Treatment methods for ovarian cancer

Abstract

Providing a method for treating ovarian cancer. [Solution] The present invention provides methods of administering PARP inhibitors to cancer patients. The invention is based, in part, on the discovery that PARP inhibitors can be used to treat cancers characterized by wild-type or mutant BRCA1 and / or BRCA2 (BRCA genes), for example, in the presence or absence of mutations in the BRCA genes. Accordingly, aspects of the invention relate to methods of treating cancer patients, the methods comprising administering an anti-PARP therapy to the patient, regardless of the BRCA status or DNA repair status of the patient or cancer.

Description

[Technical Field]

[0001] Cancer is a serious public health problem, with 562,340 people dying from it in the United States in 2009 alone. (American Cancer Society, Cancer Facts & Figures 2009, available from the American Cancer Society website). One of the major challenges in cancer treatment is identifying relevant and clinically useful individual cancer characteristics and then developing the most appropriate treatment plan for that patient based on those characteristics. [Background technology]

[0002] Ovarian cancer is the fifth leading cause of cancer death in women and accounts for 5% of all cancer deaths in women. In 2014, an estimated 21,980 new cases of ovarian cancer were projected, with an estimated 14,270 women dying from the disease. In 2012, the projected number of epithelial ovarian cancer cases in the United States was approximately 22,280 (15,500 deaths), while in Europe, the estimated number was 65,538 (42,704 deaths). Epithelial carcinomas account for 85-90% of ovarian cancers. Historically, it was thought to begin on the surface of the ovary, but new evidence suggests that at least some ovarian cancers begin in specific cells within the fallopian tubes. The fallopian tubes are small tubes connecting the ovaries to the uterus and are part of the female reproductive system. In a normal female reproductive system, there are two fallopian tubes, one on each side of the uterus. Cancer cells that originate in the fallopian tubes can reach the ovarian surface early on. The term "ovarian cancer" is often used to describe epithelial cancers that originate in the ovaries, fallopian tubes, and the peritoneum, the inner lining of the abdominal cavity. At diagnosis, most women present with advanced disease, which is a major cause of the high mortality rate.

[0003] Standard treatment for advanced ovarian cancer typically consists of surgical resection of the lesion and a chemotherapy regimen. Initial chemotherapy involves either taxanes or platinum-based chemotherapy, or a combination thereof. Approximately 75% of patients respond to frontline treatment, but 70% of those who initially respond eventually relapse within 1-3 years. After relapse, patients respond moderately or poorly to subsequent chemotherapy. Furthermore, intolerance of platinum-based agents is a clinical challenge, and the risk of cumulative toxicity increases with the course of continued treatment. Despite high response rates at the initial stage, a significant unmet need exists due to the high relapse rate. Attempts to improve standard two-agent chemotherapy (carboplatin and paclitaxel) by adding a third cytotoxic agent (topotecan, gemcitabine, or doxil) have been unsuccessful (du Bois et al, 2006 and Pfisterer et al, 2006). A major challenge in the near future will be selecting patients with advanced ovarian cancer who will benefit most from specific targeted therapies in frontline or maintenance settings. Maintenance therapy following a response to initial chemotherapy may offer clinical benefits by slowing the side effects of disease progression, delaying the need for toxic chemotherapy, and extending overall survival. Poly(ADP-ribose) polymerase (PARP) is a family of enzymes involved in various activities in the response to DNA damage. PARP-1 is an important DNA repair enzyme that mediates single-strand break (SSB) repair via the base excision repair (BER) pathway. PARP inhibitors have been shown to selectively kill tumor cells carrying BRCA1 and BRCA2 mutations. In addition, preclinical and preliminary clinical data suggest that PARP inhibitors are selectively toxic to tumors with homologous recombination repair abnormalities resulting from dysfunction of genes other than BRCA1 or BRCA2. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] du Bois et al, 2006 and Pfisterer et al, 2006 [Overview of the project] [Means for solving the problem]

[0005] The present invention is based in part on the discovery that cancers characterized by wild-type or mutant BRCA1 and / or BRCA2 (BRCA genes) can be treated using PARP inhibitors, for example, in or without the presence of mutations in the BRCA genes. Accordingly, aspects of the present invention relate to a method for treating a cancer patient, the method comprising administering anti-PARP therapy to the patient regardless of the BRCA status of the patient or cancer, or regardless of the DNA repair status. In other aspects, the present invention relates to a method for treating a cancer patient, the method comprising administering anti-PARP therapy to the patient, in which case the therapy is initiated before determining the BRCA status or HRD status of the patient or cancer. In other aspects, the present invention relates to a method for treating a cancer patient, the method comprising administering anti-PARP therapy to the patient, in which case the therapy is initiated without determining the BRCA status or DNA repair status of the patient or cancer. In another embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients characterized by the absence of mutations in BRCA1 and / or BRCA2. In another embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients characterized by the absence of mutations in genes involved in DNA repair. In another embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients characterized by the absence of mutations in genes involved in homologous recombination. In an embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients having cancer characterized by the absence of mutations in BRCA1 or BRCA2. In an embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients having cancer characterized by the absence of mutations in genes involved in homologous recombination.

[0006] In some embodiments, anti-PARP therapy is administered in doses equivalent to about 100 mg, about 200 mg, or about 300 mg of niraparib, a salt thereof, or a derivative thereof. In some embodiments, anti-PARP therapy is administered in doses equivalent to about 100 mg of niraparib, a salt thereof, or a derivative thereof. In some embodiments, anti-PARP therapy is administered in doses equivalent to about 200 mg of niraparib, a salt thereof, or a derivative thereof. In some embodiments, anti-PARP therapy is administered in doses equivalent to about 300 mg of niraparib, a salt thereof, or a derivative thereof.

[0007] In some embodiments, anti-PARP therapy is administered in regimens determined to achieve i) extended progression-free survival compared to controls, ii) a reduced hazard ratio for disease progression or death compared to controls, iii) extended overall survival compared to controls, or iv) an overall response rate of at least 30%.

[0008] In some embodiments, anti-PARP therapy involves the administration of an agent that inhibits PARP-1 and / or PARP-2. In some embodiments, the agent is a small molecule, nucleic acid, polypeptide (e.g., antibody), carbohydrate, lipid, metal, or toxin. In relevant embodiments, the agent is ABT-767, AZD 2461, BGB-290, BGP 15, CEP 9722, E7016, E7449, fluzoparib, INO1001, JPI 289, MP 124, niraparib, olaparib, ONO2231, rucaparib, SC 101914, talazoparib, veliparib, WW 46, or salts thereof or derivatives thereof. In some related embodiments, the agent is niraparib, olaparib, lucaparib, thalazoparib, beriparib, or a salt or derivative thereof. In some embodiments, the agent is niraparib, or a salt or derivative thereof. In some embodiments, the agent is olaparib, or a salt or derivative thereof. In some embodiments, the agent is lucaparib, or a salt or derivative thereof. In some embodiments, the agent is thalazoparib, or a salt or derivative thereof. In some embodiments, the agent is beriparib, or a salt or derivative thereof.

[0009] In some embodiments, the method extends progression-free survival compared to the control. In some embodiments, the method reduces the hazard ratio for disease progression or death compared to the control. In some embodiments, the method extends overall survival compared to the control. In some embodiments, the method achieves an overall response rate of at least 30%. In some embodiments, the method achieves an improved progression-free survival compared to the control. In some embodiments, the method achieves an improved complete chemotherapy-free period compared to the control. In some embodiments, the method achieves an improved time to first subsequent therapy compared to the control. In some embodiments, the method achieves an improved time to second subsequent therapy compared to the control. In some embodiments, the method is determined not to have adverse effects on quality of life as determined by FOSI and / or EQ-5D-5L. In some embodiments, the method is determined so as not to affect the efficacy of subsequent treatment with chemotherapeutic agents (e.g., platinum-based agents such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin).

