancer is a hormone-sensitive non-metastatic prostate cancer.

Embodiment I-78. The method of any of the preceding embodiments, wherein during about 4 to about 8 days of the first administration of the oral formulation, or the loading dose of the oral formulation and the maintenance dose of the oral formulation, the subject's serum testosterone levels are at or below the level of with therapeutic castration.

Embodiment I-79. The method of Embodiment I-78, wherein within 4 days of the first administration of the oral formulation, or the loading dose of the oral formulation and the maintenance dose of the oral formulation, the subject's serum testosterone levels are at or below the level of therapeutic castration.

Embodiment I-80. An oral formulation containing from about 80 mg to about 480 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in subject in need of it.

Embodiment I-81. A formulation for use in embodiment I-80, wherein the subject requires an increase in serum testosterone levels above 50 ng/dL.

Embodiment I-82. The formulation for use in Embodiment I-80 or Embodiment I-81, wherein the method includes administering the oral formulation to a subject once daily.

Embodiment I-83. A formulation for use in embodiment I-80—embodiment I-82, wherein when once daily dosing is suspended for the period of suspension, the subject experiences an increase in serum testosterone levels.

Embodiment I-84. Ready-made form for use according to embodiment I-83, characterized in that after a period of suspension, administration is not resumed.

Embodiment I-85. An oral formulation containing from about 80 mg to about 480 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, for use in a method for treating prostate cancer in subject in need of this, which includes

- 97 043716 administration to the subject of an oral ready-made form once a day;

suspending administration of the oral formulation for a period of suspension to allow serum testosterone levels to increase; and resuming administration of the once daily oral formulation to the subject at the end of the suspension period.

Embodiment I-86. A finished form for use according to embodiment I-85, characterized in that the increase in serum testosterone is an increase above the level of therapeutic castration.

Embodiment I-87. The formulation for use according to any one of embodiments I-80-I-86, wherein the increase in serum testosterone is an increase to greater than about 55 ng/dL.

Embodiment I-88. The formulation for use according to any one of embodiments I-80-I-87, wherein the increase in serum testosterone is an increase to greater than about 350 ng/dL.

Embodiment I-89. The formulation for use according to any one of embodiments I-80-I-86, wherein the increase in serum testosterone is an increase from about 300 ng/dL to about 600 ng/dL.

Embodiment I-90. Ready form for use according to any of embodiments I-80-I-89, characterized in that the prostate cancer is a hormone-dependent prostate cancer.

Embodiment I-91. Ready form for use according to any of embodiments I-80-I-90, characterized in that prostate cancer is a late stage of prostate cancer development.

Embodiment I-92. A formulation for use according to any one of embodiments I-80-I-91, wherein the prostate cancer is metastatic, non-metastatic, advanced localized cancer, advanced hormone-sensitive cancer, advanced castration-resistant cancer, or recurrent.

Embodiment I-93. The formulation for use according to any one of embodiments I-80-I-92, wherein said administration comprises administering a once daily loading dose of an oral formulation of about 240 mg to about 480 mg of N-(4-( 1-(2,6-difluorobenzyl)5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d] pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of its pharmaceutically acceptable salt, for 1-3 days at the beginning of treatment.

Embodiment I-94. The formulation for use according to any one of embodiments I-80-I-93, wherein said administration comprises administering a once daily loading dose of an oral formulation of about 240 mg to about 480 mg of N-(4-( 1-(2,6-difluorobenzyl)5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d] pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, for 1-3 days at the beginning of treatment after a period of suspension.

Embodiment I-95. The formulation for use according to any one of embodiments I-80-I-94, wherein said administration comprises once daily administration of a maintenance dose of an oral formulation of about 80 mg to about 160 mg of N-(4-(1 -(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin- 6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-96. The finished form for use according to embodiment I-95, characterized in that the administration of the maintenance dose of the oral formulation begins the next day after the administration of the last loading dose of the oral formulation.

Embodiment I-97. A ready-made form for use according to any of embodiments I-80-I-96, characterized in that the specified suspension period is up to 52 weeks.

Embodiment I-98. Ready form for use according to any of embodiments I-80-I-96, characterized in that the specified suspension period is up to 36 weeks.

Embodiment I-99. Ready form for use according to any of embodiments I-80-I-96, characterized in that the specified suspension period is up to 24 weeks.

Embodiment I-100. Ready form for use according to any of embodiments I-80-I-96, characterized in that the specified suspension period is up to 12 weeks.

Embodiment I-101. Ready form for use according to any of embodiments I-80-I-96, characterized in that the specified suspension period is up to 8 weeks.

Embodiment I-102. Ready form for use according to any of embodiments I-80-I-96, characterized in that the specified suspension period is up to 4 weeks.

Embodiment I-103. A formulation for use in any one of embodiments of I-80-I-102, wherein the suspension period is interrupted when the subject's prostate-specific antigen (PSA) level is >20% of the nadir of the subject's PSA level during treatment .

