WO2023114264A1 - Combinaison pour le traitement du cancer de la prostate hormono-sensible à haut risque - Google Patents

Combinaison pour le traitement du cancer de la prostate hormono-sensible à haut risque Download PDF

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WO2023114264A1
WO2023114264A1 PCT/US2022/052788 US2022052788W WO2023114264A1 WO 2023114264 A1 WO2023114264 A1 WO 2023114264A1 US 2022052788 W US2022052788 W US 2022052788W WO 2023114264 A1 WO2023114264 A1 WO 2023114264A1
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pharmaceutically acceptable
acceptable salt
abemaciclib
cdk4
inhibitor
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David Michael HYMAN
Andrew Joseph LITHIO
Karim NACERDDINE
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Eli Lilly And Company
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the disclosure relates to the field of treatment of men with metastatic hormonesensitive prostate cancer, and more particularly, high-risk metastatic hormone-sensitive prostate cancer.
  • Prostate cancer is a leading cause of mortality and morbidity globally and represents a substantial public health burden. With nearly 1.4 million new cases and 375,000 deaths worldwide, prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men in 2020 (Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021, 71(3):209-249).
  • mHSPC metastatic hormone-sensitive prostate cancer
  • ADT androgen deprivation therapy
  • first-generation antiandrogens has been the mainstay of treatment for mHSPC
  • Life-prolonging treatments now include ADT with docetaxel chemotherapy, or with hormonal agents, such as abiraterone, apalutamide, and enzalutamide, or with docetaxel and novel hormonal agents (triplet therapy).
  • hormonal agents such as abiraterone, apalutamide, and enzalutamide
  • triplet therapy docetaxel and novel hormonal agents
  • Abemaciclib is a potent and selective oral inhibitor of CDK4 & 6 that is approved for the treatment of early and advanced/metastatic HR+/HER2- breast cancer (Verzenio package insert, 2021).
  • the AR signaling pathway activates the CDK4 & 6-cyclin DI axis to sustain prostate cancer cell proliferation and survival (Knudsen ES, Pazzagli C, Born TL, et al. Elevated cyclins and cyclin-dependent kinase activity in the rhabdomyosarcoma cell line RD. Cancer Res. 1998;58(9):2042-2049; Xu Y, Chen SY, Ross KN, Balk SP.
  • the present disclosure provides a combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Abemaciclib is a potent and selective oral inhibitor of CDK4 & 6 that is approved for the treatment of early and advanced/metastatic HR+/HER2- breast cancer (Verzenio package insert, 2021). Dual inhibition of the AR axis and cell cycle entry with the coadministration of abiraterone and abemaciclib may demonstrate superior clinical activity compared to inhibition of the AR axis alone in patients with high-risk mHSPC.
  • the present disclosure provides a method of treating a patient with high- risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the present disclosure provides a combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing; for use in treating a patient with high-risk metastatic hormone-sensitive prostate cancer.
  • the present disclosure provides use of a CDK4 and 6 inhibitor in the manufacture of a medicament for the treatment of a patient with high-risk metastatic hormonesensitive prostate cancer, wherein the medicament is to be administered in simultaneous, separate, or sequential combination with abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing, can be, for example, simultaneous or sequential in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof.
  • a “CDK4 and 6 inhibitor,” a “CDK4/6 inhibitor,” or alternatively a “CDK4 & 6 inhibitor” refers to molecules that inhibit the activity of D-type cyclins (e.g., cyclin D3) and cyclin-dependent kinases (CDK4 and 6) protein complexes (e.g., cyclinD:CDK4 and 6 complexes), and generally function to block transition from the G1 to S phase of cell cycle through inhibition of kinase activity.
  • the CDK4 and 6 inhibitor is palbociclib, ribociclib, or abemaciclib.
  • Palbociclib is taken orally and is available as capsules (125 mg, 100 mg, and 75 mg) with a recommended starting dosage of 125 mg, once daily for 21 days followed by 7 days of off treatment.