[0010] In some embodiments, such cancers are selected from gynecological cancers (i.e., cancers of the female reproductive system). In some embodiments, cancers of the female reproductive system include, but are not limited to, ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer. In some embodiments, gynecological cancers are associated with homologous repair deficiency (HRD) and / or BRCA1 / 2 mutations. In some embodiments, gynecological cancers are platinum-sensitive. In some embodiments, gynecological cancers respond to platinum-based therapy. In some embodiments, gynecological cancers develop resistance to platinum-based therapy. In some embodiments, gynecological cancers have previously shown partial or complete response to platinum-based therapy. In some embodiments, gynecological cancers are currently resistant to platinum-based therapy.

[0011] In one embodiment, the cancer is ovarian cancer, fallopian tube cancer, or peritoneal cancer. In another embodiment, the cancer is breast cancer.

[0012] In some embodiments, the cancer is recurrent cancer.

[0013] In some embodiments, anti-PARP therapy is useful for treating cancer patients exhibiting a positive HRD status. In some embodiments, anti-PARP therapy is useful for treating cancer patients exhibiting a positive HRD status, in which case the patients are further characterized by the absence of BRCA1 and / or BRCA2 mutations. In some embodiments, anti-PARP therapy is useful for treating cancer patients exhibiting a positive HRD status, in which case the patients are further characterized by the absence of germline mutations in BRCA1 and / or BRCA2. In some embodiments, a positive HRD status is determined by quantifying a number of Indicator Chromosomal Aberration (CA) region indicators in a patient sample. In some embodiments, the patient's tumor sample has a positive HRD status.

[0014] In some embodiments, anti-PARP therapy is useful for treating cancer patients who exhibit the absence of germline mutations in BRCA1 and BRCA2. In some embodiments, anti-PARP therapy is useful for treating cancer patients with platinum-sensitive tumors, who also exhibit the absence of germline mutations in BRCA1 and BRCA2.

[0015] In some embodiments, anti-PARP therapy is useful for treating cancer patients who exhibit the absence of HRD. In some embodiments, anti-PARP therapy is useful for treating platinum-sensitive recurrent ovarian cancer patients who do not have HRD, or whose absence of HRD is characterized in this case. In some embodiments, the absence of HRD is further characterized by the absence of "chromosomal abnormalities" or "CA". CA refers to detectable variations in the chromosomal DNA of a sample. In some embodiments, CA falls into at least one of the following three overlapping categories: loss of heterozygosity (LOH), allele-allele imbalance (e.g., telomere allele-allele imbalance (TAI)), and imbalance, or large-scale transition (LST).

[0016] Accordingly, in some embodiments, the present invention provides a method for administering anti-PARP therapy to a patient having a recurrent and / or platinum-sensitive cancer selected from ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, the method comprising administering anti-PARP therapy to the patient in accordance with a regimen determined to achieve an extended progression-free survival compared to a control.

[0017] In particular, the present invention demonstrates the remarkable clinical efficacy of niraparib when administered to a certain patient population (for example, a population with or susceptible to a certain tumor, a population characterized by the presence or level of specific markers such as HRD status and / or BRCA1 / 2 mutations, a population that has received, is receiving, or has not received, or is not receiving other therapies) and / or when administered according to a certain regimen. In some embodiments, the present invention provides a method for administering anti-PARP therapy to a patient having a recurrent and / or platinum-sensitive cancer selected from ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, the method comprising administering anti-PARP therapy to the patient according to a regimen determined to achieve a reduction in the hazard ratio for disease progression or death compared to a control.

[0018] In some embodiments, the present invention provides a method for administering anti-PARP therapy to a patient having a recurrent and / or platinum-sensitive cancer selected from ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, the method comprising administering anti-PARP therapy to the patient in accordance with a regimen determined to achieve an extension of overall survival compared to a control.

[0019] In some embodiments, the present invention provides a method for administering anti-PARP therapy to a patient having a recurrent and / or platinum-sensitive cancer selected from ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, the method comprising administering anti-PARP therapy to the patient according to a regimen determined to achieve an overall response rate of at least 30%. In some embodiments, the overall response rate is evaluated according to the RECIST v1.1 guidelines.

[0020] In some embodiments, the method of administering anti-PARP therapy follows a regimen determined to achieve an extended progression-free survival (PRA) compared to a control.

[0021] In some embodiments, the method of administering anti-PARP therapy follows a regimen determined to achieve an extended chemotherapy-total rest period compared to a control.

[0022] In some embodiments, the method of administering anti-PARP therapy follows a regimen determined to achieve an extended time to the first subsequent treatment compared to a control.

[0023] In some embodiments, the method of administering anti-PARP therapy follows a regimen determined to achieve an extended time to a second subsequent treatment compared to a control.

[0024] In some embodiments, the recurrent cancer and / or platinum-sensitive cancer is ovarian cancer. In some embodiments, the ovarian cancer is platinum-sensitive ovarian cancer at the start of administration of anti-PARP therapy. In some embodiments, the ovarian cancer is platinum-sensitive recurrent ovarian cancer at the start of administration of anti-PARP therapy. In some embodiments, the ovarian cancer responded to the most recent platinum-based chemotherapy regimen prior to the start of administration of anti-PARP therapy. In some embodiments, the response to the most recent platinum-based chemotherapy is a complete response. In some embodiments, the response to the most recent platinum-based chemotherapy is a partial response. In some embodiments, the ovarian cancer responded to the second-to-last platinum-based chemotherapy regimen prior to the start of administration of anti-PARP therapy.

[0025] In some embodiments, the recurrent cancer and / or platinum-sensitive cancer is fallopian tube cancer. In some embodiments, the fallopian tube cancer is platinum-sensitive at the start of administration of anti-PARP therapy. In some embodiments, the recurrent fallopian tube cancer is platinum-sensitive at the start of administration of anti-PARP therapy. In some embodiments, the fallopian tube cancer responded to the most recent platinum-based chemotherapy regimen prior to the start of administration of anti-PARP therapy. In some embodiments, the response to the most recent platinum-based chemotherapy is a complete response. In some embodiments, the response to the most recent platinum-based chemotherapy is a partial response. In some embodiments, the fallopian tube cancer responded to the second-to-last platinum-based chemotherapy regimen prior to the start of administration of anti-PARP therapy.

[0026] In some embodiments, recurrent cancer and / or platinum-sensitive cancer is primary peritoneal cancer. In some embodiments, primary peritoneal cancer is platinum-sensitive at the start of anti-PARP therapy. In some embodiments, recurrent primary peritoneal cancer is platinum-sensitive at the start of anti-PARP therapy. In some embodiments, primary peritoneal cancer responded to the most recent platinum-based chemotherapy regimen prior to the start of anti-PARP therapy. In some embodiments, the response to the most recent platinum-based chemotherapy is a complete response. In some embodiments, the response to the most recent platinum-based chemotherapy is a partial response. In some embodiments, primary peritoneal cancer responded to the second-to-last platinum-based chemotherapy regimen prior to the start of anti-PARP therapy.

[0027] In some embodiments, the patient has at least one mutation selected from (i) germline mutations in BRCA1 and / or BRCA2, or (ii) sporadic mutations in BRCA1 and / or BRCA2.

[0028] In some embodiments, the patient has germline mutations in BRCA1 and / or BRCA2.

[0029] In some embodiments, the regimen is determined to achieve a hazard ratio of less than approximately 0.5 for disease progression. In some embodiments, the hazard ratio for disease progression is less than approximately 0.4. In some embodiments, the hazard ratio for disease progression is less than approximately 0.3.

[0030] In some embodiments, the regimen is determined to achieve an extended progression-free survival of at least 9 months. In some embodiments, the extended progression-free survival is at least 12 months. In some embodiments, the extended progression-free survival is at least 15 months. In some embodiments, the extended progression-free survival is at least 21 months.

[0031] In some embodiments, the patient has sporadic mutations in BRCA1 or BRCA2.

[0032] In some embodiments, patients are characterized by the absence of germline mutations in BRCA1 or BRCA2. In some embodiments, patients are characterized by the absence of HRD. In some embodiments, patients are characterized by the absence of germline mutations in BRCA1 or BRCA2 and the absence of HRD.

