TW202339754A - Genomic loss of heterozygosity as a predictive biomarker for treatment with talazoparib and methods of treatment thereof - Google Patents

Abstract

The present invention relates to a method of selecting a subject having a cancer with a deficiency in homologous recombination repair, for treatment with talazoparib, or a pharmaceutically acceptable salt thereof, and methods of treatment thereof, including: a) determining a gLOH score from a biopsy of the cancer; b) selecting the subject for treatment with talazoparib, or a pharmaceutically acceptable salt thereof, based on the gLOH score; and c) administering a therapeutically effective amount of talazoparib, or a pharmaceutically acceptable salt thereof, to the selected subject.

Description

Genetic loss of heterozygosity as a predictive biomarker treated with talazopanib and its treatment method

The present invention relates to methods of selecting patients for treatment with talazopanib and methods of treatment thereof.

Poly(ADP-ribose) polymerase (PARP) is involved in the naturally occurring process of deoxyribonucleic acid (DNA) repair in cells. PARP inhibition has been shown to be an effective therapeutic strategy against tumors associated with mutations in double-stranded DNA repair genes by inducing synthetic lethality (Sonnenblick, A. et al., Nat. Rev. Clin. Oncol, 2015, 12( 1), 27-4). PARP inhibition is synthetically lethal in cells with homozygous deletions or deleterious alterations, or both, in DNA damage response (DDR) genes that are directly or indirectly involved in homologous recombination repair (HRR) (Lord, CJ et al., Science , 2017; 355: 1152-1158).

DDR is a network of pathways that has evolved to repair damaged DNA. These include, inter alia, mismatch repair, base excision repair and homologous recombination repair (HRR). Given the high fidelity of HRR in repairing double-stranded DNA breaks, it is particularly important in maintaining genome integrity. Inhibition of PARP leads to the accumulation of single-stranded DNA breaks and leads to DNA stress trapped by PARP, which ultimately results in double-stranded DNA breaks. Thus, PARP inhibitors selectively kill cancer cells lacking HRR - an example of synthetic lethality, a defect in the function of one gene or gene product that alone has a minimal effect but is not related to a defect in the function of a second gene or gene product. Mechanisms by which defects become toxic when merged.

Talazopanib is an orally available and potent small molecule PARP inhibitor. It is cytotoxic to human cancer cell lines carrying genetic mutations that impair DNA repair. This effect is called synthetic lethality and occurs by capturing DNA on the DNA. PARP proteins prevent DNA repair, replication and transcription.

The compound talazopanib is "(8 S ,9 R )-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1 H -1,2,4-triazole- 5-yl)-8,9-dihydro- 2H -pyrido[4,3,2- de ]pyrido-3( 7H )-one", also known as "( 8S , 9R )- 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1 H -1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro- 3H -pyrido[4,3,2- de ]pyrido-3-one" (also known as "PF-06944076", "MDV3800" and "BMN673") is a PARP inhibitor with the following structure: Talazopanib.

Talazopanib and its pharmaceutically acceptable salts, including tosylate, are disclosed in International Publication Nos. WO 2010/017055 and WO 2012/054698. Other methods of preparing talazopanib and its pharmaceutically acceptable salts, including the tosylate salt, are described in International Publication Nos. WO 2011/097602, WO 2015/069851 and WO 2016/019125 . Other methods of treating cancer using talazopanib and its pharmaceutically acceptable salts, including tosylate, are disclosed in International Publication Nos. WO 2011/097334 and WO 2017/075091.

TALZENNA ^® (talazopanib) (0.25 mg and 1 mg capsules) is approved in several countries, including the United States, and in the European Union, and is approved or under review in anticipation of approval in other countries for use in patients with harmful or treatment of adult patients with locally advanced or metastatic breast cancer with suspected deleterious gBRCAm HER2-negative breast cancer. Other capsule strengths of 0.5 mg and 0.75 mg have been approved in the United States. Talazopanib has shown activity in metastatic castration-resistant prostate cancer harboring genetic alterations directly or indirectly associated with HRR (de Bono et al., Lancet Oncol. 2021 Sep;22(9):1250- 1264). Talazopanib is being developed for various human cancers as a single agent and in combination with other agents.

Most cancer drugs are effective in some patients but not others. This can be attributed to genetic variation between tumors and can even be observed among tumors within the same patient. Variable patient responses are particularly evident for targeted therapies. Therefore, the full potential of targeted therapies may not be realized without suitable tests to determine which patients will benefit from which drugs. According to the National Institutes of Health (NIH), the term "biomarker" is defined as "a characteristic that is objectively measured and assessed as an indicator of normal biological or pathogenic processes or pharmacological response to a therapeutic intervention."

There are three different types of cancer biomarkers: (1) prognostic biomarkers, (2) predictive biomarkers, and (3) pharmacodynamic biomarkers. Prognostic biomarkers are used to classify cancers, such as solid tumors, according to their aggressiveness, ie, growth rate and/or metastasis rate, and refractiveness to treatment. This is sometimes called distinguishing "good outcome" tumors from "poor outcome" tumors. Predictive biomarkers are used to assess the likelihood that a specific patient will benefit from treatment with a specific drug. For example, patients with breast cancer with amplification of the ERBB2 (HER2 or NEU) gene may benefit from treatment with trastuzumab ( ^HERCEPTIN® ), whereas patients without ERBB2 gene amplification are unlikely to benefit from treatment with trastuzumab (HERCEPTIN®). Tocilizumab treatment. A pharmacodynamic biomarker is an indication of how a drug affects a patient when the patient takes it. Therefore, during the early stages of clinical development of new drugs, pharmacodynamic biomarkers are often used to guide dosage levels and dosing frequency. For a discussion of cancer biomarkers, see, for example, Sawyers, 2008, Nature 452:548-552.

Talazopanib is active in metastatic castration-resistant prostate cancer harboring DNA repair gene mutations and in gBRCA-mutated HER2-negative locally advanced or metastatic breast cancer; however, talazopanib may be more effective in cancer patients than Such indications. In addition, not all patients benefit from treatment with talazopanib in indications in which talazopanib has shown activity. Therefore, there is a need to select which patients with tumors harboring DNA repair gene mutations are likely to respond to talazopanib and to identify patients who may respond to talazopanib treatment in addition to patients with cancers with DNA repair gene mutations. of cancer patients. Therefore, there is a need for diagnostic methods based on predictive biomarkers that can be used to identify cancer patients who are likely (or unlikely) to respond to treatment with talazopanib.

The present invention provides, in part, methods of selecting patients and identifying cancers for treatment with talazopanib or a pharmaceutically acceptable salt thereof, and methods of treating the same. This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used solely as an aid in determining the scope of the claimed subject matter.

According to Embodiment 1 of the present invention, there is provided a method of selecting individuals suffering from cancer with homologous recombination repair defects for treatment with talazopanib or a pharmaceutically acceptable salt thereof, which includes: a) according to the cancer The biopsy determines the genetic loss of heterozygosity (gLOH) score; and b) selecting individuals for treatment with talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score.

According to Embodiment 2 of the present invention, a method for treating cancer with homologous recombination repair defects in an individual is provided, which includes: a) determining a gene loss of heterozygosity (gLOH) score based on a biopsy of the cancer; b) selecting based on the gLOH score The subject is treated with talazopanib or a pharmaceutically acceptable salt thereof; and c) administering a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score.

According to Embodiment 3 of the present invention, a method for identifying cancers with homologous recombination repair defects that are sensitive to treatment with talazopanib or a pharmaceutically acceptable salt thereof is provided, which method includes: a) based on a biopsy of the cancer Determining a genetic loss of heterozygosity (gLOH) score; and b) selecting cancers for treatment with talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score.