  • Palbociclib may be prepared as the free base or as pharmaceutically acceptable salts, including mono- and di-acid addition salts such as, for example, the mono-isethionate salt, polymorphic forms of the isethionate salt, or the hydrochloride salt (see, e.g., WO 2003/062236, WO 2005/005426, WO 2008/032157, U.S. Pat. Nos. 6,936,612; 7,208,489; 7,345,171;
  • Palbociclib in its free base form may be anhydrous or may contain varying amounts of water or one or more solvents, (see, e.g., U.S. Pat. No. 10,723,730).
  • Ribociclib [7-cyclopentyl-A,7V-dimethyl-2- ⁇ [5-(piperazin-l-yl)pyridine-2-yl]amino ⁇ - 7H-pyrrolo[2,3-t ]pyrimidine-6-carboxamide], is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer (i) in combination with an aromatase inhibitor as an initial endocrine-based therapy in pre/perimenopausal or postmenopausal women, or (ii) in combination with fulvestrant in postmenopausal women as an initial endocrine-based therapy or following disease progression on endocrine therapy. It has the chemical structure:
  • Ribociclib is taken orally and is available as tablets (200 mg, equivalent to 254.40 mg ribociclib succinate) with a recommended starting dosage of 600 mg, (3x 200 mg tablets) taken once daily for 21 days followed by 7 days of off treatment.
  • Ribociclib may be prepared as the free base or as pharmaceutically acceptable salts, including as ribociclib succinate (see, e.g., U.S. Pat. Nos. 9,868,739; and 9,193,732).
  • Abemaciclib (LY2835219), [5-(4-ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5-fluoro-4- (7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine, is a potent and selective oral inhibitor of CDK4 & 6 that is approved for the treatment of early and advanced/metastatic HR+/HER2- breast cancer (Verzenio® package insert, 2021).
  • Abemaciclib its salt forms including the hydrochloride and mesylate salts, and methods of making and using the compound including for the treatment of cancer, in particular, breast cancer are disclosed in WO 2010/075074.
  • Methods for using abemaciclib in combination with endocrine therapy for the adjuvant treatment of adult patients diagnosed with HR+, HER2- node positive, early breast cancer at high risk of recurrence and a Ki-67 score >20% are disclosed in WO 2018/204138.
  • Abemaciclib has the following structure:
  • abemaciclib is administered at a dose of 50 mg to 200 mg twice a day. Also preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg to 150 mg twice a day. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg twice a day. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle.
  • abemaciclib is administered at a dose of 150 mg twice a day in a 28-day cycle. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg twice a day in a 28-day cycle. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg twice a day in a 28-day cycle.
  • abemaciclib is administered orally.
  • abemaciclib is administered by capsule.
  • abemaciclib is administered by tablet.
  • Abiraterone the active metabolite of abiraterone acetate, irreversibly inhibits cytochrome P450 (CYP)17 (17a-hydroxylase/C17, 20-lyase), an essential enzyme in androgen biosynthesis that is expressed in testicular, adrenal, and prostatic tumor tissues.
  • Abiraterone acetate is approved in combination with prednisone or prednisolone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) or metastatic high-risk castration- sensitive prostate cancer (CSPC) (Zytiga® package insert, 2021).
  • CRPC metastatic castration-resistant prostate cancer
  • CSPC metastatic high-risk castration- sensitive prostate cancer
  • abiraterone acetate is administered at a dose of 1000 mg once a day. More preferably, abiraterone acetate is administered at a dose of 1000 mg once a day in a 28-day cycle. Preferably, abiraterone acetate is administered orally. Preferably, abiraterone acetate is administered by tablet. In some preferred embodiments, abiraterone acetate is micronized. In some preferred embodiments, abiraterone acetate (preferably micronized abiraterone acetate) is administered at a dose of 500 mg once a day.
  • abiraterone acetate (preferably micronized abiraterone acetate) is administered at a dose of 500 mg once a day in a 28-day cycle.