[0033] In some embodiments, patients are characterized by the absence of sporadic mutations in BRCA1 or BRCA2. In some embodiments, patients are characterized by the absence of HRD. In some embodiments, patients are characterized by the absence of sporadic mutations in BRCA1 or BRCA2 and the absence of HRD. In some embodiments, the absence of HRD is further characterized by the absence of "chromosomal abnormalities" or "CA". CA refers to detectable variations in the chromosomal DNA of the sample. In some embodiments, CA falls into at least one of three overlapping categories: loss of heterozygosity (LOH), allele-imbalance (e.g., telomeric allelic imbalance (TAI)), or large-scale transition (LST).

[0034] In some embodiments, patients are characterized by the absence of mutations in BRCA1 or BRCA2 (for example, lacking both germline BRCA1 / 2 mutations and sporadic BRCA1 / 2 mutations).

[0035] In some embodiments, the patient has a tumor that is positive for homologous recombination deficiency.

[0036] In some embodiments, the present invention provides a method for administering anti-PARP therapy to a patient characterized by the absence of germline BRCA1 / 2 mutations, in which the patient has a tumor positive for homologous recombination abnormalities.

[0037] In some embodiments, the present invention provides a method for administering anti-PARP therapy to patients having sporadic mutations in BRCA1 or BRCA2, wherein the patients have tumors that are positive for homologous recombination abnormalities.

[0038] In some embodiments, the present invention relates to patients characterized by the absence of mutations in BRCA1 / 2 (i.e., BRCA wt This invention provides a method for administering anti-PARP therapy to a patient, in which case the patient has a tumor that is positive for homologous recombination abnormality.

[0039] In some embodiments, the patient has a tumor that is negative for homologous recombination abnormalities. In some embodiments, the patient has a tumor that is further characterized by being negative for germline mutations in BRCA1 or BRCA2.

[0040] In some embodiments, the present invention relates to germline mutations in BRCA1 or BRCA2 (gBRCA) according to a regimen determined to achieve a hazard ratio of less than approximately 0.4 for disease progression. mut The present invention provides a method for administering anti-PARP therapy to patients characterized by ). In some such embodiments, the hazard ratio for disease progression is less than approximately 0.3.

[0041] In some embodiments, the present invention relates to a regimen determined to achieve an extended progression-free survival of at least nine months, by addressing germline mutations in BRCA1 or BRCA2 (gBRCA1). mut The present invention provides a method for administering anti-PARP therapy to patients characterized by ). In some such embodiments, the extended progression-free survival is at least 12 months or at least 21 months.

[0042] In some embodiments, the present invention provides a method for administering anti-PARP therapy to patients characterized by the absence of germline BRCA1 / 2 mutations, according to a regimen determined to achieve a hazard ratio of less than approximately 0.5 for disease progression, in which case the patient has a tumor positive for homologous recombination abnormality. In some such embodiments, the hazard ratio for disease progression is less than approximately 0.4.

[0043] In some embodiments, the present invention provides a method for administering anti-PARP therapy to patients characterized by the absence of germline BRCA1 / 2 mutations, according to a regimen determined to achieve an extended progression-free survival of at least 12 months, in which case the patient has a tumor positive for homologous recombination abnormalities.

[0044] In some embodiments, the present invention provides a method for administering anti-PARP therapy to patients characterized by the absence of germline BRCA1 / 2 mutations, according to a regimen determined to achieve a hazard ratio of less than approximately 0.5 for disease progression.

[0045] In some embodiments, the present invention provides a method for administering anti-PARP therapy to patients characterized by the absence of germline BRCA1 / 2 mutations, according to a regimen determined to achieve an extended progression-free survival of at least 9 months or at least 12 months.

[0046] In some embodiments, the present invention provides a method for administering anti-PARP therapy to patients with sporadic mutations in BRCA1 or BRCA2, according to a regimen determined to achieve a hazard ratio of less than approximately 0.4 for disease progression, in which case the patient has a tumor positive for homologous recombination abnormality. In some embodiments, the hazard ratio for disease progression is less than approximately 0.3.

[0047] In some embodiments, the present invention provides a method for administering anti-PARP therapy to patients with sporadic mutations in BRCA1 or BRCA2, according to a regimen determined to achieve an extended progression-free survival of at least 20 months, wherein the patient has a tumor that is positive for homologous recombination abnormalities.

[0048] In some embodiments, the present invention relates to patients characterized by the absence of BRCA1 / 2 mutations (i.e., BRCA wtThe present invention provides a method for administering anti-PARP therapy to a patient(s) according to a regimen determined to achieve a hazard ratio of less than approximately 0.5 for disease progression, wherein the patient(s) have a tumor positive for homologous recombination abnormality. In some embodiments, the hazard ratio for disease progression is less than approximately 0.4.

[0049] In some embodiments, the present invention relates to patients characterized by the absence of BRCA1 / 2 mutations (i.e., BRCA wt The present invention provides a method of administering anti-PARP therapy to a patient in accordance with a regimen determined to achieve an extended progression-free survival of at least 9 months or at least 12 months, wherein the patient has a tumor that is positive for homologous recombination abnormalities.

[0050] In some embodiments, the present invention provides a method for administering anti-PARP therapy to patients characterized by the absence of germline BRCA1 / 2 mutations, in which case the patients have tumors that are negative for homologous recombination abnormalities.

[0051] In some embodiments, the patient has high-grade serous ovarian cancer or ovarian cancer predominantly of the high-grade serous histological type.

[0052] In some embodiments, the method includes treatment that is continued until the disease progresses or until it becomes unacceptably toxic.

[0053] In some embodiments, the method includes reducing the dose of anti-PARP therapy depending on therapeutic toxicity. In some related embodiments, the method includes reducing the dose of anti-PARP therapy from an approximate dose equivalent to about 300 mg to a dose equivalent to about 200 mg.

[0054] In some embodiments, the regimen includes multiple oral doses.

[0055] In some embodiments, the regimen includes once-daily (QD) administration.

[0056] In some embodiments, the regimen includes at least one 28-day cycle of anti-PARP therapy.

[0057] In some embodiments, the oral dose is administered in one or more unit dosage forms.

[0058] In some embodiments, the one or more unit dosage forms are capsules.

[0059] In some embodiments, the oral dose is an amount of anti-PARP therapy corresponding to a range of about 5 to about 400 mg of niraparib. In some embodiments, the amount of anti-PARP therapy corresponds to about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, or about 400 mg of niraparib. In some embodiments, the amount of anti-PARP therapy corresponds to about 300 mg of niraparib. In some embodiments, the amount of anti-PARP therapy corresponds to about 200 mg of niraparib.

[0060] In some embodiments, each unit dosage form corresponds to approximately 100 mg, approximately 200 mg, or approximately 300 mg of niraparib.

[0061] In some embodiments, each QD dose corresponds to approximately 100 mg, 200 mg, or 300 mg of niraparib. In some embodiments, each QD dose is administered as three unit dosage forms, each corresponding to approximately 100 mg of niraparib.

[0062] In some embodiments, progression-free survival is characterized by complete response to one or more target tumors.

[0063] In some embodiments, progression-free survival is characterized by a partial response to one or more target tumors.

[0064] In some embodiments, the patient is in a fasting state.

[0065] In some embodiments, the patient is in a feeding state.

[0066] In some embodiments, the extended progression-free survival is at least 9 months. In some embodiments, the extended progression-free survival is at least 12 months. In some embodiments, the extended progression-free survival is at least 18 months. In some embodiments, the extended progression-free survival is at least 21 months. In some embodiments, the extended progression-free survival is at least 24 months. In some embodiments, the extended progression-free survival is at least 27 months. In some embodiments, the extended progression-free survival is at least 30 months. In some embodiments, the extended progression-free survival is at least 33 months. In some embodiments, the extended progression-free survival is at least 36 months.

[0067] In some embodiments, the hazard ratio for disease progression is approximately 0.3. In some embodiments, the hazard ratio for disease progression is approximately 0.45. In some embodiments, the hazard ratio for disease progression is approximately 0.5. In some embodiments, the hazard ratio for disease progression is less than approximately 0.5. In some embodiments, the hazard ratio for disease progression is less than approximately 0.45. In some embodiments, the hazard ratio for disease progression is less than approximately 0.4. In some embodiments, the hazard ratio for disease progression is less than approximately 0.35. In some embodiments, the hazard ratio for disease progression is less than approximately 0.3.