According to Embodiment 4 of the present invention, a method for cancer with homologous recombination repair deficiency that is sensitive to treatment with talazopanib or a pharmaceutically acceptable salt thereof is provided, which method includes: a) based on biopsy determination of the cancer Gene loss of heterozygosity (gLOH) score; b) selecting cancers for treatment with talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score; and c) administering a therapeutically effective amount of talazopanib based on the gLOH score Pany or its pharmaceutically acceptable salt.

Embodiments of the present invention are described below, wherein for convenience, Embodiments 1, 2, 3 and 4 (E1, E2, E3 and E4) are consistent with the embodiments provided above.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of the invention as claimed.

The present invention can be more easily understood with reference to the following detailed description of the embodiments and preferred embodiments of the invention. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It is further understood that unless specifically limited herein, terms used herein have their conventional meanings as known in the relevant art.

E1 A method of selecting individuals with cancers that are defective in homologous recombination repair, as defined above.

E2 A method of treating cancer in an individual that is defective in homologous recombination repair, as defined above.

E3 A method of identifying cancers with homologous recombination repair deficiency that are susceptible to treatment with talazopanib or a pharmaceutically acceptable salt thereof, as defined above.

E4 A method of treating cancer having homologous recombination repair deficiency that is susceptible to treatment with talazopanib or a pharmaceutically acceptable salt thereof, as defined above.

E5 The method of embodiment 1 or 2, wherein the cancer is sensitive to treatment with talazopanib.

E6 The method of any one of embodiments 1 to 4, wherein the cancer is prostate cancer.

E7 The method of embodiment 6, wherein the prostate cancer is metastatic prostate cancer.

E8 The method of embodiment 6, wherein the prostate cancer is castration-resistant prostate cancer.

E9 The method of embodiment 8, wherein the castration-resistant prostate cancer is metastatic castration-resistant prostate cancer.

E10: The method of embodiment 1 or 3, wherein the homologous recombination repair defect of the cancer is determined by next-generation sequencing.

E11: The method of embodiment 1 or 3, wherein step a) is performed by next-generation sequencing.

E12 The method of any one of embodiments 1 to 11, wherein the gLOH fraction is at least about 8.0%.

E13 The method of any one of embodiments 1 to 11, wherein the gLOH fraction is at least about 8.3%.

E14 The method of any one of embodiments 1 to 11, wherein the gLOH fraction is at least about 8.8%.

E15 The method of any one of embodiments 1 to 11, wherein the gLOH fraction is at least about 9%; at least about 9.2%; at least about 10%; at least about 11%; at least about 12%; at least about 13%; at least about 14%; at least about 15%; at least about 16%; at least about 17%; at least about 18%; at least about 19%; at least about 20%; at least about 21%; at least about 22%; at least about 23%; at least about 24%; or at least about 25%.

E16 The method of any one of embodiments 1 to 11, wherein the gLOH fraction is at least 8.0%.

E17 The method of any one of embodiments 1 to 11, wherein the gLOH fraction is at least 8.3%.

E18 The method of any one of embodiments 1 to 11, wherein the gLOH fraction is at least 8.8%.

E19 The method of any one of embodiments 1 to 11, wherein the gLOH fraction is at least 9%; at least 9.2%; at least 10%; at least 11%; at least 12%; at least 13%; at least 14%; at least 15%; At least 16%; at least 17%; at least 18%; at least 19%; at least 20%; at least 21%; at least 22%; at least 23%; at least 24%; or at least 25%.

E20: The method of embodiment 1 or 2, wherein the individual system is human.

Each embodiment of the invention described herein may be combined with one or more other embodiments of the invention described herein that are inconsistent with the embodiment with which it is merged. In addition, the various examples of the invention described below contemplate pharmaceutically acceptable salts of the compounds of the invention within their scope.

Unless otherwise specified, as used herein, the singular forms "a/an" and "the" include plural references.

As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the amount of talazopanib) means that the parameter may be lower or higher relative to the stated numerical value of the parameter. Maximum 10% variation. For example, a dose of approximately 1 mg may vary between 0.9 mg and 1.1 mg.

Unless otherwise specified, as used herein, "abnormal cell growth" refers to cell growth that does not rely on normal regulatory mechanisms (eg, loss of contact inhibition). Abnormal cell growth can be benign (noncancerous) or malignant (cancerous).

For the purposes of the present invention, "DDR mutation(s)", "DDR alteration(s)", "HRR mutation(s)" and "HRR alteration(s)" s))” refers to changes/mutation in genes involved directly or indirectly in homologous recombination repair (HRR). Although it is not as scientific as the phrase "DNA damage response", it is generally understood that "DDR" can also be called "DNA damage repair" or "DNA repair".

The terms "cancer", "cancerous" and "malignant" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. As used herein, "cancer" refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. As used herein, "cancer" refers to a solid tumor, named after the type of cells that form the tumor, or a cancer of the blood, bone marrow, or lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. The term "cancer" includes, but is not limited to, primary cancers that originate in a specific part of the body, metastatic cancers that spread from the initial location to other parts of the body, initial primary cancers that recur after remission, and new primary cancers that are new to an individual. A second primary cancer in which the individual has a prior history of cancer that is of a different type than the subsequent cancer. Examples of cancer include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More specific examples of such cancers include squamous cell carcinoma, myeloma, lung cancer, small cell lung cancer, small cell prostate cancer, non-small cell lung cancer, glioma, hodgkin's lymphoma, non-Hodgkin's lymphoma, Non-hogkin's lymphoma (non-hogkin's lymphoma), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLCBCL), acute myeloid leukemia (AML), multiple myeloma, gastrointestinal (tract) cancer, Kidney cancer, ovarian cancer, uterine cancer, endometrial cancer, liver cancer, kidney cancer, renal cell carcinoma, prostate cancer, castration-sensitive prostate cancer (CSPC), castration-resistant prostate cancer (CRPC), thyroid cancer, melanoma , chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma, polymorphic cell tumor, cervical cancer, rectal cancer, brain cancer, stomach cancer, bladder cancer, liver cancer, hepatocellular carcinoma, breast cancer, colorectal cancer , head and neck cancer and salivary gland cancer.

The term "patient" or "subject" refers to any single individual in need of treatment or who is participating in a clinical trial, epidemiological study or control, including human and mammalian veterinary patients, such as cattle, Horses, dogs and cats. In certain preferred embodiments, the patient or subject is a human.