  • micronized abiraterone acetate is administered orally.
  • micronized abiraterone acetate is administered by tablet.
  • Prednisone, prednisolone, and methylprednisolone are glucocorticoids.
  • Prednisone, prednisolone, and methylprednisolone have the following structures.
  • prednisone or prednisolone is administered at a dose of 5 mg once a day. More preferably, prednisone or prednisolone is administered at a dose of 5 mg once a day in a 28-day cycle. Preferably, prednisone or prednisolone is administered orally. Preferably, prednisone or prednisolone is administered by tablet. In some preferred embodiments, methylprednisolone is administered at a dose of 4 mg twice a day. More preferably, methylprednisolone is administered at a dose of 4 mg twice a day in a 28-day cycle. Preferably, methylprednisolone is administered orally. Preferably, methylprednisolone is administered by tablet.
  • abemaciclib is administered at a dose of 200 mg twice a day; abiraterone acetate is administered at a dose of 1000 mg once a day; and prednisone or prednisolone is administered at a dose of 5 mg once a day.
  • abemaciclib is administered at a dose of 200 mg twice a day in a 28-day cycle; abiraterone acetate is administered at a dose of 1000 mg once a day in the 28-day cycle; and prednisone or prednisolone is administered at a dose of 5 mg once a day in the 28-day cycle.
  • abemaciclib is administered at a dose of 200 mg twice a day; abiraterone acetate (preferably micronized abiraterone acetate) is administered at a dose of 500 mg once a day; and methylprednisolone is administered at a dose of 4 mg twice a day.
  • abemaciclib is administered at a dose of 200 mg twice a day in a 28-day cycle; abiraterone acetate (preferably micronized abiraterone acetate) is administered at a dose of 500 mg once a day in the 28-day cycle; and methylprednisolone is administered at a dose of 4 mg twice a day in the 28-day cycle.
  • a CDK4 and 6 inhibitor in accordance with the aspects and embodiments of the disclosure may be prepared and administered as the inhibitor compound, or as a pharmaceutically acceptable salt thereof.
  • abemaciclib may be prepared and/or administered as the free base.
  • abemaciclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, the hydrochloride or mesylate salt.
  • ribociclib may be prepared and/or administered as the free base.
  • or ribociclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, ribociclib succinate.
  • palbociclib may be prepared and/or administered as the free base. In some other embodiments, palbociclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, the isethionate or the hydrochloride salt.
  • abiraterone or abiraterone acetate may be prepared and administered as their free bases, or as a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salts of abiraterone acetate are disclosed in WO 2015/000451.
  • prednisone, prednisolone, or methylprednisolone may be prepared and administered as their free bases, or as a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salts of prednisolone are disclosed in U.S. Pat. No. 8,637,076.
  • the patient has >4 bone metastases. [0029] In some preferred embodiments, the patient has >1 visceral metastases.
  • the patient has de novo high-risk metastatic hormonesensitive prostate cancer.
  • the patient has recurrent high-risk metastatic hormonesensitive prostate cancer.
  • the patient has histologically confirmed adenocarcinoma of the prostate.
  • the patient received one or more other therapeutic interventions (e.g., androgen deprivation therapy, first generation anti-androgens, or taxane therapy) for prostate cancer prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • therapeutic interventions e.g., androgen deprivation therapy, first generation anti-androgens, or taxane therapy
  • the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, pre
  • the patient received treatment with androgen deprivation therapy (ADT) prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the ADT included administration of a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist.
  • LHRH luteinizing hormone-releasing hormone
  • the LHRH agonist or antagonist was riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADT included bilateral orchiectomy.
  • the patient received treatment with a taxane prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the taxane was docetaxel.
  • the patient received treatment with androgen deprivation therapy (ADT) and taxane therapy (e.g., docetaxel) prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the ADT included administration of a luteinizing hormone- releasing hormone (LHRH) agonist or antagonist.