[0068] In some embodiments, anti-PARP therapy is administered as maintenance therapy.

[0069] In some embodiments, maintenance therapy for anti-PARP therapy does not significantly affect the efficacy of subsequent lines of treatment (e.g., subsequent treatment). In some embodiments, the subsequent line of treatment is the administration of a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a platinum-based agent. In some such embodiments, the platinum-based agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenantriplatin, picoplatin, or satraplatin. In embodiments of the present invention, for example, the following items are provided. (Item 1) A method for treating a cancer patient, comprising administering a therapy that inhibits poly[ADP-ribose] polymerase (anti-PARP therapy) to the patient, wherein the therapy is administered independently of the DNA repair status and optionally independently of the BRCA status. (Item 2) A method for treating a cancer patient, comprising administering to the patient a therapy that inhibits poly[ADP-ribose] polymerase (anti-PARP therapy), wherein the therapy is initiated before determining the patient's DNA repair status or before determining the patient's BRCA status. (Item 3) A method for treating a cancer patient, comprising administering to the patient a therapy that inhibits poly[ADP-ribose] polymerase (anti-PARP therapy), wherein the therapy is initiated without determining the patient's DNA repair status or the patient's BRCA status. (Item 4) The method according to any one of items 1 to 3, wherein the patient is characterized by the absence of BRCA1 and / or BRCA2 mutations. (Item 5) The method according to any one of items 1 to 3, wherein the patient has at least one mutation in BRCA1 and / or BRCA2. (Item 6) A method for treating a cancer patient, comprising administering to the patient a therapy that inhibits poly[ADP-ribose] polymerase (anti-PARP therapy), wherein the patient is characterized by the absence of mutations in BRCA1 and / or BRCA2. (Item 7) A method for treating a cancer patient, comprising administering to the patient a therapy that inhibits poly[ADP-ribose] polymerase (anti-PARP therapy), wherein the cancer is characterized by the absence of mutations in BRCA1 or BRCA2. (Item 8) The anti-PARP therapy is administered in a dose equivalent to about 100 mg, about 200 mg, or about 300 mg of niraparib, a salt thereof, or a derivative thereof, as described in any one of items 1 to 7. (Item 9) The aforementioned anti-PARP therapy is the method described in any one of items 1 to 8, comprising the administration of an agent that inhibits PARP-1 and / or PARP-2. (Item 10) The method according to item 9, wherein the agent is a low molecular weight, nucleic acid, polypeptide (e.g., antibody), carbohydrate, lipid, metal, or toxin. (Item 11) The method according to item 10, wherein the agent is selected from the group consisting of ABT-767, AZD 2461, BGB-290, BGP 15, CEP 9722, E7016, E7449, fluzoparib, INO1001, JPI 289, MP 124, niraparib, olaparib, ONO2231, rucaparib, SC 101914, talazoparib, veliparib, WW 46, and salts or derivatives thereof. (Item 12) The method according to item 11, wherein the agent is selected from the group consisting of niraparib, olaparib, lucaparib, thalazoparib, beriparib, and salts or derivatives thereof. (Item 13) The method according to item 15, wherein the agent is niraparib or a salt thereof or a derivative thereof. (Item 14) The cancer is a gynecological cancer, as described in any one of items 1 to 13. (Item 15) The method according to item 14, wherein the gynecological cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer. (Item 16) The cancer is a recurrent cancer, as described in any one of items 1 to 15. (Item 17) The method described above is the method described in any one of items 1 to 16, which extends progression-free survival compared to a control. (Item 18) The method described above is the method according to any one of items 1 to 17, which reduces the hazard ratio for disease progression or death compared to a control. (Item 19) The method described above is the method described in any one of items 1 to 18, which extends overall survival compared to a control. (Item 20) The method described above is the method according to any one of items 1 to 19, which achieves an overall response rate of at least 30%. (Item 21) The anti-PARP therapy according to any one of items 1 to 16, administered in a regimen determined to achieve i) extended progression-free survival compared to a control, ii) a reduced hazard ratio for disease progression or death compared to a control, iii) extended overall survival compared to a control, or iv) an overall response rate of at least 30%. (Item 22) A method for treating a patient having recurrent cancer selected from ovarian cancer, fallopian tube cancer, or peritoneal cancer, comprising administering niraparib to the patient in accordance with a regimen determined to achieve i) extended progression-free survival compared to a control, ii) a reduced hazard ratio for disease progression or death compared to a control, iii) extended overall survival compared to a control, or iv) an overall response rate of at least 30%. (Item 23) The cancer is ovarian cancer, as described in any one of items 1 to 22. (Item 24) The ovarian cancer described above is platinum-sensitive at the start of treatment, as described in item 23. (Item 25) The method according to any one of items 1 to 22, wherein the cancer is fallopian tube cancer. (Item 26) The fallopian tube cancer described above is platinum-sensitive at the start of treatment, according to the method described in item 25. (Item 27) The method according to any one of items 1 to 22, wherein the cancer is peritoneal cancer. (Item 28) The peritoneal cancer described above is platinum-sensitive at the start of treatment, as described in item 27. (Item 29) The method according to any one of items 1-3, 5, and 8-28, wherein the patient has at least one germline mutation in BRCA1 and / or BRCA2, or (ii) a mutation selected from sporadic mutations in BRCA1 and / or BRCA2. (Item 30) The method according to item 29, wherein the patient has germline mutations in BRCA1 and / or BRCA2. (Item 31) The method according to item 29, wherein the patient has sporadic mutations in BRCA1 and / or BRCA2. (Item 32) The method according to any one of items 1-4 and 6-28, wherein the patient is characterized by the absence of BRCA1 and / or BRCA2 mutations. (Item 33) The method according to item 32, wherein the patient is characterized by the absence of germline mutations in BRCA1 and / or BRCA2. (Item 34) The method according to item 32, wherein the patient is characterized by the absence of sporadic mutations in BRCA1 and / or BRCA2. (Item 35) The method according to any one of items 1-3, 5, and 8-31, wherein the patient has a tumor with a positive homologous recombination anomaly. (Item 36) The method according to any one of items 1-4, 6-28, and 32-34, wherein the patient has a tumor with a negative homologous recombination anomaly. (Item 37) The regimen is determined to achieve a hazard ratio of less than approximately 0.5 for disease progression, according to the method of any one of items 21 to 36. (Item 38) The method described in item 37, wherein the hazard ratio for disease progression is less than approximately 0.3. (Item 39) The regimen is determined to achieve an extended progression-free survival of at least nine months, as described in any one of items 21 to 38. (Item 40) The method described in item 39, wherein the extended progression-free survival is at least 12 months. (Item 41) The method according to item 40, wherein the extended progression-free survival is at least 21 months. (Item 42) The patient has high-grade serous ovarian cancer or ovarian cancer predominantly of high-grade serous histological type, according to the method of item 23. (Item 43) The method described above includes the treatment being continued until the disease progresses or until it becomes unacceptably toxic. (Item 44) The method according to item 43, wherein the method comprises reducing the dose of anti-PARP therapy or niraparib depending on toxicity. (Item 45) The method according to item 44, comprising reducing the dose of anti-PARP therapy from an approximate dose equivalent to about 300 mg to a dose equivalent to about 200 mg. (Item 46) The method described above is the method described in item 44, comprising reducing the dose of niraparib from about 300 mg to about 200 mg. (Item 47) The method described above is the method described in any one of items 1 to 44, which includes administering multiple oral doses. (Item 48) The method described above is the method described in item 47, which includes administration once daily (QD). (Item 49) The method described above is the method according to any one of items 1 to 48, comprising at least one 28-day cycle of administration. (Item 50) The oral dose is administered in one or more unit dosage forms, according to the method described in any one of items 47 to 49. (Item 51) The method according to item 50, wherein one or more unit dosage forms are capsules. (Item 52) The method according to any one of items 1-7, 9-43, and 47-51, wherein the oral dose is within the range of approximately 5 to approximately 400 mg of niraparib. (Item 53) The method described in item 52, wherein the amount corresponds to approximately 5, approximately 10, approximately 25, approximately 50, approximately 100, approximately 150, approximately 200, approximately 250, approximately 300, approximately 350, or approximately 400 mg of niraparib. (Item 54) The aforementioned amount corresponds to approximately 300 mg of niraparib, as described in item 53. (Item 55) The aforementioned amount corresponds to approximately 200 mg of niraparib, as described in item 53. (Item 56) The method according to item 53, wherein each unit dosage form contains an amount equivalent to approximately 100 mg, approximately 200 mg, or approximately 300 mg of niraparib. (Item 57) The method described in item 48 or item 56, wherein each QD dose corresponds to approximately 100 mg, approximately 200 mg, or approximately 300 mg of niraparib. (Item 58) Each QD dose is administered as three unit dosage forms, each equivalent to approximately 100 mg of niraparib, as described in item 48. (Item 59) Progression-free survival is characterized by complete response to one or more target tumors, as described in any one of items 17-58. (Item 60) Progression-free survival is characterized by a partial response to one or more target tumors, as described in any one of items 17-58. (Item 61) The method described above is the method according to any one of items 1 to 60, including administration to the patient in a fasted state. (Item 62) The method described above is the method according to any one of items 1 to 60, including administration to the patient in a feeding state. (Item 63) The method according to any one of items 17 to 62, wherein the extended progression-free survival is at least 9 months. (Item 64) The method according to item 63, wherein the extended progression-free survival is at least 12 months. (Item 65) The method according to item 64, wherein the extended progression-free survival is at least 15 months. (Item 66) The method described in item 65, wherein the extended progression-free survival is at least 18 months. (Item 67) The method according to item 66, wherein the extended progression-free survival is at least 21 months. (Item 68) The method described in item 67, wherein the extended progression-free survival is at least 24 months. (Item 69) The method described in item 68, wherein the extended progression-free survival is at least 27 months. (Item 70) The method described in item 69, wherein the extended progression-free survival is at least 30 months. (Item 71) The method according to item 70, wherein the extended progression-free survival is at least 33 months. (Item 72) The method according to item 71, wherein the extended progression-free survival is at least 36 months. (Item 73) The method according to any one of items 18 to 72, wherein the hazard ratio for disease progression is approximately 0.3. (Item 74) The method according to any one of items 18 to 72, wherein the hazard ratio for disease progression is approximately 0.45. (Item 75) The method according to any one of items 18 to 72, wherein the hazard ratio for disease progression is approximately 0.5. (Item 76) The method according to any one of items 18 to 72, wherein the hazard ratio for disease progression is less than approximately 0.5. (Item 77) The method described in item 76, wherein the hazard ratio for disease progression is less than approximately 0.45. (Item 78) The method described in item 77, wherein the hazard ratio for disease progression is less than approximately 0.4. (Item 79) The hazard ratio for disease progression is less than approximately 0.35, as described in item 78. (Item 80) The method described in item 79, wherein the hazard ratio for disease progression is less than approximately 0.3. (Item 81) Anti-PARP therapy or niraparib is administered as maintenance therapy, as described in any one of items 1 to 80. (Item 82) A method for administering niraparib to a patient having a recurrent cancer selected from platinum-sensitive ovarian cancer, fallopian tube cancer, or primary peritoneal cancer lacking homologous recombination repair abnormalities, comprising administering niraparib to the patient in accordance with a regimen determined to achieve an extension of progression-free survival compared to a control. (Item 83) The method described above is further determined to achieve an improvement of 2 in progression-free survival compared to a control, according to any one of items 1 to 65. (Item 84) The method described above is further determined to achieve an improvement in the complete chemotherapy-free period compared to a control, according to any one of items 1 to 83. (Item 85) The method described above is further determined to achieve an improvement in the time to the first posttreatment compared to a control, according to any one of items 1 to 84. (Item 86) The method described above is further determined to achieve an improvement in the time to a second subsequent treatment compared to a control, according to any one of items 1 to 85. (Item 87) The method described above is determined to be such as that which does not have adverse effects on quality of life, as determined by FOSI and / or EQ-5D-5L, according to any one of items 1 to 86. (Item 88) The method described above is determined so as not to affect the effectiveness of subsequent treatment with chemotherapeutic agents, according to any one of items 1 to 87. (Item 89) The method according to item 88, wherein the following chemotherapeutic agent is a platinum-based preparation. (Item 90) The method according to item 89, wherein the platinum-based preparation is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenantriplatin, picoplatin, or satraplatin. [Brief explanation of the drawing]