Embodiment I-104. The formulation for use according to any one of embodiments I-80-I-103, wherein the suspension period is interrupted when the subject's PSA level is >50% of the subject's pre-treatment PSA level.

Embodiment I-105. The formulation for use according to any one of embodiments I-80-I-104, wherein the suspension period is interrupted when the subject's PSA level is greater than the subject's PSA level at the beginning of the suspension period.

Embodiment I-106. The formulation for use according to any one of embodiments I-80-I-105, wherein the suspension period is interrupted when the subject experiences a return of symptoms of prostate cancer.

Embodiment I-107. The formulation for use according to any one of embodiments I-80-I-106, wherein the suspension period is interrupted when the subject's PSA level is >3 ng/ml.

Embodiment I-108. The formulation for use according to any one of embodiments I-80-I-107, wherein the suspension period is interrupted when the subject's PSA level is >10 ng/ml.

Embodiment I-109. The formulation for use according to any one of embodiments I-80-I-108, wherein the suspension period is interrupted when the subject's PSA level is >20 ng/ml.

Embodiment I-110. The formulation for use according to any one of embodiments I-80-I-109, wherein the suspension period is interrupted when the subject's PSA level is >30 ng/ml.

Embodiment I-111. The formulation for use according to any one of embodiments I-80-I-110, wherein the oral formulation is administered for 12 consecutive weeks or more.

Embodiment I-112. The formulation for use according to any one of embodiments I-80-I-111, wherein the oral formulation is administered for 24 consecutive weeks or more.

Embodiment I-113. The formulation for use according to any one of embodiments I-80-I-112, wherein the oral formulation is administered for 48 consecutive weeks or more.

Embodiment I-114. The formulation for use according to any one of embodiments I-80-I-113, wherein the oral formulation is administered for 52 consecutive weeks or more.

Embodiment I-115. The formulation for use according to any one of embodiments I-80-I-114, wherein the oral formulation is administered for 72 consecutive weeks or more.

Embodiment I-116. The formulation for use according to any one of embodiments I-80-I-115, wherein the oral formulation is administered for 96 consecutive weeks or more.

Embodiment I-117. The finished form for use according to any of embodiments I-80-I-110, characterized in that the administration is suspended after at least 24 consecutive weeks of treatment.

Embodiment I-118. The finished form for use according to embodiment I-117, characterized in that the administration is suspended after at least 36 consecutive weeks of treatment.

Embodiment I-119. The finished form for use according to embodiment I-117, characterized in that the administration is suspended after at least 52 consecutive weeks of treatment.

Embodiment I-120. The formulation for use according to any one of embodiments I-93-I-119, wherein the loading dose of the oral formulation contains about 240 mg, about 360 mg, or about 480 mg Na(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl) phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-121. The finished form for use according to embodiment I-120, characterized in that the loading dose of the oral finished form contains about 360 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-( 6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

- 99 043716

Embodiment I-122. The formulation for use according to any one of embodiments I-95-I-121, wherein the maintenance dose of the oral formulation contains about 80 mg, about 120 mg, or about 160 mg K-(4-(1-(2.6 -difluorobenzyl)-5-((dimethylamino)methyl)-3-(6methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl )phenyl)-N'methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-123. Formulation for use according to embodiment I-122, characterized in that the maintenance dose of the oral formulation contains about 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylαamino)methyl)-3 -(6-methoxy-3-niridαzinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable amount thereof salt.

Embodiment I-124. The finished form for use according to any of embodiments I-95-I-121, characterized in that the loading dose of the oral finished form contains about 360 mg of K-(4-(1-(2,6-difluorobenzyl)-5-(( dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, and is administered once daily for 1 treatment, and the maintenance dose of the oral formulation contains about 120 mg of K-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl) -3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount thereof pharmaceutically acceptable salt, and is administered once daily.

Embodiment I-125. The formulation for use according to any one of embodiments I-80-I-92 or I-97-I-119, wherein the oral formulation contains from about 80 mg to about 160 mg K-(4-(1-( 2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine -6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-126. Ready form for use according to any of the embodiments I-80-I-125, characterized in that the administration is carried out before meals.

Embodiment I-127. Ready form for use according to any of embodiments I-80-I-126, characterized in that the administration is carried out at least 1 hour before meals and at least 2 hours after meals.

Embodiment I-128. Ready form for use according to any of embodiments I-80-I-125, characterized in that the administration is carried out at least 30 minutes before meals or on an empty stomach.

Embodiment I-129. The formulation for use according to any one of embodiments I-80-I-128, wherein the oral formulation, the loading dose of the oral formulation, and the maintenance dose of the oral formulation are immediate release formulations.

Embodiment I-130. The finished form for use according to any of embodiments I-95-I-119, characterized in that the maintenance dose of the oral formulation contains from 102 to 204 mg of mannitol, from 6 to 12 mg of hydroxypropylcellulose, from 10 to 20 mg of sodium starch glycolate, and 2 to 4 mg magnesium stearate.