As used herein, the term "treating" cancer means administering to an individual suffering from cancer or diagnosed with cancer a therapy according to the present invention to achieve at least one positive therapeutic effect, such as reducing the number of cancer cells , reduce the size of a tumor, reduce the rate of infiltration of cancer cells into surrounding organs, or reduce the rate of tumor metastasis or tumor growth, reverse, alleviate, inhibit the disease or condition to which such terms apply, or the effect of such disease or condition Progression or prevention of recurrence of one or more symptoms. Unless otherwise indicated, the term "treatment" as used herein refers to the act of treating as "treatment" is defined immediately above. The term "treatment" also includes adjuvant and neoadjuvant treatment of an individual. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of neoplastic or cancerous cells (or destroying neoplastic or cancerous cells); inhibiting metastasis or neoplastic cells cells; shrink or reduce the size of tumors; remission of cancer; reduce symptoms caused by cancer; improve the quality of life of people with cancer; reduce the dosage of other drugs needed to treat cancer; slow the progression of cancer; cure cancer; overcome cancer one or more resistance mechanisms; and prolonging the survival of patients with cancer. Active therapeutic effects in cancer can be measured in a variety of ways (see, eg, WA Weber, J. Nucl. Med. 50:1S-10S (200)). In some embodiments, treatment achieved by the methods of the invention is any of the following: partial response (PR), complete response (CR), stable disease (SD), progressive disease (PD), overall response (OR) , objective response rate (ORR), progression-free survival (PFS), radiation PFS, disease-free survival (DFS) and overall survival (OS). PFS (also known as "time to tumor progression") refers to the time during and after treatment when the cancer is not growing, and includes the amount of time the patient has experienced CR or PR and the amount of time the patient has experienced stable disease (SD) quantity. DFS refers to the length of time during and after treatment that a patient remains disease-free. OS refers to the increase in life expectancy compared to a new or untreated individual or patient. In some embodiments, the response to the methods of the invention is any of PR, CR, SD, PD, PFS, DFS, ORR, OR, or OS. Response to the methods of the invention, including duration of soft tissue response, was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) response criteria. In some embodiments, treatment achieved by the methods of the invention is measured by time to PSA progression, time to initiation of cytotoxic chemotherapy, and proportion of patients with a PSA response greater than or equal to 50%. The treatment regimen of the methods of the present invention for effective treatment of cancer patients can vary depending on factors such as the condition of the disease, the age and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the individual. Although embodiments of any aspect of the invention may not be effective in achieving a positive therapeutic effect in each individual, they should be in a statistically significant number of individuals as determined by any statistical test known in the art. To achieve such an effect, tests such as but not limited to Cochran-Mantel-Haenszel log-rank test, Student's t-test, chi-square test (chi2 -test), U test based on Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere test -Terpstrat-test) and Wilcon on-test. The term "treatment" also encompasses in vitro and ex vivo treatment of, for example, a cell by means of an agent, diagnostic agent, binding compound or by another cell.

As used herein, a "dosage", "amount", "effective dosage" or "effective amount" of a drug, compound or pharmaceutical formulation is sufficient to treat a disease, An amount that has a beneficial or desirable effect on any one or more symptoms (biochemical, histological and/or behavioral) of its complications and intermediate pathological phenotypes present during the development of the disease. For therapeutic uses, a "therapeutically effective amount" means an amount of a compound administered that will alleviate to some extent one or more of the symptoms of the condition being treated. Regarding the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects: (1) reduce the size of the tumor, (2) inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis, (3) (i.e., slow down, preferably stop) tumor growth or tumor invasiveness to a certain extent, (4) alleviate (or preferably eliminate) one or more symptoms associated with cancer to a certain extent or symptoms, (5) reduce the dose of other drugs needed to treat the disease, (6) enhance the effect of another drug, and/or (7) delay the progression of the patient's disease. An effective dose may be administered in one or more administration forms. For the purposes of the present invention, an effective dose of a drug, compound or pharmaceutical formulation is an amount sufficient to effect, directly or indirectly, prophylactic or therapeutic treatment. As understood in the clinical context, an effective dose of a drug, compound or pharmaceutical formulation may or may not be achieved together with another drug, compound or pharmaceutical formulation.

In one embodiment, a certain amount of talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate is administered once a day at about 0.1 mg to about 2 mg, preferably at a dosage of about 0.25 mg once a day. mg to about 1.5 mg, and preferably administered at a daily dose of about 0.5 mg to about 1.0 mg once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate is administered once daily at about 0.1 mg, about 0.25 mg, about 0.35 mg, about 0.5 mg, about 0.75 mg mg or a daily dose of approximately 1.0 mg administered. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate is administered once daily at about 0.1 mg, about 0.25 mg, about 0.35 mg or about 0.5 mg once daily. Dosage administration. In one embodiment, talazopanib, or a pharmaceutically acceptable salt thereof and preferably its tosylate salt, is administered at a daily dose of about 0.25 mg, about 0.35 mg, or about 0.5 mg once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate salt is administered at a daily dose of about 0.5 mg, about 0.75 mg, or about 1.0 mg once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate salt is administered at a daily dose of about 0.1 mg once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate salt is administered at a daily dose of about 0.25 mg once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate salt is administered at a daily dose of about 0.35 mg once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate salt is administered at a daily dose of about 0.5 mg once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate salt is administered at a daily dose of about 0.75 mg once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof and preferably its tosylate salt is administered at a daily dose of about 1.0 mg once daily. The dosages provided herein refer to the dosage of the free base form of talazopanib or calculated as the free base equivalent of the salt form of talazopanib administered. For example, doses or amounts of talazopanib such as 0.5, 0.75 mg or 1.0 mg refer to free base equivalents. This dosage regimen can be adjusted to provide optimal therapeutic response. For example, the dosage may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.

Unless otherwise specified, the term "pharmaceutically acceptable salt" as used herein refers to salts that do not cause significant irritation to the organism to which they are administered and do not eliminate the biological activity and properties of the compound. Formulations of compounds. In some cases, pharmaceutically acceptable salts are prepared by combining a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methane sulfonic acid, ethane sulfonic acid, p-toluene Obtained from the reaction of sulfonic acid, salicylic acid and their analogues. In some cases, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group described herein with a base to form a salt, such as an ammonium salt; a base, or by other predetermined methods. Metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; salts of organic bases, such as dicyclohexylamine; N-methyl-D-reduced glucosamine; ginseng (hydroxymethyl) Methylamine and its salts with amino acids such as arginine, lysine and the like.

"Neoplasm" when applied to an individual diagnosed with or suspected of having cancer means a malignant or potentially malignant neoplasm or mass of tissue of any size and includes primary tumors and secondary neoplasms. Solid tumors are abnormal growths or masses of tissue that usually do not contain cysts or areas of fluid. Examples of solid tumors are sarcomas, carcinomas and lymphomas. Leukemias (blood cancers) do not usually form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

"Tumor burden", also known as "tumor burden", refers to the total amount of tumor material distributed in the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor in the entire body, including lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, such as using calipers, or when in the body using imaging techniques such as ultrasound, bone scans, computed tomography (CT) or magnetic resonance imaging ( MRI) scan.

The term "tumor size" refers to the total size of the tumor as measured by the length and width of the tumor. Tumor size can be determined by a variety of methods known in the art, such as after removal from the subject, such as using a caliper, or while in the body using imaging techniques such as bone scans, ultrasound, CR or MRI scans. Measure the size of the tumor.

The present invention relates to a method of selecting individuals with cancer having homologous recombination repair deficiency for treatment with talazopanib or a pharmaceutically acceptable salt thereof, comprising: a) determining a gLOH score based on a biopsy of the cancer ; and b) selecting individuals for treatment with talazopanib or a pharmaceutically acceptable salt thereof based on gLOH score. The method further includes administering talazopanib or a pharmaceutically acceptable salt thereof to the selected individual.

The present invention relates to a method of selecting individuals suffering from cancer with homologous recombination repair deficiency for treatment with talazopanib or a pharmaceutically acceptable salt thereof, comprising: a) determining the gLOH score based on a biopsy of the cancer; and b) selecting an individual for treatment with talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score; and further comprising administering talazopanib or a pharmaceutically acceptable salt thereof to the selected individual .

The methods of the invention are suitable for selecting individuals for treatment with talazopanib. In particular, the methods of the present invention are suitable for selecting individuals with cancers having homologous recombination repair defects for treatment with talazopanib or a pharmaceutically acceptable salt thereof.

The present invention relates to a method for treating cancer with homologous recombination repair deficiency in an individual, which includes: a) determining a gLOH score based on a biopsy of the cancer; and b) administering a therapeutically effective amount of talazopanib or talazopanib based on the gLOH score. Its pharmaceutically acceptable salt.