[0070] [Figure 1] This graph shows the progression-free survival (PAS) in patients with genomic BRCA mutations (gBRCAmut) under niraparib treatment versus placebo treatment. The y-axis represents the estimated survival function value, and the x-axis represents time (months) since randomization. The hazard ratio for disease progression is shown on the graph as HR (95% CI) 0.27 (0.173, 0.410).

[0071] [Figure 2] This graph shows progression-free survival in patients with HRD-positive tumors (positive HRD status) but without genomic BRCA mutations (non-gBRCA), under niraparib treatment versus placebo treatment. The y-axis represents the estimated survival function value, and the x-axis represents time (months) since randomization. The hazard ratio for disease progression is shown on the graph as HR (95% CI) 0.38 (0.243, 0.586).

[0072] [Figure 3] This graph shows progression-free survival in patients without genomic BRCA mutations (non-gBRCA) during niraparib treatment or placebo treatment. This population includes patients with and without HRD. The y-axis shows the estimated survival function value, and the x-axis shows time (months) since randomization. The hazard ratio for disease progression is shown on the graph as HR (95% CI) 0.45 (0.338, 0.607).

[0073] [Figure 4] This graph shows progression-free survival in patients with niraparib treatment or placebo treatment in patients lacking genomic BRCA mutations (non-gBRCA) and with HRD-negative tumors (negative HRD status). The y-axis represents the estimated survival function value, and the x-axis represents time (months) since randomization. The hazard ratio for disease progression is shown on the graph as HR (95% CI) 0.58 (0.361, 0.922).

[0074] [Figure 5] This graph shows progression-free survival (PAS) at the time of niraparib treatment or placebo treatment for a mixed trial population consisting of gBRCAmut and non-gBRCAmut patients. The y-axis represents the estimated survival function value, and the x-axis represents the time (months) since randomization.

[0075] [Figure 6]This graph shows progression-free survival in the HRD-positive / BRCAwt subgroup of the non-gBRCAmut cohort, comparing treatment with niraparib or placebo. The y-axis represents the estimated survival function value, and the x-axis represents time (months) since randomization.

[0076] [Figure 7] This graph shows progression-free survival in the HRD-positive / somatic BRCAmut subgroup of the non-gBRCAmut cohort, comparing treatment with niraparib or placebo. The y-axis represents the estimated survival function value, and the x-axis represents time (months) since randomization.

[0077] [Figure 8] A graph showing the mean change (±SE) over time from baseline for platelet counts is displayed for the entire patient cohort.

[0078] [Figure 9] This graph shows progression-free survival in the gBRCAmut cohort based on IRC assessments, for the longest-duration niraparib dose (niraparib patients in the safety population).

[0079] [Figure 10] This graph shows progression-free survival in the non-gBRCAmut cohort based on IRC assessments, for the longest-duration niraparib dose (niraparib patients in the safety population).

[0080] [Figure 11] A table of secondary endpoints in the primary efficacy population should be provided.

[0081] [Figure 12A] Figure 12A shows a graph of progression-free survival analysis in the gBRCAmut cohort, Figure 12B shows a graph of progression-free survival analysis in the non-gBRCAmut, HRD-positive subgroup, and Figure 12C shows a graph of progression-free survival analysis in the entire non-gBRCAmut cohort. [Figure 12B] Same as above. [Figure 12C] Same as above.

[0082] [Figure 13] The graphs show the analysis of complete chemotherapy-free survival in the gBRCAmut cohort (left panel), the all-non-gBRCAmut cohort (center panel), and the non-gBRCAmut, HRD-positive subgroup (right panel).

[0083] [Figure 14] The graphs show the analysis of the time to first subsequent treatment in the gBRCAmut cohort (left panel), the all-non-gBRCAmut cohort (center panel), and the non-gBRCAmut, HRD-positive subgroup (right panel).