  • LHRH luteinizing hormone- releasing hormone
  • the LHRH agonist or antagonist was riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADT included bilateral orchiectomy.
  • the patient received treatment with an anti-androgen prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the anti-androgen was bicalutamide, nilutamide, or flutamide.
  • the period of time the patient received the one or more other therapeutic interventions prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing, may be years, months, weeks, days, a single day.
  • the patient received three months or less of androgen deprivation therapy (when given without docetaxel) prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the patient received up to six cycles of docetaxel with androgen deprivation therapy prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the patient receives treatment with ADT on one or more days of administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the patient receives concurrent treatment with a luteinizing horm one-releasing hormone (LHRH) agonist or antagonist during the combination therapy; or the patient has had bilateral orchiectomy.
  • LHRH luteinizing horm one-releasing hormone
  • the LHRH agonist or antagonist is riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.
  • the administration of the combination therapy provided herein results in an increase in radiographic progression-free survival as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the administration of the combination therapy provided herein results in an increase in overall survival as compared to the administration of a combination of
  • prednisone prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the administration of the combination therapy provided herein results in an increase in clinical progression-free survival (cPFS) as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • cPFS clinical progression-free survival
  • the administration of the combination therapy provided herein results in an increase in castration-resistant prostate cancer (CRPC)-free survival as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • CRPC castration-resistant prostate cancer
  • the administration of the combination therapy provided herein results in an increase in time to PSA progression as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the administration of the combination therapy provided herein results in an increase in time to initiation of new anticancer therapy as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the administration of the combination therapy provided herein results in an increase in time to symptomatic progression as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • a method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer comprising administering to the patient a combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 7 The method according to clause 3, wherein abemaciclib is administered as a 50 mg oral dose twice daily.
  • Clause 8 The method according to clause 3, wherein abemaciclib is administered as a 100 mg oral dose twice daily.
  • Clause 11 The method according to any one of clauses 1-10, wherein abiraterone acetate is administered as a 500 mg oral dose once daily.
  • Clause 13 The method according to any one of clauses 1-10, wherein abiraterone acetate is administered as a 1000 mg oral dose once daily.
  • Clause 14 The method according to any one of clauses 1-13, wherein prednisone or prednisolone is administered as a 5 mg oral dose once daily.
  • Clause 15 The method according to any one of clauses 1-13, wherein methylprednisolone is administered as a 4 mg oral dose twice daily.
  • Clause 16 The method according to clause 3, wherein abemaciclib is administered as a 50 mg oral dose twice daily on days 1-28 of a 28-day cycle.
  • Clause 17 The method according to clause 3, wherein abemaciclib is administered as a 100 mg oral dose twice daily on days 1-28 of a 28-day cycle.
  • Clause 20 The method according to any one of clauses 16-19, wherein abiraterone acetate is administered as a 500 mg oral dose once daily on days 1-28 of the 28-day cycle.
  • Clause 21 The method according to clause 20, wherein the abiraterone acetate is micronized abiraterone acetate.
  • Clause 22 The method according to any one of clauses 16-19, wherein abiraterone acetate is administered as a 1000 mg oral dose once daily on days 1-28 of the 28-day cycle.
  • Clause 23 The method according to any one of clauses 16-22, wherein prednisone or prednisolone is administered as a 5 mg oral dose once daily on days 1-28 of the 28-day cycle.
  • Clause 24 The method according to any one of clauses 16-22, wherein methylprednisolone is administered as a 4 mg oral dose twice daily on days 1-28 of the 28-day cycle.
  • Clause 25 A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) abemaciclib; (ii) abiraterone acetate; and (iii) prednisone.
  • a method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily; (ii) a 1000 mg oral dose of abiraterone acetate once daily; and (iii) a 5 mg oral dose of prednisone once daily.
  • a method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily on days 1-28 of a 28-day cycle; (ii) a 1000 mg oral dose of abiraterone acetate once daily on days 1-28 of the 28-day cycle; and (iii) a 5 mg oral dose of prednisone once daily on days 1-28 of the 28-day cycle.