Embodiment I-131. Ready form for use according to any of embodiments I-80-I-130, characterized in that the method additionally includes the administration of an antiandrogen.

Embodiment I-132. Finished form for use according to embodiment I-131, characterized in that the anti-androgen is selected from the group consisting of flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole , topilutamide (fluridil) and cimetidine.

Embodiment I-133. Ready form for use according to any of the embodiments of I-80-I-132, characterized in that the method additionally includes the administration of a CYP17 lyase inhibitor.

Embodiment I-134. The finished form for use according to embodiment I-133, characterized in that the CYP17 lyase inhibitor is abiraterone.

Embodiment I-135. Ready form for use according to any of embodiments I-80-I-130 or I-133-I-134, characterized in that the method does not include the administration of an antiandrogen.

Embodiment I-136. Ready form for use according to any of embodiments I-80-I-135, characterized in that the method does not include the administration of prednisone.

Embodiment I-137. Ready form for use according to any of embodiments I-80-I-135, characterized in that the method additionally includes the administration of prednisone.

Embodiment I-138. The finished form for use according to any of the previous embodiments of I-80-I-137, characterized in that the method further includes the step of suspending administration for a subsequent period of suspension after completion of the suspension period

- 100 043716 and resumption of administration.

Embodiment I-139. The formulation for use in embodiment I-138, wherein the subsequent suspension period occurs at least 12 weeks after resuming the once daily oral formulation containing from about 80 mg to about 480 mg of Na(4-( 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4dioxo-1,2,3,4-tetrahydrothieno[2,3-d ]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment I-140. The finished form for use according to any of embodiments I-80-I-139, characterized in that the prostate cancer is castration-resistant metastatic prostate cancer.

Embodiment I-141. The finished form for use according to any of embodiments I-80-I-140, characterized in that the prostate cancer is castration-resistant non-metastatic prostate cancer.

Embodiment I-142. Ready form for use according to any of embodiments I-80-I-141, characterized in that the prostate cancer is a hormone-sensitive metastatic prostate cancer.

Embodiment I-143. Ready form for use according to any of embodiments I-80-I-142, characterized in that the prostate cancer is a hormone-sensitive non-metastatic prostate cancer.

Embodiment I-144. Application No.(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'methoxyurea or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prostate cancer.

Embodiment I-145. Use according to embodiment I-144, wherein the prostate cancer is a hormone-dependent prostate cancer.

Embodiment I-146. Use according to embodiment I-144, wherein the prostate cancer is an advanced stage of prostate cancer.

Embodiment I-147. Use according to embodiment I-144, wherein the prostate cancer is metastatic, non-metastatic, advanced localized cancer, advanced hormone-sensitive cancer, advanced castration-resistant cancer, or recurrent.

Embodiment I-148. Use according to embodiment I-144, wherein the prostate cancer is castration-resistant metastatic prostate cancer.

Embodiment I-149. Use according to embodiment I-144, wherein the prostate cancer is castration-resistant, non-metastatic prostate cancer.

Embodiment I-150. Use according to embodiment I-144, wherein the prostate cancer is hormone-sensitive metastatic prostate cancer.

Embodiment I-151. Use according to embodiment I-144, wherein the prostate cancer is a hormone-sensitive, non-metastatic prostate cancer.

Embodiment I-152. Use according to any one of embodiments I-144-1-151, wherein the medicinal product contains from about 80 mg to about 480 mg N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl )-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount a pharmaceutically acceptable salt thereof.

Some embodiments of the present invention relate to Embodiment II as follows.

Embodiment II-1. The method according to any one of embodiments I-1-I-78, characterized in that a PK profile is achieved in which the average AUC( _0-tau ) in plasma increases by at least 1.5 times when measurements are taken from the first to the last day of the treatment period.

Embodiment II-2. The method according to any one of embodiments I-1-I-78, characterized in that a PK profile is achieved in which the average C _max increases by at least 2 times when measurements are taken from the first to the last day of the treatment period.

Embodiment II-3. The method according to embodiment II-1, characterized in that the magnification is at least 1.5 times, or 2 times, or more.

Embodiment II-4. The method according to any one of embodiments II-1-II-3, characterized in that the administration is carried out without any requirements for administration on an empty stomach.

Embodiment II-5. The method according to any one of embodiments II-1-II-3, characterized in that the average _Cmax is higher when administered before a meal than when administered after a meal

- 101 043716 food.

Embodiment II-6. The method of any one of embodiments 11-1-11-3, wherein the mean plasma AUC( _{0_tau} ) is higher when administered before a meal than when _administered after a meal at least 30 minutes later.

Embodiment II-7. The method according to any one of embodiments I-1-I-78 or II-1-II-6, characterized in that the oral formulation contains at least one filler that improves stability while maintaining load-bearing capacity.

Embodiment II-8. The method according to any one of embodiments I-1-I-78 or II-1-II-7, characterized in that the oral formulation is a tablet.