In one aspect, the invention relates to the use of talazopanib or a pharmaceutically acceptable salt thereof in the treatment of cancer with homologous recombination repair deficiency in an individual, comprising: a) based on a biopsy of the cancer Determine the gLOH score; and b) administer a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score.

In one aspect, the present invention relates to the use of talazopanib or a pharmaceutically acceptable salt thereof as an agent for treating cancer with homologous recombination repair deficiency in an individual, comprising: a) Determine the gLOH score based on the biopsy of the cancer; and b) administer a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score.

The method of the invention is suitable for treating cancer. In particular, the methods of the present invention are suitable for the treatment of cancers with defects in homologous recombination repair. Furthermore, the methods of the present invention are suitable for identifying cancers with homologous recombination repair defects that are sensitive to cancer treatments, such as treatment with talazopanib. In some embodiments, the provided methods result in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) Inhibit cancer cell metastasis; (5) inhibit angiogenesis; or (6) overcome one or more resistance mechanisms related to cancer treatment.

In one embodiment, the present invention relates to a method for identifying cancers with homologous recombination repair defects that are sensitive to treatment with talazopanib or a pharmaceutically acceptable salt thereof, which comprises: a) based on the characteristics of the cancer Biopsy determines the gene loss of heterozygosity (gLOH) score; and b) administers a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score.

"Genomic loss of heterozygosity" or "gLOH" is caused by homologous recombination repair (HRR) defects and results in a region of the gene body where genes exist in a homozygous or semi-zygous state. According to the methods of the invention, individuals with cancers having homologous recombination repair defects are selected for treatment with talazopanib based on gLOH scores. The gLOH score can be determined according to Sokol et al., JCO Precis Oncol . 2020;4:442-465, which provides a detailed description of gLOH measurement and performance as follows: Method: Assayed using FoundationOne ^® CDx (Foundation Medicine, Inc.) Sequenced genome-wide aneuploidy/copy number map and minor allele frequency (AF) of >3,500 polymorphic single nucleotide polymorphisms (SNPs), inferred LOH segments of 22 autosomal chromosomes . Using a comparative genomic hybridization-type approach, a log-ratio profile of the sample was obtained by normalizing the sequence coverage obtained at all exons and genome-wide SNPs against a normal control matched to the treatment (Frampton GM et al.: Nat. Biotechnol 31 :1023-1031, 2013). This map was segmented and interpreted using AF of sequenced SNPs to estimate the number of copies (Ci) and minor allele count (Mi) at each segment (i). If Ci≠0 and Mi=0, the segment is determined to have LOH. Low tumor content or low aneuploidy systems are the most common reasons for failure to pass quality control for gLOH inference. Calculation of percent gLOH excludes two types of LOH segments: LOH segments spanning ≥90% of the entire chromosome or chromosome arm because these LOH events typically arise via non-HRD mechanisms (e.g., mitotic nondisjunction), and LOH inference is not clear area. For each tumor, the percent gLOH was calculated as 100×the total length of the non-excluded LOH regions (xi) divided by the total length of the non-excluded regions of the genome.

In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 8.8%; at least about 9%; at least about 9.2%; at least about 10%; at least about 11%; at least about 12%; at least about 13%; At least about 14%; at least about 15%; at least about 16%; at least about 17%; at least about 18%; at least about 19%; at least about 20%; at least about 21%; at least about 22%; at least about 23%; At least about 24%; or at least about 25%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 24%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 23%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 22%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 21%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 20%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 19%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 18%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 17%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 16%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 15%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 14%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 13%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 12%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 11%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 10%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 9%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 8.8%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 8.3%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least about 8.0%.

In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 8.8%; at least 9%; at least 9.2%; at least 10%; at least 11%; at least 12%; at least 13%; at least 14%; at least 15 %; at least 16%; at least 17%; at least 18%; at least 19%; at least 20%; at least 21%; at least 22%; at least 23%; at least 24%; or at least 25%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 24%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 23%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 22%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 21%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 20%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 19%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 18%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 17%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 16%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 15%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 14%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 13%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 12%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 11%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 10%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 9%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 8.8%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 8.3%. In one embodiment of the invention, the gLOH fraction or gLOH percentage is at least 8.0%.

Next generation sequencing (NGS) is any of several high-throughput methods for DNA sequencing that use the concept of massively parallel processing. Although there are many different NGS platforms using different sequencing technologies, all NGS platforms perform sequencing of millions of small DNA fragments in parallel. Those skilled in the art are familiar with next generation sequencing.

According to the methods of the present invention, homologous recombination repair defects in cancer or tumors can be determined using next generation sequencing.

According to the methods of the present invention, next generation sequencing can be used to determine the gLOH score from a cancer biopsy. For example, a panel-based sequencing assay capable of assessing gLOH can be used, such as FoundationOne® CDx (Foundation Medicine, Inc.). gLOH is available as part of the FoundationOne® CDx test in select gynecological conditions. Dual genetic alterations in DDR/HRR genes have been reported to be associated with increased gLOH in a range of tumor types, including those that benefit from PARP inhibitors, such as breast, ovarian, prostate, and pancreatic cancers (Westphalen B et al., Clin Cancer Res. 2021). However, in general, gLOH scores are relatively low in prostate cancer and do not exhibit the dynamic range seen in breast and ovarian cancer (Sokol ES et al. JCO Precis Oncol. 2020;4:442-465).

A method of selecting individuals with cancer having homologous recombination repair deficiency for treatment with talazopanib or a pharmaceutically acceptable salt thereof, comprising: a) determining loss of gene heterozygosity based on a biopsy of the cancer ( gLOH) score; and b) if the gLOH score is at least 8.8%, select the individual for treatment with talazopanib or a pharmaceutically acceptable salt thereof.

A method of identifying cancers with homologous recombination repair defects that are susceptible to treatment with talazopanib or a pharmaceutically acceptable salt thereof, comprising: a) determining genetic loss of heterozygosity (gLOH) based on a biopsy of the cancer score; and b) if the gLOH score is at least 8.8%, administer a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention relates to a method of treating cancer in an individual with homologous recombination repair deficiency, comprising: a) determining the gLOH score based on a biopsy of the cancer; and b) if the gLOH score is at least 8.8%, then Administer a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to the use of talazopanib or a pharmaceutically acceptable salt thereof in the treatment of cancer in an individual with homologous recombination repair deficiency, comprising: a) based on a biopsy of the cancer Determine the gLOH score; and b) if the gLOH score is at least 8.8%, administer a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to the use of talazopanib or a pharmaceutically acceptable salt thereof as a medicament for the treatment of cancer in an individual with homologous recombination repair deficiency, comprising: a) according to Biopsy of the cancer determines the gLOH score; and b) if the gLOH score is at least 8.8%, administer a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the individual is a mammal.

In one embodiment of the invention, the individual system is human.