  • Clause 28 A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) abemaciclib; (ii) abiraterone acetate; and (iii) prednisolone.
  • a method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily; (ii) a 1000 mg oral dose of abiraterone acetate once daily; and (iii) a 5 mg oral dose of prednisolone once daily.
  • a method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily on days 1-28 of a 28-day cycle; (ii) a 1000 mg oral dose of abiraterone acetate once daily on days 1-28 of the 28-day cycle; and (iii) a 5 mg oral dose of prednisolone once daily on days 1-28 of the 28-day cycle.
  • a method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer comprising administering to the patient a combination of (i) abemaciclib; (ii) abiraterone acetate; and (iii) methylprednisolone.
  • a method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily; (ii) a 500 mg oral dose of micronized abiraterone acetate once daily; and (iii) a 4 mg oral dose of methylprednisolone twice daily.
  • a method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily on days 1-28 of a 28-day cycle; (ii) a 500 mg oral dose of micronized abiraterone acetate once daily on days 1-28 of the 28-day cycle; and (iii) a 4 mg oral dose of methylprednisolone twice daily on days 1-28 of the 28-day cycle.
  • Clause 34 The method according to any one of clauses 1-33, wherein the patient has >4 bone metastases.
  • Clause 35 The method according to any one of clauses 1-34, wherein the patient has >1 visceral metastases.
  • Clause 36 The method according to any one of clauses 1-35, wherein the patient has recurrent high-risk metastatic hormone-sensitive prostate cancer.
  • Clause 37 The method according to any one of clauses 1-36, wherein the patient received treatment with androgen deprivation therapy (ADT) prior to the first administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the ADT comprised administration of a luteinizing horm one-releasing hormone (LHRH) agonist or antagonist.
  • LHRH luteinizing horm one-releasing hormone
  • Clause 41 The method according to any one of clauses 1-40, wherein the patient received treatment with a taxane prior to the first administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 42 The method according to clause 41, wherein the taxane was docetaxel.
  • Clause 43 The method according to any one of clauses 1-35, wherein the patient has de novo high-risk metastatic hormone-sensitive prostate cancer.
  • Clause 44 The method according to any one of clauses 1-43, wherein the patient receives treatment with ADT on one or more days of administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 45 The method according to clause 44, wherein the ADT comprises administration of a luteinizing horm one-releasing hormone (LHRH) agonist or antagonist.
  • LHRH luteinizing horm one-releasing hormone
  • Clause 46 The method according to clause 45, wherein the LHRH agonist or antagonist is riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.
  • Clause 47 The method according to any one of clauses 1-46, wherein the administration of the combination results in an increase in radiographic progression-free survival as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0096] Clause 48.
  • Clause 49 The method according to any one of clauses 1-48, wherein the administration of the combination results in an increase in clinical progression-free survival (cPFS) as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • cPFS clinical progression-free survival
  • Clause 51 The method according to any one of clauses 1-50, wherein the administration of the combination results in an increase in time to PSA progression as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 52 The method according to any one of clauses 1-51, wherein the administration of the combination results in an increase in time to initiation of new anticancer therapy as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0101] Clause 53.
  • Clause 62 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 59, wherein the CDK4 and 6 inhibitor is ribociclib.
  • Clause 63 Abemaciclib for use in simultaneous, separate, or sequential combination with (i) abiraterone acetate; and (ii) prednisone; in the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer.
  • Clause 66 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 50-200 mg oral dose twice daily.
  • Clause 67 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 50 mg oral dose twice daily.
  • Clause 68 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 100 mg oral dose twice daily.
  • Clause 69 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 150 mg oral dose twice daily.
  • Clause 70 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 200 mg oral dose twice daily.
  • Clause 71 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of clauses 55 to 62 or Abemaciclib for use according to any one of clauses to 63 to 70, wherein abiraterone acetate is administered as a 500 mg oral dose once daily.