Embodiment II-9. The method according to any one of embodiments II-1-II-3, characterized in that the average T _1/2 in plasma is from about 37 hours to about 42 hours, as measured at the end of administration.

Embodiment II-10. The method according to any of embodiments II-1-II-3, characterized in that the average _Cmax is reached between 1 and 2 hours ( _Tmax ) from the beginning of administration.

Embodiment II-11. The method according to any of the embodiments II-1-II-3, characterized in that a stable state is achieved within 10 days from the start of administration.

Embodiment II-12. The method according to any one of embodiments II-1-II-3, characterized in that the prostate-specific antigen (PSA) level in the subject is reduced to a level less than or equal to 4 ng/ml.

Embodiment II-13. The method of any one of embodiments II-1-II-3, characterized in that the prostate-specific antigen (PSA) level in the subject is reduced to a level less than or equal to 2 ng/ml.

Embodiment II-14. The method according to any one of embodiments II-1-II-3, characterized in that less than 4% X(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6 -methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea is excreted unchanged into the subject's urine as measured in day 14 or day 28 from the beginning of administration.

Embodiment II-15. The method according to any of embodiments II-1-II-3, characterized in that levels as during therapeutic castration are achieved and maintained from 14 to 28 days from the start of administration, less than or equal to 50 ng/dl (1.73 nmol/l ) serum testosterone.

Option P-16. The method according to any one of embodiments II-1-II-15, characterized in that after administration of once daily 360 mg loading dose of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt thereof and 120 mg of maintenance doses of the oral formulation or the corresponding amount thereof pharmaceutically acceptable salt for 48 consecutive weeks achieve therapeutic castration levels less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone by the beginning of the 5th week, and are maintained by the end of the 48th week.

Embodiment II-17. The method according to any one of embodiments II-1-II-15, characterized in that after administration of once daily 80 mg or 120 mg maintenance doses of the oral formulation or an appropriate amount of a pharmaceutically acceptable salt thereof for 13 consecutive weeks, changes in mean serum concentration PSA compared to the initial value at the end of 13 consecutive weeks is a decrease of 8-12 times for the 80 mg dose and 9-13 times for the 120 mg dose.

Embodiment II-18. The method according to any one of embodiments II-1-II-15, characterized in that after administration of once daily 80 or 120 mg maintenance doses of the oral formulation or an appropriate amount of a pharmaceutically acceptable salt thereof for 25 consecutive weeks, the median residual plasma concentration (C _min ) unchanged compound N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2 ,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, ranged between 2.0 and 8.0 ng/ml for the 80 mg dose and between 4.0 and 12.0 ng/ml for a dose of 120 mg.

Embodiment II-19. The method according to any one of embodiments II-1-II-3, characterized in that the administration causes C _min to be maintained constant during the administration.

Embodiment II-20. The method according to any of embodiments II-1-II-15, characterized in that after administration of once daily 80 or 180 mg maintenance doses of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt thereof for 16 consecutive days, changes in the average serum concentration of luteinizing agent hormone (LH) compared to the initial value at the end of 16 days in a row is a decrease of 12-16 times for a dose of 80 mg and 15-19 times for a dose of 180 mg.

Embodiment II-21. The method according to any one of embodiments II-1-II-15, characterized in that after administration of once daily 80 or 180 mg maintenance doses of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt thereof for 16 days

- 102 043716 consecutive changes in the average serum testosterone concentration compared to the initial value at the end of 16 consecutive days is a decrease of 27-31 times for a dose of 80 mg and 22-26 times for a dose

180 mg.

Embodiment II-22. The method according to any of embodiments II-1-II-15, characterized in that after administration of once daily 80 or 180 mg maintenance doses of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt for 16 consecutive days, changes in the average serum concentration of follicle-stimulating agent hormone (FSH) compared to the initial value at the end of 16 days in a row is a decrease of 7-11 times for a dose of 80 mg and 10-14 times for a dose of 180 mg.

Embodiment II-23. The method according to any one of embodiments II-1-II-15, characterized in that after administration of once daily 80 mg or 180 mg maintenance doses of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt thereof for 16 consecutive days, changes in the average serum concentration dihydrotestosterone (DHT) compared to the initial value at the end of 16 days in a row is a decrease of 1.1-3 times for a dose of 80 mg and 1.1-4 times for a dose of 180 mg.

Embodiment II-24. The method according to any one of embodiments II-1-II-3, characterized in that the administration is such that there is no stimulation of sex hormones and thereby clinical exacerbation is prevented or minimized.