In embodiments, the methods of the present invention may be suitable for treating cancer, including but not limited to the following cancers: Circulatory system, such as heart (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-related vascular tissue; Respiratory tract, such as nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi and lungs, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated Large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma; Gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glycemic cystoma, gastrinoma, carcinoid, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid, Karposi's sarcoma (Karposi's sarcoma), leiomyoma, hemangioma, lipoma, nerve Fibroids, fibroids), large intestine (adenocarcinoma, ductal adenoma, ciliated adenoma, hamartoma, leiomyoma); Genitourinary tract, such as kidney (adenocarcinoma, Wilm's tumor [Wilm's tumor], lymphoma, leukemia), bladder and/or urethra (squamous cell carcinoma, transitional cell or urothelial carcinoma) , adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroglandular tumors, adenomatoid tumors, lipomas); Liver (such as liver cancer, hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hematoma, pancreatic endocrine tumors (such as pheochromocytoma, insulinoma, vasoactive intestinal peptide tumors , islet cell tumors and glucagonoma); Bones, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell Chordoma, osteochondroma (osteochondral exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system, such as tumors of the central nervous system (CNS), primary CNS lymphoma, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis malformation), meninges (meningioma, meningiosarcoma) , glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, blastoma [pineal tumor], glioblastoma multiforme, oligodendroma Glioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma; Reproductive system, such as gynecology, uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma] tumor], theca cell tumor, Sertoli-Leydig cell tumor (Sertoli-Leydig cell tumor), dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma) , adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), fallopian tube (carcinoma) and other parts associated with female reproductive organs; Placenta, penis, prostate, testicles and other parts associated with male reproductive organs; Blood system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease , non-Hodgkin's lymphoma [malignant lymphoma]; Oral cavity, such as lips, tongue, gingiva, floor of the mouth, palate and other parts of the mouth, parotid glands and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, piriform fossa, hypopharynx, and other parts of the lips , oral cavity and pharynx; Skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma and keloid; Adrenal gland: neuroblastoma; and Other tissues, including connective and soft tissue, retroperitoneal cavity and peritoneum, eye, intraocular melanoma and adnexa, breast, head or/and neck, anal area, thyroid, parathyroid, adrenal and other endocrine glands and related Secondary and unspecified malignant neoplasms of structures, lymph nodes, secondary malignant neoplasms of respiratory and digestive systems, and secondary malignant neoplasms of other parts.

When used herein in connection with the present invention, examples of "cancer" include cancers selected from the group consisting of: lung cancer (NSCLC and SCLC), breast cancer (including triple-negative breast cancer, hormone-positive breast cancer, HER2-negative breast cancer, HER2-positive breast cancer, and triple-positive breast cancer). Breast cancer), ovarian cancer, colorectal cancer, rectal cancer, anal area cancer, prostate cancer (including castration-sensitive or hormone-sensitive prostate cancer and hormone-refractory prostate cancer, also known as castration-resistant prostate cancer), hepatocellular carcinoma , diffuse large B-cell lymphoma, follicular lymphoma, melanoma and salivary gland tumors, or a combination of one or more of the foregoing cancers.

When used herein in connection with the present invention, examples of "cancer" include cancers selected from the group consisting of: lung cancer (NSCLC and SCLC), breast cancer (including triple-negative breast cancer, hormone-positive breast cancer and HER2-negative breast cancer), ovarian cancer, prostate cancer (including castration-sensitive or hormone-sensitive prostate cancer and hormone-refractory prostate cancer, also known as castration-resistant prostate cancer), or a combination of one or more of the foregoing cancers.

As used herein in connection with the present invention, examples of "cancer" include cancers selected from the group consisting of prostate cancer, androgen receptor-positive breast cancer, hepatocellular carcinoma, and salivary gland tumors, or one or more of the foregoing. combination.

As used herein in connection with the present invention, examples of "cancer" include cancers selected from the group consisting of androgen receptor-positive breast cancer, hepatocellular carcinoma, and salivary gland tumors, or a combination of one or more of the foregoing.

When used herein in connection with the present invention, examples of "cancer" include cancers selected from the group consisting of triple-negative breast cancer, hormone-positive breast cancer, HER2-negative breast cancer, triple-positive breast cancer, castration-sensitive prostate cancer, castration-resistant prostate cancer, Hepatocellular carcinoma, salivary gland tumors, or a combination of one or more of the foregoing cancers.

As used herein in connection with the present invention, examples of "cancer" include cancers selected from the group consisting of triple-negative breast cancer, hormone-positive breast cancer, and HER2-negative breast cancer, or a combination of one or more of the foregoing.

As used herein in connection with the present invention, examples of "cancer" include cancers selected from the group consisting of castration-sensitive prostate cancer and castration-resistant prostate cancer, or a combination of one or more of the foregoing.

In one embodiment of the invention, the cancer is a solid tumor.

In one embodiment of the invention, the cancer is a solid tumor that is androgen dependent.

In one embodiment of the invention, the cancer is a solid tumor that expresses androgen receptors.

In one embodiment, the cancer is prostate cancer.

In one embodiment, the cancer is high risk prostate cancer.

In one embodiment, the cancer is locally advanced prostate cancer.

In one embodiment, the cancer is high risk locally advanced prostate cancer.

In one embodiment, the cancer is metastatic prostate cancer.

In one embodiment, the cancer is hormone-sensitive prostate cancer, also known as castration-sensitive prostate cancer. Hormone-sensitive prostate cancer is usually characterized by histologically or cytologically confirmed adenocarcinoma of the prostate that remains responsive to androgen ablation therapy.

In one embodiment, the cancer is non-metastatic hormone-sensitive prostate cancer.

In one embodiment, the cancer is high-risk non-metastatic hormone-sensitive prostate cancer.

In one embodiment, the cancer is metastatic hormone-sensitive prostate cancer.

In one embodiment, the cancer is castration-sensitive prostate cancer.

In one embodiment, the cancer is non-metastatic castration-sensitive prostate cancer.

In one embodiment, the cancer is metastatic castration-sensitive prostate cancer.

In one embodiment, the cancer is castration-sensitive prostate cancer harboring a DDR mutation. In one embodiment, the cancer is non-metastatic castration-sensitive prostate cancer harboring a DDR mutation. In one embodiment, the cancer is metastatic castration-sensitive prostate cancer harboring a DDR mutation. Mutated DDR genes include, but are not limited to, ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C.

In one embodiment, the cancer is castration-resistant prostate cancer, also known as hormone-refractory prostate cancer or androgen-independent prostate cancer. Castration-resistant prostate cancer is typically characterized by histological or cytological confirmation in the setting of castrate levels of testosterone (e.g., ≤1.7 nmol/L testosterone or ≤50 ng/dL testosterone). The adenocarcinoma of the prostate is castration-resistant (e.g., defined as 2 or more consecutive increases in PSA, with ≥1 week between assessments, leading to 2 or more increases above the nadir as appropriate) A 50% or greater increase in PSA levels ≥2 ng/mL), castration of testosterone is achieved by androgen ablation therapy and/or after orchiectomy.

In one embodiment, the cancer is castration-resistant prostate cancer.

In one embodiment, the cancer is non-metastatic castration-resistant prostate cancer.

In one embodiment, the cancer is metastatic castration-resistant prostate cancer.

In one embodiment, the cancer is castration-resistant prostate cancer harboring a mutation. In one embodiment, the cancer is non-metastatic castration-resistant prostate cancer harboring a DDR mutation. In one embodiment, the cancer is metastatic castration-resistant prostate cancer harboring a DDR mutation. Mutated DDR genes include, but are not limited to, ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C.

In one embodiment, the cancer is breast cancer.

In one embodiment, the cancer is locally advanced or metastatic breast cancer.

In one embodiment, the cancer is triple negative breast cancer.

In one embodiment, the cancer is hormone-positive breast cancer, including estrogen-positive breast cancer and/or progesterone-positive breast cancer.

In one embodiment, the cancer is HER2 negative breast cancer.

In one embodiment, the cancer is germline BRCA-mutated HER2-negative breast cancer.

In one embodiment, the cancer is HER2-positive breast cancer.

In one embodiment, the cancer is triple positive breast cancer.

In one embodiment, the cancer is ovarian cancer.

In one embodiment, the cancer is small cell lung cancer.

In one embodiment, the cancer is Ewing's sarcoma.

In one embodiment, the cancer is hepatocellular carcinoma.

In one embodiment, the cancer is a salivary gland tumor.

In one embodiment, the cancer is locally advanced.