[0084] [Figure 15] This graph shows the efficacy analysis of the following line of treatment in the combined gBRCAmut and non-gBRCAmut cohorts.

[0085] [Figure 16] This graph shows the estimated probability of disease progression 6 months after the final dose of platinum-based therapy.

[0086] [Figure 17] This graph shows the effect of the number of chemotherapy lines on the proportion of time patients have to disease progression. It is presented for the platinum-based chemotherapy gBRCAmut cohort (A), the platinum-based chemotherapy non-gBRCAmut cohort (B), the total chemotherapy gBRCAmut cohort (C), and the total chemotherapy non-gBRCAmut cohort (D).

[0087] [Figure 18] This graph shows patient-reported outcomes for quality of life (QOL) assessment in cancer drug therapy using the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI) and EQ-5D-5L. [Modes for carrying out the invention]

[0088] definition As used herein, the term “administration” typically refers to the administration of a composition to a subject or system. Those skilled in the art will recognize the various routes that may be used for administration to a subject, such as a human subject, under appropriate conditions. For example, in some embodiments, administration may be intraocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., by bronchial infusion), oral cavity, skin (e.g., one or more topical locations such as the dermis, intradermal, interdermal, transdermal, etc., or include them), intestine, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, ventricle, intra-organ (e.g., intrahepatic), mucous membrane, nose, oral, rectal, subcutaneous, sublingual, topical, trachea (e.g., by intratracheal infusion), vagina, vitreous humor, etc. In some embodiments, administration may include intermittent administration (e.g., multiple doses divided by time) and / or periodic administration (e.g., individual doses divided by a common period). In some embodiments, administration may include continuous administration (e.g., perfusion) over a selected period of time.

[0089] As used herein, the terms “dosage form” or “unit dosage form” refer to a physically distinct unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount is a suitable unit dose (or its entire fraction) for administration, according to a regimen determined to correlate with a desirable or beneficial outcome when administered to the relevant population (i.e., according to a therapeutic regimen). Those skilled in the art will recognize that the total amount of a therapeutic composition or agent administered to a particular subject may be determined by one or more physicians and may include administration of multiple dosage forms.

[0090] As used herein, the term “regmen” typically refers to a set of unit doses (often two or more) administered individually to a subject, divided into one or more time periods. In some embodiments, a given therapeutic agent is administered according to a regime which may comprise one or more doses. In some embodiments, a regime comprises multiple doses, each separated from the others by time. In some embodiments, individual doses are separated from one another by periods of equal length. In some embodiments, a regime comprises multiple doses, which are separated by periods of different lengths. In some embodiments, a regime comprises the same amount of dose. In some embodiments, a regime comprises different amounts of dose. In some embodiments, a regime comprises at least one dose, which comprises one unit dose of the therapeutic agent. In some embodiments, a regime comprises at least one dose, which comprises two or more unit doses of the therapeutic agent. For example, a 250 mg dose may be administered as a single unit dose of 250 mg, or as two unit doses of 125 mg each. In some embodiments, a regimen, when administered to the entire relevant population, correlates with or produces a desirable or beneficial outcome (i.e., a therapeutic regimen).

[0091] Where used herein, the terms “patient,” “subject,” or “test subject” refer to any organism to which the compounds provided herein are administered in accordance with the Invention, for example, experimental, diagnostic, preventive, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; others, etc.). In preferred embodiments, the subject is human. In some embodiments, the subject may be susceptible to and / or prone to diseases, disorders, and / or conditions (e.g., cancers such as ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer). In some embodiments, the patient is a human having one or more female reproductive organs. In some embodiments, the patient is a human female (i.e., woman) diagnosed with gynecological cancer (e.g., cancers such as ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer). Where used herein, “patient population” or “subject population” refers to a group of patients or subjects.

[0092] As used herein, “therapeutic dose” refers to the amount of a therapeutic agent administered that produces the desired effect for which it was intended. In some embodiments, the term refers to the amount sufficient to treat a disease, disorder, and / or condition when administered according to a regimen to a population that is suffering from or susceptible to the disease, disorder, and / or condition. In some embodiments, the therapeutic dose is the amount that reduces the incidence and / or severity of one or more symptoms of the disease, disorder, and / or condition, and / or delays their onset. Those skilled in the art will recognize that the term “therapeutic dose” does not actually require successful treatment in a particular individual. Rather, the therapeutic dose may be the amount that, when administered to a patient in need of such treatment, produces a particular desired pharmacological response in a large portion of the target population. In some embodiments, the reference to the therapeutic dose may refer to the amount measured in one or more specific tissues (e.g., tissues affected by the disease, disorder, or condition) or liquids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those skilled in the art will recognize that, in some embodiments, a therapeutically effective dose of a particular agent or therapy may be formulated and / or administered as a single dose. In some embodiments, a therapeutically effective agent may be formulated and / or administered as multiple doses, for example, as part of a regimen.

[0093] As used herein, “chemotherapeutic agent” refers to a chemical agent that inhibits the proliferation, growth, lifespan, and / or metastatic activity of cancer cells. In some embodiments, the chemotherapeutic agent is a platinum-based agent. In some such embodiments, the platinum-based agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenantriplatin, picoplatin, or satraplatin.

[0094] As used herein, “CA-125” means cancer antigen 125. The CA-125 test measures the amount of the protein CA-125 in a patient’s blood. The CA-125 test may be used to monitor certain cancers during and after treatment, including for evaluating the extension of progression-free survival. In some cases, the CA-125 test may be used to look for early signs of ovarian cancer in women at very high risk of ovarian cancer.

[0095] As used herein, “homologous recombination” refers to the process by which nucleotide sequences are exchanged between separate DNA strands. Homologous recombination is involved in many different biological processes, for example, as part of DNA repair processes (e.g., the double-strand break repair pathway and the synthesis-dependent strand annealing pathway). It occurs during the strand annealing pathway and the process of meiosis / gamete formation in eukaryotes. As used herein, “homologous recombination deficiency,” “homologous recombination repair deficiency,” “homologous repair deficiency,” or “HRD” refers to a decrease or dysfunction of the homologous recombination process. While we do not wish to be bound by theory, because homologous recombination is involved in DNA repair, it is thought that a sample with homologous recombination deficiency would be unable to repair DNA damage, such as double-strand breaks, or would have a reduced ability to do so. Therefore, a sample with HRD would accumulate genomic errors, meaning that chromosomal aberrations can be used as biomarkers for HRD. As used herein, “chromosomal aberration” or “CA” refers to a detectable variation in the chromosomal DNA of a sample. In some embodiments, CA is classified into at least one of three overlapping categories: loss of heterozygosity (LOH), allele-imbalance (e.g., telomeric allelic imbalance (TAI)), or large-scale transition (LST). In some embodiments, “HRD status” is determined by the detection of CA in a sample taken from a patient (e.g., a tumor sample). In some embodiments, a positive HRD status means that a sample taken from a patient matches a numerical threshold or level of CA in a specified number of chromosomal indicator regions. In some embodiments, HRD status is determined using a commercially available diagnostic device that detects chromosomal abnormalities in a sample (e.g., a tumor sample) and / or assesses whether the sample can repair double-strand DNA breaks. An example of a commercially available diagnostic device for assessing HRD status is the myChoice HRD® diagnostic kit.

[0096] As used herein, loss of heterozygosity (LOH) refers to a change in a target polymorphic locus from heterozygous to homozygous. Since an individual typically receives one copy from their biological father and one from their biological mother, polymorphic loci (e.g., single nucleotide polymorphisms (SNPs)) within the human genome are generally heterozygous within individual germline cells. However, in somatic cells, this heterozygosity can change to homozygosity (through mutation), which is referred to herein as LOH. LOH can arise from several mechanisms. For example, in some cases, a chromosomal locus may be deleted in somatic cells. If only one copy (not two) of the locus exists in the genome of the affected cell, the locus still present on other chromosomes (other non-sex chromosomes for males) is the LOH locus. This type of LOH event results in a copy number reduction. In other examples, a locus on a chromosome in a somatic cell (for example, a non-sex chromosome in a male) can be replaced with a copy of that locus from another chromosome, thereby eliminating any heterozygosity that could have existed within the replaced locus. In such cases, the locus still present on each chromosome is a LOH locus, which may be referred to as a copy-neutral LOH locus. The LOH and its use in HRD determination are described in detail in the international patent application PCT / US2011 / 040953 (published as WO / 2011 / 160063), the entire contents of which are incorporated herein by reference.