Embodiment II-25. A method of treating hormone-dependent prostate cancer in a subject, comprising administering to the subject once daily for at least one day during the first treatment period a loading dose of an oral formulation containing from about 240 mg to about 480 mg of N(4-( 1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d ]pyrimidin-6-yl)phenyl)-N'-methoxyurea; and administering to the subject once daily for 24 consecutive weeks or more during the second treatment period a maintenance dose of an oral formulation containing from 80 to 160 mg of N-(4-(1(2,6-difluorobenzyl)-5-(( dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of _a pharmaceutically acceptable salt thereof, wherein the maintenance dose of the oral formulation has a PK profile in which the mean plasma AUC( _{0_tau} ) increases by at least 1.5-fold when measured from the first day of the first treatment period to the last days of the second treatment period.

Embodiment II-26. A method of treating hormone-dependent prostate cancer in a subject, comprising administering to the subject once daily for at least one day during the first treatment period a loading dose of an oral formulation containing from about 240 mg to about 480 mg of N-(4- (1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3- d]pyrimidin-6-yl)phenyl)-N'-methoxyurea; and administering to the subject once daily for 24 consecutive weeks or more during the second treatment period a maintenance dose of an oral formulation containing from 80 to 160 mg of N-(4-(1(2,6-difluorobenzyl)-5-(( dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, wherein the maintenance dose of the oral formulation has a PK profile in which the mean plasma C _max increases by at least 2-fold when measured from the first day of the first treatment period to the last day of the second treatment period.

Embodiment II-27. A method of reducing the levels of one or more sex hormones in a subject having hormone-dependent prostate cancer, comprising administering to the subject once daily for at least one day during the first treatment period a loading dose of an oral formulation containing from about 240 mg up to about 480 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2 ,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea; and administering to the subject once daily for 24 consecutive weeks or more during the second treatment period a maintenance dose of an oral formulation containing from 80 to 160 mg of N-(4-(1(2,6-difluorobenzyl)-5-(( dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of _a pharmaceutically acceptable salt thereof, wherein the maintenance dose of the oral formulation has a PK profile in which the mean plasma AUC( _{0_tau} ) increases by at least 1.5-fold when measured from the first day of the first treatment period to the last days of the second treatment period.

Embodiment II-28. A method of reducing the levels of one or more sex hormones in a subject having hormone-dependent prostate cancer, comprising

- 103 043716 administering to the subject once daily for at least one day during the first treatment period a loading dose of an oral formulation containing from about 240 mg to about 480 mg Na(4-(1-(2,6-difluorobenzyl) -5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl) -N'-methoxyurea; and administering to the subject once daily for 24 consecutive weeks or more during the second treatment period a maintenance dose of an oral formulation containing from 80 to 160 mg of N-(4-(1(2,6-difluorobenzyl)-5-(( dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, wherein the maintenance dose of the oral formulation has a PK profile in which the mean plasma C _max increases by at least 2-fold when measured from the first day of the first treatment period to the last day of the second treatment period.

Embodiment II-29. The method of embodiment II-25 or II-27, wherein at least 1.5 times is 2 times or more.

Embodiment II-30. The method according to any one of embodiments II-25-II-29, characterized in that the first treatment period is 1 day or more.

Embodiment II-31. The method according to any one of embodiments II-25-II-29, characterized in that the first treatment period is 2 days or more.

Embodiment II-32. The method according to any one of embodiments II-25-II-29, characterized in that the first treatment period is 3 days or more.

Embodiment II-33. The method according to any one of embodiments II-25-II-29, characterized in that the second treatment period is 52 consecutive weeks or more.

Embodiment II-34. The method according to any one of embodiments II-25-II-29, characterized in that the second treatment period is 72 consecutive weeks or more.

Embodiment II-35. The method according to any one of embodiments II-25-II-29, characterized in that the second treatment period is 96 consecutive weeks or more.

Embodiment II-36. The method according to any of embodiments II-25-II-29, characterized in that the administration is carried out before a meal.

Embodiment II-37. The method according to any of embodiments II-25-II-29, characterized in that the administration is carried out at least 1 hour before a meal and at least 2 hours after a meal.

Embodiment II-38. The method according to any of embodiments II-25-II-29, characterized in that the administration is carried out at least 30 minutes before meals or on an empty stomach.

Embodiment II-39. The method according to any one of embodiments II-25-II-29, characterized in that the administration is carried out without any requirements for administration on an empty stomach.

Embodiment II-40. The method according to any one of embodiments II-25-II-29, characterized in that the average _Cmax is higher when administered before a meal than when administered after a meal.

Embodiment II-41. The method of any one of embodiments II-25-II-29, wherein the mean plasma AUC( _0-tau ) is higher when administered before a meal than when administered after a meal at least 30 minutes later.

Embodiment II-42. The method according to any one of embodiments II-25-II-29, characterized in that the loading dose of the oral formulation and the maintenance dose of the oral formulation are tablets.

Embodiment II-43. The method according to any one of embodiments II-25-II-29, characterized in that the loading dose of the oral formulation and the maintenance dose of the oral formulation have a rapid release profile.

Embodiment II-44. The method of any one of embodiments II-25-II-29, wherein the average T _1/2 in plasma is from about 37 to about 42 hours, as measured at the end of administration.