In one embodiment, the cancer is non-metastatic.

In one embodiment, the cancer is metastatic.

In one embodiment, the cancer is refractory to treatment.

In one embodiment, the cancer recurs.

In one embodiment, the cancer is intolerant to standard treatments.

In one embodiment of the invention, the method is administered to an individual diagnosed with cancer that has become resistant to treatment.

In another aspect, the methods of the present invention may additionally comprise administering other anti-cancer agents, such as anti-neoplastic agents, anti-angiogenic agents, signal transduction inhibitors, and anti-proliferative agents, in amounts that together are effective to treat the cancer. In some such embodiments, the anti-neoplastic agent is selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radioactive agents, cell cycle inhibitors, enzymes , topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, antihormonal agents, androgen ablation therapy and anti-androgens. In one embodiment of the invention, the other anti-cancer agent is an anti-androgen agent. In one embodiment of the invention, the antiandrogen is enzalutamide or apalutamide.

Example 1 : Based on talazopanib monotherapy in patients with DNA fix changes (TALAPRO-1) Open labeling in metastatic castration-resistant prostate cancer 2 Genomic analysis of phase 1 trials : gLOH Exploratory correlation analysis of scores and associations method

Clinical trial design: Open-label phase II clinical trial of the PARP inhibitor talazopanib in patients with metastatic castration-resistant prostate cancer with DNA repair alterations (de Bono et al., Lancet Oncol. 2021 Sep;22(9):1250-1264).

Eligibility criteria : Eligible patients are men 18 years of age or older with progressive metastatic castration-resistant prostate cancer with adenocarcinoma histology. Disease progression was defined as at least three increasing prostate-specific antigen (PSA) values with a time interval of at least 1 week between readings, worsening of soft tissue disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or by progression of soft tissue disease Progression of skeletal disease with two or more new metastatic lesions on bone scan as defined by Prostate Cancer Working Group 3 (PCWG3) criteria. To qualify candidates solely by PSA progression, the screening central laboratory PSA value needs to be 2 µg/L or higher. Clinical trial inclusion criteria were revised after initiation. The original clinical trial design allowed for the enrollment of patients with measurable and non-measurable disease in two overlapping cohorts: Cohort A, which included patients with DDR alterations that may be sensitive to PARP inhibition in genes directly or indirectly involved in HRR patients; and Group B, which includes patients with DNA defects in the expanded genome that are likely or likely to be sensitive to PARP inhibition. Subject to the approval of Amendment 3 of the Agreement on February 15, 2018, registration was limited to patients with measurable disease and patients with DNA alterations that may be sensitive to PARP inhibition, which initially comprised a panel of 13 genes. FANCD2 and FANCI failed subsequent validation requirements, leaving the following group of 11 HRR genes for analysis: ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C (called "DDR11 ”). Other inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status 0-2; undergoing bilateral orchiectomy or ongoing androgen ablation therapy using gonadotropin-releasing hormone agonists or antagonists, and serum testosterone levels at screening Ketones 50 ng/dL or less (≤1.73 nmol/L); stable bisphosphonate or denosumab dose for at least 4 weeks for patients receiving these therapies; estimated life expectancy is at least 6 months months (estimated by investigators); and previously received one in the setting of metastatic disease (castrate-sensitive prostate cancer or castration-resistant prostate cancer; patients may have received radium-233 or cabazitaxel, or both) or two chemotherapy regimens (≥1 taxane-based) and at least one novel hormonal therapy (enzalutamide, abiraterone, or both) for progression of metastatic castration-resistant prostate cancer.

Treatment : Patients were administered talazopanib 1 mg orally daily (or 0.75 mg daily for patients with moderate renal impairment, defined as an estimated glomerular filtration of 30-59 mL/min per 1.73 m² rate), provide dose modification or appropriate supportive care, or both, for recovery from a Grade 3 or 4 adverse event. Administration of talazopanib was continued until progression, as judged by radiographic imaging, unacceptable toxicity, investigator decision-making, withdrawal of consent, or determination of death. An increase in PSA or circulating tumor cell count alone is not a reason to discontinue talazopanib.

Assess tumor response: Radiographic assessment (CT [preferably] or MRI of the abdomen and pelvis, CT of the chest and whole-body radionuclide bone scan) every 8 weeks for the first 24 weeks and then every 12 weeks thereafter. Confirmation of soft tissue response according to RECIST 1.1 at least 4 weeks after identification of response with CT or MRI, with no confirmed evidence of skeletal progression according to Prostate Cancer Working Group 3 criteria after repeat bone scan at least 6 weeks after independent central review.

Tumor Genomics : DDR11 mutations were assessed in formalin-fixed paraffin-embedded (FFPE) tumor tissue using FoundationOne ^® CDx (Foundation Medicine, Inc.). The gLOH score was determined by late genome analysis of the FoundationOne ^® CDx assay (methods detailed in Sokol et al., JCO Precision Oncology 2020;4:442-465).

Statistical analysis : The patient population evaluable for anti-tumor activity (N=104) was defined as those with measurable soft tissue disease at screening, as assessed by investigators, and 11 predefined DDR-HRR genes (ATM, ATR, BRCA1, BRCA2 All enrolled patients with genetic alterations in , CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C) who have received at least one dose of talazopanib. Patients with measurable disease at baseline and at least one valid assessment after baseline were assessed by blinded independent central review as the best change from baseline in the sum of diameters of target lesions (as an objective response rate outcome). part). According to RECIST version 1.1, tumor response was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Through blinded independent central review, the primary endpoint was confirmed to be objective response rate (ORR), defined as the best overall soft tissue response of complete response or partial response according to RECIST 1.1. Secondary endpoints include time to objective response, duration of objective response, proportion of patients with a 50% or greater reduction in PSA from baseline, time to PSA progression, and proportion of patients with conversion of circulating tumor cell count (A decrease of ≥5 to <5 cells per 7.5 mL of blood or a decrease of ≥1 to 0 cells per 7.5 mL of blood at any time from baseline, or any increase from <5 cells per 7.5 mL of blood), no progression from radiation Progression in survival (from first dose of talazopanib to soft tissue (as determined by RECIST 1.1 radiography, blinded independent central review and investigator assessment), progression in bone (as determined by Prostate Cancer Working Group 3 standard and independent center review), or death from any cause, whichever occurs first), overall survival, safety, patient-reported outcomes and pharmacokinetics.

Post hoc anti-tumor activity endpoints were analyzed by the HRR gene alteration panel (BRCA1, BRCA2, PALB2, ATM and other genes in a predefined set of 11 DDR-HRR genes), using a hierarchical strategy in which the disease was differentiated by HRR gene alterations. Patients were separated in which BRCA1 or BRCA2 ranked higher than PALB2, PALB2 ranked higher than ATM, and ATM ranked higher than all other changes.

Results Patient characteristics of the anti-tumor efficacy group (N=104) : 9 (9%) patients were in Gleason group 1, 31 (30%) patients were in Gleason group 2, and 63 (61%) patients were in Gleason group 2 Patients were Gleason group 3, and 1 (1%) patient did not report Gleason group [Gleason grade and related grade groups (1 to 5) refer to how cancer cells look when compared to normal prostate cells how. The higher the Gleason grade group, the more likely the cancer will grow and spread]. Thirty-six (35%) patients had visceral disease and 68 (65%) patients had non-visceral disease. The patients' initial M stage at initial diagnosis was M0 in 39 (38%), M1 in 48 (46%), MX in 13 (13%), and 4 (4%) patients did not report [M category captures whether the cancer Has been transferred to other parts of the body. M0: The cancer has not spread to other parts of the body. M1: The cancer has spread to other parts of the body. MX: No transfer detected]. Patients' prior taxane use was as follows: 54 (52%) patients were on docetaxel only, 49 (47%) were on both docetaxel and cabazitaxel, and 1 (1%) was on docetaxel The patient reported no prior taxane use. Patients' prior hormone therapy use was as follows: 37 (36%) patients used abiraterone only, 37 (36%) patients only used enzalutamide, and 28 (27%) patients used abiraterone only. and enzalutamide, and prior hormonal therapy was not reported in 2 (2%) patients.