  • Clause 72 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 71, wherein abiraterone acetate is administered on days 1-28 of a 28-day cycle.
  • Clause 73 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of clauses 55 to 62 or Abemaciclib for use according to any one of clauses to 63 to 70, wherein abiraterone acetate is administered as a 1000 mg oral dose once daily.
  • Clause 74 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 73, wherein abiraterone acetate is administered on days 1-28 of a 28-day cycle.
  • Clause 75 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 71 to 74, wherein abiraterone acetate is administered as micronized abiraterone acetate.
  • Clause 76 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 56 or Abemaciclib for use according to clause 63, wherein prednisone is administered as a 5 mg oral dose once daily.
  • Clause 78 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 57 or Abemaciclib for use according to clause 64, wherein prednisolone is administered as a 5 mg oral dose once daily.
  • Clause 79 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 78, wherein prednisolone is administered on days 1-28 of a 28-day cycle.
  • Clause 80 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 58 or Abemaciclib for use according to clause 65, wherein methylprednisolone is administered as a 4 mg oral dose twice daily.
  • Clause 81 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 80, wherein methylprednisolone is administered on days 1-28 of a 28-day cycle.
  • Clause 82 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 81, wherein the patient has >4 bone metastases.
  • Clause 83 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or
  • Clause 84 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 83, wherein the patient has recurrent high-risk metastatic hormone-sensitive prostate cancer.
  • ADT androgen deprivation therapy
  • Clause 87 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 86, wherein the LHRH agonist or antagonist was riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.
  • Clause 88 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 85, wherein the ADT comprised bilateral orchiectomy.
  • Clause 89 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 88, wherein the patient received treatment with a taxane prior to the first administration of the simultaneous, separate, or sequential combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 90 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 89, wherein the taxane was docetaxel.
  • Clause 91 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 83, wherein the patient has de novo high-risk metastatic hormone-sensitive prostate cancer.
  • Clause 92 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 91, wherein the patient receives treatment with ADT on one or more days of administration of the simultaneous, separate, or sequential combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 94 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 93, wherein the LHRH agonist or antagonist is riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.
  • the LHRH agonist or antagonist is riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.
  • Clause 95 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 94, wherein the treatment results in an increase in radiographic progression-free survival as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 96 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 95, wherein the treatment results in an increase in overall survival as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 97 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 96, wherein the treatment results in an increase in clinical progression-free survival (cPFS) as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • cPFS clinical progression-free survival
  • Clause 98 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 97, wherein the treatment results in an increase in castration-resistant prostate cancer (CRPC)-free survival as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • CRPC castration-resistant prostate cancer
  • Clause 99 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 98, wherein the treatment results in an increase in time to PSA progression as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 100 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 99, wherein the treatment results in an increase in time to initiation of new anticancer therapy as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • Clause 101 A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 100, wherein the treatment results in an increase in time to symptomatic progression as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • prednisone prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • the term "patient” refers to an adult male, who has or is diagnosed with high-risk metastatic hormone-sensitive prostate cancer.
  • cancer and “cancerous” refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation.
  • the term "effective amount” refers to the amount or dose of (i) a CDK4 and 6 inhibitor (such as e.g., abemaciclib, palbociclib, or ribociclib), or a pharmaceutically acceptable salt thereof, (ii) the amount or dose of abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) the amount or dose of prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing, which provides an effective response in the patient under treatment.
  • a CDK4 and 6 inhibitor such as e.g., abemaciclib, palbociclib, or ribociclib
  • the term "effective response" of a patient or a patient's “responsiveness” to treatment with a combination of agents refers to the clinical or therapeutic benefit imparted to a patient upon administration of (i) a CDK4 and 6 inhibitor (such as e.g., abemaciclib, palbociclib, or ribociclib) or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.