Embodiment II-45. The method according to any of embodiments II-25-II-29, characterized in that the average _Cmax is reached between 1 and 2 hours ( _Tmax ) from the beginning of administration.

Embodiment II-46. The method according to any of the embodiments II-25-II-29, characterized in that a stable state is achieved within 10 days from the start of administration.

Embodiment II-47. The method of any one of embodiments II-25-II-29, wherein the subject's serum testosterone level is reduced to a castration level of less than or equal to 50 ng/dL (1.73 nmol/L).

Embodiment II-48. The method of any one of embodiments II-25-II-29, wherein the serum testosterone level in the subject is reduced to a fully castrated level of less than or equal to 20 ng/dL (0.69 nmol/L).

Embodiment II-49. The method according to any one of embodiments II-25-II-29, characterized in that the level of prostate-specific antigen (PSA) is reduced in the subject to a level

- 104 043716 less than or equal to 4 ng/ml.

Embodiment II-50. The method of any one of embodiments 11-25-11-29, wherein the prostate-specific antigen (PSA) level in the subject is reduced to a level less than or equal to 2 ng/ml.

Embodiment II-51. The method according to any one of embodiments II-25-II-29, characterized in that the loading dose of the oral formulation is 240, or 360, or 480 mg, or the corresponding amount of a pharmaceutically acceptable salt thereof, and the maintenance dose of the oral formulation is 80, or 120 or 160 mg, or the corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment II-52. The method according to any one of embodiments II-25-II-29, characterized in that the loading dose of the oral formulation is 360 mg or the corresponding amount of a pharmaceutically acceptable salt thereof and the maintenance dose of the oral formulation is 120 mg or the corresponding amount of a pharmaceutically acceptable salt thereof.

Embodiment II-53. The method according to any one of embodiments II-25-II-29, characterized in that the loading dose of the oral formulation is 360 mg or the corresponding amount of a pharmaceutically acceptable salt thereof, and is administered on day 1 of the first treatment period and the maintenance dose of the oral formulation is 120 mg or an appropriate amount of a pharmaceutically acceptable salt thereof, and administered starting on day 1 or day 2 of the second treatment period.

Embodiment II-54. The method according to any one of embodiments II-25-II-29, characterized in that less than 4% Na(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6 -methoxy-3pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea is excreted unchanged into the subject's urine as measured in day 14 or day 29 from the beginning of the first treatment period.

Embodiment II-55. The method according to any of the embodiments, characterized in that levels of therapeutic castration less than or equal to 50 ng/dL (1.73 nmol/L) of serum testosterone are achieved and maintained from 14 to 28 days from the start of administration.

Embodiment II-56. The method according to any one of embodiments II-25-II-29, characterized in that after administration of once daily 360 mg loading dose of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt thereof and 120 mg of maintenance doses of the oral formulation or the corresponding amount thereof pharmaceutically acceptable salt for 48 consecutive weeks, therapeutic castration levels of less than or equal to 50 ng/dL (1.73 nmol/L) serum testosterone are achieved by the beginning of the 5th week and maintained by the end of the 48th week.

Embodiment II-57. The method according to any one of embodiments II-25-II-29, characterized in that after administration of once daily 80 or 120 mg maintenance doses of the oral formulation or an appropriate amount of a pharmaceutically acceptable salt thereof for 13 consecutive weeks, changes in the mean serum PSA concentration compared to the initial value at the end of 13 consecutive weeks is a decrease of 8-12 times for a dose of 80 mg and 9-13 times for a dose of 120 mg.

Embodiment II-58. The method according to any one of embodiments II-25-II-29, characterized in that after administration of once daily 80 or 120 mg maintenance doses of the oral formulation or an appropriate amount of a pharmaceutically acceptable salt thereof for 25 consecutive weeks, the median residual plasma concentration (C _min ) unchanged compound N-(4-(1(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a pharmaceutically acceptable salt thereof, ranged between 2.0 and 8.0 ng/ml for the 80 mg dose and between 4.0 and 12.0 ng/ml for the 120 mg dose.

Embodiment II-59. The method according to any one of embodiments II-25-II-29, characterized in that the administration causes C _min to be maintained constant during the second treatment period.

Embodiment II-60. The method according to any of embodiments II-25-II-29, characterized in that after administration of once daily 80 mg or 180 mg maintenance doses of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt thereof, for 16 consecutive days, changes in the average serum concentration of luteinizing hormone (LH) compared to the initial value at the end of 16 consecutive days is a decrease of 12-16 times for a dose of 80 mg, and a decrease of 15-19 times for a dose of 180 mg.

Embodiment II-61. The method according to any one of embodiments II-25-II-29, characterized in that after administration of once daily 80 or 180 mg maintenance doses of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt thereof, for 16 consecutive days, changes in mean serum testosterone concentration compared to the initial value at the end of 16 days in a row is a decrease of 27-31 times for a dose of 80 mg and a decrease of 22-26 times for a dose of 180 mg.