Fifty-five patients (53%) were evaluable for gLOH, 45 were not evaluable for gLOH, and four lacked central laboratory gLOH results (gLOH evaluability reflects insufficient tissue purity and/or quality).

Talazopanib Efficacy : After a median follow-up of 16.4 months, the objective response rate was 29.8% (31 of 104 patients; 95% confidence interval (CI) 21.2-39.6).

Evaluation of tumor gLOH score as a predictive biomarker of talazopanib response : The potential association of high/low gLOH status with talazopanib response was explored and the results are presented in Tables 1 and 2 below. Two gLOH high/low thresholds have been explored. 8.8% is based on published studies demonstrating that this cutoff differentiates prostate cancer harboring BRCA doublet mutations from BRCA wild-type prostate cancer with optimal sensitivity and specificity (Sokol et al., JCO Precision Oncology 2020;4:442 -465) (results presented in Table 1) selection. Additionally, an agnostic threshold based on the median gLOH score in the efficacy population (9.2%) was explored (results are presented in Table 2). Based on 8.8% cutoff, compared with gLOH-low [3/25 (12.0%), 95% CI 2.5, 31.2%; odds ratio 8.381, two-sided p-value 0.0017, based on Fisher's exact test] In comparison, the ORR was significantly higher for gLOH-high [16/30 (53.3%), 95% CI, 34.3, 71.7% by Clopper-Pearson method). Based on 9.2% gLOH cutoff, relative to gLOH-low [4/27 (14.8%); 95% CI 4.2, 33.7; odds ratio 6.635, p value 0.0041], gLOH-high [15/28 (53.6%), The ORR (95% CI 33.9, 72.5%] was also significantly higher. The 8.8% threshold was selected for use in other gLOH high/low analyzes detailed below.

In summary, using either cutoff, gLOH-high had a significantly higher ORR relative to gLOH-low, although responses were seen in gLOH-low patients at both cutoffs. Table 1 : Response ( evaluable efficacy population for gLOH , N=55) based on BICR assessment (RECIST 1.1 ; PCWG3) by gLOH high / low status based on 8.8% threshold . reaction gLOH- High (n=30) gLOH- low (n=25) Confirm best overall response, n(%) Complete response (CR) 3 (10.0) 1 (4.0) Partial response (PR) 13 (43.3) 2 (8.0) Stable disease (SD) 6 (20.0) 11 (44.0) Non-CR/Non-PD 2 (6.7) 0 Progressive disease (PD) 4 (13.3) 7 (28.0) Not evaluable (NE) 2 (6.7) 4 (16.0) Objective response (CR+PR) , n (% [95% CI ^a ]) 16 (53.3 [34.3,71.7]) 3 (12.0 [2.5,31.2]) ORR comparison versus gLOH-low non-stratified analysis Odds ratio (95% CI ^b ) 8.381 (1.833,50.950) Two-sided P value ^c 0.0017 ^a The Clopper-Pearson method used; ^b Odds ratio >1 indicates that higher results are better than lower ones; accurate CI is calculated. ^c P value based on Fisher’s exact test. Table 2 : Response based on BICR assessment (RECIST 1.1 ; PCWG3) by gLOH high / low status based on 9.2% cutoff (gLOH evaluable efficacy population , N=55) reaction gLOH- High (n=28) gLOH- low (n=27) Confirm best overall response, n(%) Complete response (CR) 2 (7.1) 2 (7.4) Partial response (PR) 13 (46.4) 2 (7.4) Stable disease (SD) 5 (17.9) 12 (44.4) Non-CR/Non-PD 2 (7.1) 0 Progressive disease (PD) 4 (14.3) 7 (25.9) Not evaluable (NE) 2 (7.1) 4 (14.8) Objective response (CR+PR), n (% [95% CI ^a ]) 15 (53.6 [33.9,72.5]) 4 (14.8 [4.2,33.7]) ORR comparison versus gLOH-low non-stratified analysis Odds ratio (95% CI ^b ) 6.635 (1.596,32.224) Two-sided P ^valuec 0.0041 ^a The Clopper-Pearson method used; ^b Odds ratio >1 indicates that higher results are better than lower ones; accurate CI is calculated. ^c P value based on Fisher’s exact test.

Subsequently, potential correlations between gLOH scores and responses within gene mutation groups were explored using bar plots of gLOH marked by best response, mutation group, mutation type, and mutation adapter pattern (Graph).

Selected results from this analysis are listed in Table 3. Table 3 : Best overall response according to RECIST v.1.1 by gene mutation group and gLOH high / low status (gLOH evaluable efficacy population , N=55) Gene #gLOH- low #gLOH- High ORR (%)(gLOH- Low) ORR (%)(gLOH- High) BRCA1 (n=2) 0 2 (100%) - 2/2 (100%) BRCA2 (n=30) 13 (43%) 17 (57%) 3/13 (23%) 12/17 (71%) PALB2 (n=2) 2 (100%) 0 0/2 (0%) - ATM (n=10) 6 (60%) 4 (40%) 0/6 (0%) 2/4 (50%) Others(n=11) 4 (36%) 7 (64%) 0/4 (0%) 0/7 (0%)

As shown in Table 4, within the BRCA2 mutation group, the ORR was stable regardless of gLOH status, but for gLOH-high (12/17, 70.6%), the ORR of gLOH-high was significantly higher than that of gLOH-low (3 /13, 23.1%) [p=0.0253 according to Fisher's exact test]. Table 4 : Association of gLOH status and response to tumors harboring BRCA2 alterations based on 8.8% cutoff reaction BRCA2 gLOH- High (n=17) gLOH- low (n=13) Confirm best overall response, n(%) Complete response (CR) 2 (11.8) 1 (7.7) Partial response (PR) 10 (58.8) 2 (15.4) Stable disease (SD) 2 (11.8) 7 (53.8) Non-CR/Non-PD 2 (11.8) 0 Progressive disease (PD) 0 1 (7.7) Not evaluable (NE) 1 (5.9) 2 (15.4) Objective response (CR+PR) , n (% [95% CI ^a ]) 12 (70.6 [44.0,89.7]) 3 (23.1 [5.0,53.8]) ORR comparison versus gLOH-low non-stratified analysis Odds ratio (95% CI ^b ) 8.000 (1.220,60.952) Two-sided P value ^c 0.0253 ^a The Clopper-Pearson method used; ^b Odds ratio >1 indicates that high results are better than low ones; accurate CI is calculated; ^c P value based on Fisher's exact test

As shown in Table 5, within the ATM mutant subgroup, the ORR for gLOH-high (2/4, 50%) was numerically higher than for gLOH-low (0/6, 0%), but Not significant (P=0.1333). Table 5 : Association of gLOH status and response to tumors harboring ATM alterations based on 8.8% cutoff reaction ATM gLOH- High (n=4) gLOH- low (n=6) Confirm best overall response, n(%) Complete response (CR) 1 (25.0) 0 Partial response (PR) 1 (25.0) 0 Stable disease (SD) 1 (25.0) 3 (50.0) Non-CR/Non-PD 0 0 Progressive disease (PD) 1 (25.0) 3 (50.0) Not evaluable (NE) 0 0 Objective response (CR+PR) , n (% [95% CI ^a ]) 2 (50.0 [6.8,93.2]) 0 (0 [0,45.9]) ORR comparison versus gLOH-low non-stratified analysis Odds ratio (95% CI ^b ) NE Two-sided P value ^c 0.1333 ^a The Clopper-Pearson method used; ^b Odds ratio >1 indicates that high results are better than low ones; accurate CI is calculated; ^c P value based on Fisher's exact test