  • a CDK4 and 6 inhibitor such as e.g., abemaciclib, palbociclib, or ribociclib
  • abiraterone or abiraterone acetate or a pharmaceutically acceptable salt of the foregoing
  • a measure of an effective response can include, but is not limited to, any one or more of progression free survival (PFS) (e.g., based on investigator assessment or blinded independent review (BICR)), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR), safety, patient-reported outcomes (PRO), pharmacokinetics (PK), or a best overall response (BOR) that may include complete response (CR), partial response (PR), or stable disease (SD).
  • PFS progression free survival
  • OS overall survival
  • ORR objective response rate
  • CBR clinical benefit rate
  • DCR disease control rate
  • DoR duration of response
  • PRO patient-reported outcomes
  • PK pharmacokinetics
  • BOR best overall response
  • an effective response is not limited to curing, eliminating, or ameliorating the disease or the clinical symptoms associated with the disease.
  • rPFS radiographic progression-free survival
  • rPFS refers to the time from the date of randomization in the Study to the earliest date of investigator-assessed radiographic disease progression in soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 [(RECIST 1.1) Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009, 45(2):228-247)] or bone disease per adapted Prostate Cancer Clinical Trials Working Group 3 [(PCWG3) Journal of Clinical Oncology 34, no. 12 (April 20, 2016) 1402-1418], or death from any cause, whichever occurs first.
  • OS all survival
  • cPFS clinical progression-free survival
  • the term “castration-resistant prostate cancer (CRPC)-free survival” refers to the time from the date of randomization in the Study to the earliest date of castration resistance, as demonstrated by any of the following (whichever occurs earliest): confirmed PSA progression with serum testosterone ⁇ 50 ng/dL ( ⁇ 1.73 nmol/L); investigator-assessed radiographic progression with serum testosterone ⁇ 50 ng/dL ( ⁇ 1.73 nmol/L); or death from any cause.
  • time to symptomatic progression refers to the time from randomization in the Study to any of the following (whichever occurs earlier): symptomatic skeletal event (SSE), defined as cancer-related symptomatic fracture, surgery or radiation to bone, or spinal cord compression; pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anticancer therapy; or development of clinically significant symptoms due to loco-regional tumor progression requiring surgical intervention or radiation therapy.
  • SSE symptomatic skeletal event
  • time to PSA progression refers to the time from the date of randomization in the Study to the date of first observation of prostate-specific antigen (PSA) progression.
  • PSA prostate-specific antigen
  • the PSA progression is defined as a >25% increase and an absolute increase of >2 ng/mL above the nadir (or baseline value if baseline is the lowest on study), which is confirmed by a second value obtained three or more weeks later. Any post-baseline PSA measurements within twelve weeks since baseline will be ignored in determining PSA progression.
  • time to initiation of new anticancer therapy refers to the time from randomization in the Study until the first initiation of a new anticancer therapy.
  • the term "advanced” or “metastatic” means cancers that have spread to one or more parts of the body that were not the site of the original cancerous tissue.
  • treating means the administration of a drug or drugs to a patient.
  • the terms can also be used in connection with diminishing, inhibiting, reducing, arresting, or ameliorating the disease, or to delay the onset of the biological manifestation of disease progression.
  • high-risk refers to the presence of >4 bone metastases or >1 visceral metastases.
  • bone metastases refers to cancer that has spread to the bone (e.g., the ribs, pelvis, or spine), wherein the metastases originated from a primary cancer site (e.g., prostate).
  • the term “visceral metastases” refers to cancer that has spread to the internal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the metastases originated from a primary cancer site (e.g., prostate).
  • a primary cancer site e.g., prostate
  • metastatic hormone-sensitive prostate cancer refers to metastatic hormone-sensitive prostate cancer at initial diagnosis.
  • recurrent metastatic hormone-sensitive prostate cancer or “relapsed metastatic hormone-sensitive prostate cancer” refers to prostate cancer that has reoccurred and metastasized after initial treatment.