[0097] A broader classification of chromosomal abnormalities that encompasses LOH is allele-imbalance. Allele-imbalance occurs when the relative copy number (i.e., copy ratio) at a specific locus in somatic cells differs from that of the germline. For example, if the germline has one copy of allele A and one copy of allele B at a particular locus, and the somatic cell has two copies of allele A and one copy of allele B, then the copy ratio of the somatic cell (2:1) and the copy ratio of the germline (1:1) are different, resulting in allele-imbalance at that locus. Since the somatic cell has a copy ratio (1:0 or 2:0) different from that of the germline (1:1), LOH is an example of allele-imbalance. However, allele-imbalance encompasses many more types of chromosomal abnormalities. For example, a 2:1 germline to a 1:1 somatic cell, a 1:0 germline to a 1:1 somatic cell, a 1:1 germline to a 2:1 somatic cell, and so on. Analysis of allele-allelic imbalance regions encompassing chromosome telomeres is particularly useful in the present invention. Therefore, a “telomere-allelic imbalance region” or “TAI region” is defined as a region with allele-allelic imbalance that (a) extends to one of the periphery of a telomere and (b) does not cross over to the centromere. The TAI and its use in HRD determination are described in detail in the international patent application PCT / US2011 / 048427 (published as WO / 2012 / 027224), the entire contents of which are incorporated herein by reference.

[0098] A broader classification of chromosomal abnormalities, encompassing LOH and TAI, is referred to herein as large-scale transition (LST). An LST is any somatic cell copy number transition (i.e., a breakpoint) along the length of a chromosome, which is the length between two regions of at least approximately the shortest length (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more megabases) after removing a region shorter than the approximate maximum length (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4 or more megabases). For example, if, after removing a region shorter than 3 megabases, the somatic cell has a breakpoint transition to a region of at least 10 megabases with a copy number ratio of, for example, 1:1 for at least 10 megabases, and then to a region of at least 10 megabases with a copy number ratio of, for example, 2:2, this is an LST. Another way to define the same phenomenon is through LST regions. An LST region is a genomic region adjacent by a breakpoint that has a stable copy number over at least the shortest approximate length (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 megabases) at which the copy number changes (i.e., transitions) to at least another region of this shortest length. For example, after a region shorter than 3 megabases is removed, the somatic cell has a region of at least 10 megabases with a 1:1 copy number, and this region is adjacent on one side by a breakpoint that transitions to, for example, a region of at least 10 megabases with a 2:2 copy number, and on the other side by a breakpoint that transitions to, for example, a region of at least 10 megabases with a 1:2 copy number, in which case these are two LSTs. Note that this is broader than allele imbalance. This is because such a change in copy number would not be considered an allele imbalance (since copy ratios of 1:1 and 2:2 are the same; in other words, there is no change in copy ratio).Its use in determining LST and HRD is described by Popova et al., "Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with HRD." This is described in detail in BRCA1 / 2 inactivation, CANCER RES. (2012) 72:5454-5462.

[0099] As used herein, “BRCA mutation” or “BRCA mutation” refers to a change or difference in the sequence of at least one copy of either the BRCA1 gene or the BRCA2 gene, or both, compared to a suitable reference sequence (e.g., a wild-type reference and / or a sequence present in the non-cancerous cell of the subject). Mutations in BRCA1 / 2 may result in BRCA1 / 2 abnormalities, which may include loss or reduction of expression or function of the BRCA gene and / or the protein it encodes. Such mutations may also be referred to as “harmful mutations,” or may be presumed to be harmful mutations. A BRCA mutation may also be a “germline BRCA mutation,” which suggests that it was inherited from one or both parents. Germline mutations affect all cells of an organism and are passed down to offspring. BRCA mutations may also be acquired during an individual’s lifetime; that is, they may occur spontaneously in any cell of the body (somatic cells) at any time during the patient’s life (i.e., non-hereditary). This is interchangeably referred to herein as “sporadic BRCA mutations” or “somatic BRCA mutations.” Genetic testing is also available and known to those skilled in the art. For example, the BRACAnalysis CDx® kit is an in vitro diagnostic kit for the detection and classification of BRCA1 / 2 variants. Using isolated genomic DNA, BRACAnalysis CDx identifies mutations in protein-coding regions and at intron / exon boundaries of BRCA1 and BRCA2. Single nucleotide variants and small insertions and deletions (indels) can be identified by polymerase chain reaction (PCR) and nucleotide sequence analysis. Large deletions and duplications of BRCA1 and BRCA2 can be detected using multiplex PCR. An indicator of “BRCA status” refers to the presence or absence of a mutation in at least one copy of either BRCA1 or BRCA2 in at least some cases. In some embodiments, an indicator of BRCA status refers to mRNA expression levels, methylation levels, or other epigenetic modifications of either or both BRCA1 and BRCA2.In some embodiments, a patient having a "positive BRCA status" refers to a patient whose sample has been determined to contain a mutation in BRCA1 and / or BRCA2. In some embodiments, a positive BRCA status refers to the presence of either a germline BRCA mutation (gBRCA. mut ) or a somatic BRCA mutation (sBRCA mut ). In some embodiments, a patient having a "positive BRCA status" refers to a patient whose sample has been determined to have reduced expression of BRCA1 and / or BRCA2. In some embodiments, the BRCA status is determined for germline BRCA mutations (e.g., gBRCA mut ), and is performed on a blood sample of the subject. In some embodiments, the BRCA status is determined for somatic BRCA mutations (e.g., sBRCA mut ), or is determined for total BRCA mutations (tBRCA mut , which includes both somatic and germline BRCA mutations).

[0100] As used herein, the term “genes involved in DNA repair” means any gene involved in DNA repair in a cell. Table 8 lists representative sets of genes involved in DNA repair. These include genes involved in homologous recombination (HR), a type of genetic recombination in which nucleotide sequences are exchanged between similar or identical DNA molecules. HR is most widely used in cells to precisely repair harmful breaks that occur on both strands of a DNA strand, known as double-strand breaks. For example, BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, DMC1, EME1 (MMS4L), EME2, GEN1, GIYD2 (SLX1B), MRE11A, MUS81, NBN, PALB2, RAD50, RAD51, RAD51B, RD51C, RAD51D, RAD52, RAD54B, RAD54L, RBBP8, SHFM1 (DSS1), XRCC2, and XRCC3 are genes known to be involved in HR. Those skilled in the art will be able to determine whether a gene is involved in DNA repair or homologous recombination. DNA repair status refers to the presence or absence of mutations in one or more genes involved in DNA repair. In some embodiments, the present invention includes treating cancer patients with PARP inhibitors, regardless of DNA repair status.

[0101] As used herein, the term "PARP inhibitor" means an agent that inhibits the activity or reduces the function of any one of the poly(ADP-ribose) polymerase (PARP) family of proteins. This includes inhibitors of one or more of the more than 15 different enzymes in the PARP family, which are involved in a variety of cellular functions, including the regulation of the cell cycle, transcription, and DNA damage repair.

[0102] As used herein, the term “progression-free survival” means the period during which a subject with a disease (e.g., cancer) survives without significant deterioration of the disease. Progression-free survival may be assessed as the period during which there is no progression of tumor growth and / or the period during which the patient’s disease state is not determined to be a progressive disease. In some embodiments, progression-free survival for a subject with cancer is assessed by assessing the size of the tumor (lesion site), the number of tumors (lesion sites), and / or metastasis.

[0103] As used herein, “progression-free survival 2” (PFS2) is defined as the period from treatment randomization to the date of progression assessment in the next anticancer treatment after the investigational treatment, or the earlier of the date of death from any cause. In some embodiments, the determination of progression may be assessed by clinical and / or radiological evaluation.