Radiation progression-free survival (RECIST 1.1; BICR) in the gLOH-evaluable efficacy population was numerically, but not significantly, better for gLOH-high than gLOH-low using either cutoff (hazard ratio 0.68). The results based on the 8.8% threshold are listed in Table 6. Signs of the early separation of gLOH-high and gLOH-low shown in Table 6 were subsequently missing. The risk ratio (95% CI ^b ) of the 9.2% threshold was 0.68 (0.317, 1.448); two-sided P value = 0.3131 (detailed results are not shown). Table 6 : Radiation progression-free survival by gLOH high / low status based on 8.8% cutoff (RECIST 1.1 ; BICR) ( gLOH efficacy evaluable population , N=55) . gLOH- High (n=30) gLOH- low (n=25) Kaplan-Meier estimates of time to event, months (95% CI) ^a Quartile 1 5.4 (1.7,8.3) 1.8 (1.6,3.7) median 10.9 (7.5,NE) 11.1 (2.1,19.2) Quartile 3 NE (19.3,NE) 19.2 (11.1,19.2) rPFS comparison versus gLOH-low non-stratified analysis Risk ratio (95% CI ^b ) 0.68 (0.319,1.456) Two-sided P value ^c 0.3219 ^aBased on the Brookmeyer and Crowley method; ^bHazard ratio based on the Cox proportional hazard model; under proportional hazards, a hazard ratio <1 indicates a reduction in the hazard rate compared to gLOH-low. Favoring gLOH-high; ^c P value based on log-rank test;

Thus, gLOH-high status was associated with response within the efficacy group and also with response within the BRCA2 gene mutation group.

The same annotated bar graphs were then used to explore potential correlations between gLOH scores and responses within subgroups of gene zygote patterns and mutation types (Figure). Based on this observation, it is apparent that there is no clear relationship between zygote pattern and gLOH. Regarding mutation types, DDR11 short variants (i.e., single nucleotide variants, short insertions/deletions) are widely distributed across the gLOH spectrum. In contrast, copy number deletions (which were restricted to a subset of BRCA2 gene alterants; n=13 pts) were numerically associated with high gLOH scores and responses: 3/25 gLOH-low had BRCA2 copy number deletions (2 SD , 1 NE), whereas 10/30 gLOH-high had BRCA2 copy number deletions (8 CR/PR, 1 SD, 1 non-CR/PD). This demonstrates statistically superior overall efficacy of DDR11m-gLOH-high versus DDR11m-gLOH-low (53% versus 12%, p=0.0017) and superior efficacy of BRCA2m-gLOH-high versus BRCA2m-gLOH-low (71 % vs. 23%, p=0.0253) was reflected to some extent by the relatively high fraction of BRCA2 copy number deletions in the gLOH-high group.

Based on these retrospective ad hoc exploratory analyzes in this heavily pretreated mCRPC population, gLOH-high status was associated with enhancement of talazopanib within the gLOH-evaluable efficacy population and within the gLOH-evaluable BRCA2 alteration subgroup. reaction is related. These results demonstrate the predictive potential for gLOH-high status in DDR11m prostate cancer and also within some of the 11 predefined DDR-HRR gene alteration subgroups.

In summary, these retrospective exploratory analyzes in TALAPRO-1 demonstrate that high gLOH status is associated with response to talazopanib in metastatic castration-resistant prostate cancer with DNA repair gene mutations.

All publications and patent applications cited in this specification are incorporated herein by reference in their entirety. Although the foregoing invention has been described in considerable detail by way of illustration and example, it will be apparent to those skilled in the art from the teachings of the invention that the invention may be practiced without departing from the spirit or scope of the appended claims. Make certain changes and modifications thereto.

Graph showing bar chart of best overall response (confirmed) based on blinded independent center review of gLOH scores. Bar graphs are annotated by best response, mutation group, mutation type, and mutation zygote pattern. Abbreviations include: CR, complete response; PR, partial response; SD, stable disease; non-CR/non-PD, non-complete response/non-progressive disease; PD, progressive disease; NE, not evaluable; gLOH (gene loss of heterozygosity) and alt (change or mutation). Other DDR11 genes include, but are not limited to, ATR, CHEK2, FANCA, MLH1, MRE11A, NBN and RAD51C. Tumor variant types are based on corresponding DDR11 mutation sets. The definitions of the zygote pattern include: homozygous, the patient has ≥1 homozygous DDR11 mutation; heterozygous, the patient does not have homozygous DDR11 mutation, but has ≥1 heterozygous DDR11 mutation; unknown, the patient does not have homozygous DDR11 mutation or heterozygous DDR11 mutation, but with ≥1 DDR11 mutation of unknown zygote type; not evaluable, the patient does not have sufficient DDR11 mutations.

Claims (16)

A method of selecting individuals with cancer having homologous recombination repair deficiency for treatment with talazopanib or a pharmaceutically acceptable salt thereof, comprising: a) determining loss of gene heterozygosity based on a biopsy of the cancer (gLOH) score; and b) selecting the individual for treatment with talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score. A method of treating cancer with homologous recombination repair deficiency in an individual, comprising: a) selecting the individual according to the method of claim 1; and b) administering a therapeutically effective amount of talazopanib or based on the gLOH score Its pharmaceutically acceptable salt. A method of identifying cancers with homologous recombination repair defects that are sensitive to treatment with talazopanib or a pharmaceutically acceptable salt thereof, comprising: a) determining gene loss of heterozygosity (gLOH) based on a biopsy of the cancer ) score; and b) selecting the cancer for treatment with talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score. A method of treating cancer with homologous recombination repair deficiency that is sensitive to treatment with talazopanib or a pharmaceutically acceptable salt thereof, comprising: a) selecting the cancer according to the method of claim 3; and b ) administer a therapeutically effective amount of talazopanib or a pharmaceutically acceptable salt thereof based on the gLOH score. The method of claim 1 or claim 2, wherein the cancer is sensitive to treatment with talazopanib. The method of any one of claims 1 to 4, wherein the cancer is prostate cancer. The method of claim 6, wherein the prostate cancer is metastatic prostate cancer. The method of claim 6, wherein the prostate cancer is castration-resistant prostate cancer. The method of claim 8, wherein the castration-resistant prostate cancer is metastatic castration-resistant prostate cancer. The method of claim 1 or claim 3, wherein the homologous recombination repair defect of the cancer is determined by next-generation sequencing. The method of claim 1 or claim 3, wherein step a) is performed by next-generation sequencing. The method of any one of claims 1 to 11, wherein the gLOH fraction is at least about 8.0%. The method of any one of claims 1 to 11, wherein the gLOH fraction is at least about 8.3%. The method of any one of claims 1 to 11, wherein the gLOH fraction is at least about 8.8%. The method of any one of claims 1 to 11, wherein the gLOH fraction is at least about 9%; at least about 9.2%; at least about 10%; at least about 11%; at least about 12%; at least about 13%; at least about 14%; at least about 15%; at least about 16%; at least about 17%; at least about 18%; at least about 19%; at least about 20%; at least about 21%; at least about 22%; at least about 23%; at least about 24%; or at least about 25%. Such as the method of claim 1 or 2, wherein the system is human.