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Embodiment II-62. The method according to any of embodiments 11-25-11-29, characterized in that after administration of once daily 80 or 180 mg maintenance doses of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt for 16 consecutive days, changes in the average serum concentration of follicle-stimulating agent hormone (FSH) compared to the initial value at the end of 16 days in a row is a decrease of 7-11 times for a dose of mg and 10-14 times for a dose of 180 mg.

Embodiment II-63. The method according to any one of embodiments II-25-II-29, characterized in that after administration of once daily 80 or 180 mg maintenance doses of the oral formulation or the corresponding amount of a pharmaceutically acceptable salt thereof for 16 consecutive days, changes in the average serum concentration of dihydrotestosterone (DHT) compared to the initial value at the end of 16 days in a row is a decrease of 1.1-3 times for a dose of 80 mg and 1.1-4 times for a dose of 180 mg.

Embodiment II-64. The method according to any one of embodiments II-25-II-29, characterized in that the subject has local late stages of development of hormone-dependent prostate cancer.

Embodiment II-65. The method of any one of embodiments II-25-II-29, wherein administration may be suspended for a period of 4 weeks or less to 24 weeks or more after at least 24 consecutive weeks of administration.

Embodiment II-66. The method of Embodiment II-65, wherein, upon interruption of administration, a return to baseline serum testosterone levels is achieved within 4 weeks to 12 weeks after the last dose.

Embodiment II-67. The method of Embodiment II-65, wherein upon resumption of administration, within 24 to 48 hours a return to castration levels is achieved in the subject.

Embodiment II-68. The method according to any one of embodiments II-25-II-29, characterized in that the administration is such that there is no stimulation of sex hormones, and thereby clinical exacerbation is prevented or minimized.

Embodiment II-69. The method according to any one of embodiments II-25-II-29, characterized in that the prostate cancer represents late stages of prostate cancer development.

Embodiment II-70. The method according to any one of embodiments II-25-II-29, characterized in that the treatment is palliative and the prostate cancer represents late stages of prostate cancer.

Embodiment II-71. The dose package contains a daily loading dose of an oral formulation containing 240 to 480 mg of N-(4-(1(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl )-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, and excipients; and a daily maintenance dose of an oral formulation containing 80 to 160 mg N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, and excipients, with a daily maintenance dose of oral formulation has a PK profile in which the mean plasma AUC( _{0_tau} ) increases by at least 1.5-fold when measured from the first to the last day of the treatment _period , with a treatment period of a maintenance dose of the once-daily oral formulation being 24 weeks in a row or more.

Embodiment II-72. The dose package contains a daily loading dose of an oral formulation containing 240 to 480 mg of N-(4-(1(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl )-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, and excipients; and a daily maintenance dose of an oral formulation containing 80 to 160 mg N(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, and excipients, with a daily maintenance dose of oral formulation has a PK profile in which the mean C _max increases by at least 2-fold when measured from the first to the last day of the treatment period, with a maintenance dose period of the once-daily oral formulation being treated for 24 consecutive weeks or more.

Embodiment II-73. The method of Embodiment II-71, wherein at least 1.5 times is 2 times or more.

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Embodiment II-74. Dosage packaging according to embodiment II-71 - II-72, characterized in that the loading dose of the oral formulation contains from 306 to 612 mg of mannitol, from 18 to 36 mg of hydroxypropylcellulose, from 30 to 60 mg of sodium starch glycolate and from 6 to 12 mg magnesium stearate.

Embodiment II-75. Dose packaging according to embodiment II-74, characterized in that the loading dose of the oral formulation additionally contains from 21.36 to 42.72 mg of hypromellose 2910, from 2.4 to 4.8 mg of titanium dioxide, from 0.2 to 0 .48 mg of iron oxide and a sufficient amount of carnauba wax.

Embodiment II-76. Dosage packaging according to embodiment II-71 or II-72, characterized in that the maintenance dose of the oral formulation contains from 102 to 204 mg of mannitol, from up to 12 mg of hydroxypropylcellulose, from 10 to 20 mg of sodium starch glycolate, and from 2 to 4 mg Magnesium stearate.

Embodiment II-77. Dose packaging according to embodiment II-76, characterized in that the maintenance dose of the oral formulation additionally contains from 7.12 to 14.24 mg of hypromellose 2910, from 0.8 to 1.6 mg of titanium dioxide, from 0.08 to 0 , 16 mg of iron oxide and a sufficient amount of carnauba wax.

Embodiment II-78. The dose packaging of embodiment II-75 or II-77, wherein the loading dose of the oral formulation and the maintenance dose of the oral formulation contain at least one filler that improves stability while maintaining capacity.

Embodiment II-79. Dosage packaging of embodiment II-74 or II-76, wherein sodium starch glycolate in loading dose oral formulation and maintenance dose oral formulation improves stability and carrying capacity for N-(4-(1-(2,6difluorobenzyl )-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl )-N'-methoxyurea, or a pharmaceutically acceptable salt thereof, in a loading dose of an oral formulation and a maintenance dose of an oral formulation.