  • Example 1 Randomized, Double-Blind, Placebo-Controlled Study of Abemaciclib in Combination with Abiraterone plus Prednisone in Men with High-Risk Metastatic Hormone-Sensitive Prostate Cancer (“The Study”)
  • Participants must have initiated ADT with LHRH agonist or antagonist or had bilateral orchiectomy prior to randomization. Up to 3 months of ADT prior to randomization is permitted with or without first-generation anti-androgen (for example, bicalutamide).
  • first-generation anti-androgen for example, bicalutamide
  • Prednisolone may be used in lieu of prednisone per local abiraterone prescribing information or where prednisone is not commercially available.
  • Control arm Placebo 200 mg orally twice daily.
  • Randomization will be stratified according to the following factors:
  • the primary endpoint of the study is investigator-assessed radiographic progression- free survival (rPFS) or death from any cause, whichever occurs first.
  • rPFS radiographic progression- free survival
  • rPFS In addition to the primary endpoint of rPFS by investigator-assessed radiographic disease progression or death, rPFS by BICR will be assessed. A central radiology vendor will collect and store images for BICR review. Secondary efficacy endpoints include clinical progression-free survival (cPFS), castration-resistant prostate cancer (CRPC)-free survival, time to PSA progression, time to initiation of new anticancer therapy, time to symptomatic progression and overall survival (OS).
  • cPFS clinical progression-free survival
  • CRPC castration-resistant prostate cancer
  • AE adverse event
  • ECG electrocardiogram
  • EQ-5D-5L European Quality of Life - 5 dimensions - 5 level
  • FACT-P Functional Assessment of Cancer Therapy - Prostate
  • PK pharmacokinetics
  • PSA prostate-specific antigen
  • PCS physical component summary
  • rPFS radiographic progression-free survival
  • SAE serious adverse event
  • TEAE treatment-emergent adverse event.
  • Well- differentiated neuroendocrine carcinoma, small cell or large cell neuroendocrine carcinoma, sarcomatoid, and carcinoid tumors are excluded.
  • visceral metastasis for example, liver, lung, adrenal
  • CT or MRI Local invasion (for example, bladder) or lymph node involvement does not qualify as visceral metastases.
  • a previously irradiated visceral lesion as the sole site of disease can meet high-risk metastatic disease criteria provided there has been subsequent radiographic progression at that site.
  • ADT Up to 3 months of ADT prior to randomization is permitted with or without first- generation anti-androgen (for example, bicalutamide).
  • first- generation anti-androgen for example, bicalutamide.
  • the start of ADT is the earliest date an LHRH agonist/antagonist was administered, or date of surgical castration.
  • bone-modifying agents for example, bisphosphonates or denosumab
  • dose must be stable for at least 4 weeks prior to randomization. This does not apply to patients on osteoporosis dosing.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • G-CSF granulocyte colonystimulating factor
  • LVEF left ventricular ejection fraction
  • ULN upper limit of normal. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.
  • Active systemic infections for example, bacterial infection requiring intravenous [IV] antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection requiring systemic therapy
  • viral load such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]). Screening is not required for enrollment. Have received live vaccination ⁇ 4 weeks prior to randomization. Inactivated vaccines are permitted. Current enrollment in a clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study. Have participated in any clinical trial for which treatment assignment is still blinded.

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Abstract

L'invention concerne des procédés, des utilisations et des combinaisons pour le traitement du cancer de la prostate hormono-sensible à haut risque, les procédés, les utilisations et des combinaisons comprenant l'administration (i) d'un inhibiteur de CDK4 et 6 ou d'un sel pharmaceutiquement acceptable de celui-ci, (ii) d'abiratérone ou d'acétate d'abiratérone, ou d'un sel pharmaceutiquement acceptable de ceux-ci ; et (iii) de la prednisone, de la prednisolone, ou de la méthylprednisolone, ou d'un sel pharmaceutiquement acceptable de ceux-ci.
PCT/US2022/052788 2021-12-15 2022-12-14 Combinaison pour le traitement du cancer de la prostate hormono-sensible à haut risque WO2023114264A1 (fr)

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