Embodiment II-80. Dosage packaging according to embodiment II-71 or II-72, characterized in that the loading dose of the oral formulation contains 240, or 360, or 480 mg of N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino )methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment II-81. Dosage packaging according to embodiment II-71 or II-72, characterized in that the maintenance dose of the oral formulation contains 80, or 120, or 160 mg of N-(4-(1-(2,6-difluorobenzyl)-5-( (dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment II-82. Dosage packaging according to embodiment II-71 or II-72, characterized in that the loading dose of the oral formulation contains 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3 -(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable amount thereof salt, and the maintenance dose of the oral formulation contains 120 mg N-(4-(1-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof.

Embodiment II-83. Dosage packaging according to embodiment II-71 or II-72, characterized in that the loading dose of the oral formulation and the maintenance dose of the oral formulation are tablets.

Embodiment II-84. The dose packaging of embodiment II-71 or II-72, wherein the loading dose of the oral formulation and the maintenance dose of the oral formulation have a rapid release profile.

Embodiment II-85. The dose package of embodiment II-71 or II-72 further contains at least one of an anti-androgen or a CYP17 lyase inhibitor.

Embodiment II-86. The dosage pack of Embodiment II-85, wherein the anti-androgen includes enzalutamide, bicalutamide, enzalutamide, or flutamide, and the CYP17 lyase inhibitor includes abiraterone.

Embodiment II-87. The dose package of embodiment II-71 or II-72 is used for the treatment of hormone-dependent prostate cancer.

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Claims (14)

CLAIM 1. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)2,4-dioxo-1,2,3 ,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer in a subject in need thereof, wherein a loading dose of an oral formulation containing 360 mg K-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4 α-tetrahydrothieno[2,3-d]pyrimidin6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, is administered to the subject once on the first day of the treatment period; and a maintenance dose of an oral formulation containing 120 mg K-(4-(1-(2,6-difluorobenzyl)5-((dimetulamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin6-yl)phenyl)-N'-methoxyurea, or an appropriate amount of a pharmaceutically acceptable salt thereof, is administered to the subject once daily beginning on the second day of the treatment period. 2. Use according to claim 1, wherein the administration of the oral formulation is suspended for a period of suspension to allow serum testosterone levels to increase. 3. The use of claim 2, wherein the subject's serum testosterone level increases to more than 55 ng/dL within 30 days of the start of the suspension period. 4. The use of claim 2, wherein the subject's serum testosterone level increases to greater than 280 ng/dL within 12 weeks of the start of the suspension period. 5. Use according to any one of claims 1 to 4, characterized in that the administration is suspended after at least 24 consecutive weeks of treatment, preferably after at least 36 consecutive weeks of treatment and most preferably after at least 52 consecutive weeks of treatment . 6. Use according to any one of claims 1 to 5, characterized in that the subject requires an increase in serum testosterone levels due to intercurrent illness, radiation therapy, bed rest, previous trauma, previous surgical or other invasive procedure, or a desire to resume sexual function on certain period. 7. Use according to any one of claims 1 to 6, wherein after administration of a maintenance dose for 48 consecutive weeks, a therapeutic castration level of less than or equal to 50 ng/dL (1.73 nmol/L) of serum testosterone is achieved, to the beginning 5th week and maintained by the end of the 48th week. 8. Application of K-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)2,4-dioxo-1,2,3 ,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof for reducing the levels of one or more sex hormones selected from luteinizing hormone, testosterone, dihydrotestosterone and FSH (follicle stimulating hormone) in a subject with hormone-dependent prostate cancer, where a loading dose of an oral formulation containing 360 mg K-(4-(1-(2,6-difluorobenzyl)-5((dimethylamino)methyl)-3-( 6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin6-yl)phenyl)-K'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, administered to the subject once daily for at least one day during the first treatment period; and a maintenance dose of an oral formulation containing 120 mg K-(4-(1-(2,6-difluorobenzyl)5-((dimetulamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin6-yl)phenyl)-N'-methoxyurea or an appropriate amount of a pharmaceutically acceptable salt thereof, administered to the subject once daily for a subsequent 24 weeks or more during the second treatment period. 9. Use according to claim 8, wherein the sex hormone is FSH. 10. Use according to claim 9, wherein the subject's FSH is between 0.6 and 1.6 mIU/ml over a 48-week course of treatment. 11. Application according to any one of paragraphs. 1 or 8, where complete castration is achieved. 12. Application according to claim 11, where complete castration is achieved within 24 to 48 hours from the beginning of administration and is maintained until the end of administration. 13. Use according to any one of claims 1 or 8, wherein the time to castration resistance is longer than that of a subject receiving gonadotropin releasing hormone (GnRH) agonist therapy. 14. Use according to any one of claims 1 or 8, where enzalutamide is additionally administered. - 108 -