[0104] Where used herein in relation to the state of cancer, the terms “progression” or “progressive disease (PD)” of tumor growth refer to an increase in the total diameter of the target lesion site (tumor). In some embodiments, progression of tumor growth refers to an increase of at least 20% in the total diameter of the target lesion site, taking the smallest total in the study as a reference (including the baseline total if the baseline total is the smallest total in the study). In some embodiments, in addition to a relative increase of 20%, the total diameter of the target lesion site must also show an absolute increase of at least 5 mm. The appearance of one or more new lesion sites may also be incorporated into the determination of progression of tumor growth. For the purpose of determining progression-free survival, progression may be determined if at least one of the following criteria is met: 1) Tumor evaluation by CT / MRI clearly shows progressive disease in accordance with RECIST 1.1 criteria, or 2) Additional diagnostic tests (e.g., histology / cytology, ultrasound, endoscopy, positron emission tomography) identify new lesion sites, or existing lesion sites are clearly progressive disease and Gynecologic Cancer Intergroup(GCIG)-Standard(Rustin et al.,Int J See Gynecol Cancer 2011;21:419-423. The following criteria determine that CA-125 progression is applicable according to the following: 3) Definitive clinical signs and symptoms of PD ([i] refractory cancer-related pain, [ii] malignant bowel obstruction / worsening dysfunction, or [iii] obvious symptomatic worsening of ascites or pleural effusion), and CA-125 progression according to the GCIG criteria.

[0105] As used herein, the terms “partial response” or “PR” refer to a reduction in tumor progression in a subject, indicated by a reduction in the total diameter of the target lesion site, with reference to the total diameter of the baseline lesion. In some embodiments, PR refers to a reduction of at least 30% in the total diameter of the target lesion site, with reference to the total diameter of the baseline lesion. Examples of methods for evaluating partial response are identified in the RECIST guidelines. See EAEisenhauer, et al., “New response evaluation criteria in solid tumors: Revised RECIST Guidelines (Version 1.1),” Eur.J.of Cancer, 45:228-247 (2009).

[0106] As used herein, “stabilization” or “stable disease” (SD) of tumor growth means that there is no contraction sufficient to qualitatively classify as PR and no increase sufficient to qualitatively classify as PD. In some embodiments, stabilization refers to a change (increase or decrease) of less than 30%, 25%, 20%, 15%, 10%, or 5% of the total diameter of the target lesion site, with reference to the total diameter of baseline. Examples of methods for evaluating stabilization or stable disease of tumor growth are identified in the RECIST guidelines. See EAEisenhauer, et al., “New response evaluation criteria in solid tumors: Revised RECIST Guidelines (Version 1.1),” Eur.J.of Cancer, 45:228-247 (2009).

[0107] As used herein, the terms “complete response” or “CR” are used to mean the disappearance of all or substantially all of the target lesion site. In some embodiments, CR refers to a reduction of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the total diameter of the target lesion site, with reference to the total diameter of the baseline (i.e., disappearance of the lesion site). In some embodiments, CR indicates that less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the total diameter of the lesion site remains after treatment. Examples of methods for evaluating complete response are identified in the RECIST guidelines. See EAEisenhauer, et al., “New response evaluation criteria in solid tumors: Revised RECIST Guidelines (Version 1.1),” Eur.J.of Cancer, 45:228-247 (2009).

[0108] Where used herein, “hazard ratio” (or “HR” where used in the context of calculating the efficacy of niraparib treatment, e.g., HR 0.38) is a representation of the hazard or opportunity for an event to occur in the treatment group as the ratio of the event to occur in the control group. The hazard ratio may be determined by a Cox model, a regression method on survival data, which provides estimates of the hazard ratio and confidence interval. The hazard ratio is an estimate of the ratio of hazard rates in the treatment group to the control group. The hazard rate is the probability that the event in question will occur in the next period if it has not yet occurred, divided by the length of that period. The assumption of proportional hazards regression is that the hazard ratio is constant over time.

[0109] In some embodiments, the present invention involves comparing results achieved for two or more agents, entities, situations, conditions, or groups. As will be understood by those skilled in the art, such agents, entities, situations, conditions, groups, etc., may be considered "comparable" if they are not identical but are sufficiently similar to be comparable, and reasonable conclusions can be drawn based on observed differences or similarities. In some embodiments, a comparable setting of conditions, environments, individuals, or groups is characterized by several substantially identical characteristics and one or a few diverse characteristics. Those skilled in the art will understand, in context, the degree of identity required for two or more such agents, entities, situations, or conditions to be considered comparable in any given environment. For example, a person skilled in the art would recognize that environmental, individual, or population settings are comparable when they are characterized by a sufficient number and types of substantially identical characteristics, which justifies the conclusion that differences in results obtained or differences in observed phenomena under different environmental, individual, or population settings, or using different environmental, individual, or population settings, are caused by or indicators of variability in those characteristics.

[0110] Comparisons described herein are often made against a suitable “reference.” As used herein, the term “reference” refers to a standard or control against which a comparison is made. For example, in some embodiments, the agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is examined and / or determined substantially concurrently with the examination or determination of the interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium of representation. Typically, as will be understood by those skilled in the art, the reference or control is determined or feature-analyzed under conditions or circumstances equivalent to those being evaluated. Those skilled in the art will recognize when sufficient similarity exists to justify reliability and / or comparison to a particular possible reference or control.

[0111] As used herein, the term “treatment” (or “to treat” or “to treat”) means any administration of therapy that partially or completely alleviates, improves, restores, inhibits, delays the onset, reduces the severity, and / or reduces the incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be the treatment of a subject that does not show any signs of the disease, disorder, and / or condition in question, and / or the treatment of a subject that shows only early signs of the disease, disorder, and / or condition. Alternatively, or further, such treatment may be the treatment of a subject that shows one or more established signs of the disease, disorder, and / or condition in question. In some embodiments, the treatment may be the treatment of a subject that has been diagnosed with the disease, disorder, and / or condition in question. In some embodiments, the treatment may be the treatment of a subject that is known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the disease, disorder, and / or condition in question.

[0112] As used herein, the term “fasting state” refers to a state in which a subject has not ingested food for a certain period of time. In some embodiments, fasting state indicates that there is substantially no food residue in the subject’s stomach. In some embodiments, fasting state refers to the state of a subject from about two hours after food ingestion to about 30 minutes before the next food ingestion. In some embodiments, the fasting state of a subject includes any point in time from about two hours, three hours, 3.5 hours, four hours, six hours, eight hours, or twelve hours after food ingestion to about 30 minutes before the next food ingestion, or any point in time including the end of that period.

[0113] As used herein, the term “feeding state” refers to the state of the subject in which food is present in the subject’s stomach at the time of administration of the therapeutic agent (e.g., niraparib). In some embodiments, the feeding state refers to the state of the subject at any time including the end of either of the following periods, from the start of food intake to approximately two hours after food intake, for example, during food intake, immediately after food intake, approximately 30 minutes after food intake, approximately one hour after food intake, approximately 1.5 hours after food intake, or approximately two hours after food intake. As used herein, food intake refers to the intake of a substantial amount of food, either by volume or total calories, for example, at least one-third of the subject’s normal diet.

[0114] As used herein, the term “polymorph” refers to the crystalline structure of a compound. As used herein, the term “solvate” refers to a crystalline form with either a stoichiometric or non-stoichiometric amount of solvent incorporated into the crystalline structure. Similarly, the term “hydrate” refers to a crystalline form with either a stoichiometric or non-stoichiometric amount of water incorporated into the crystalline structure.

[0115] As used herein, the term “pharmaceutically acceptable salt” refers to salts that, within the bounds of reasonable medical judgment, are commensurate with a reasonable benefit / risk ratio and are suitable for use involving contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc. Pharmaceutically acceptable salts are known in the art. For example, SMBerge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference, describe pharmaceutically acceptable salts in detail. Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodide, and 2-hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonic acid, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates.

[0116] Suitable salts derived from bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 Examples include salts of alkyl(4) metals. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations produced using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0117] As used herein, the term “pharmaceutical composition” refers to a composition formulated in which an active agent is combined with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a therapeutic regimen that demonstrates a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for oral administration, such as liquid drugs (aqueous or non-aqueous solutions or suspensions), tablets such as those targeting oral, sublingual, and systemic absorption, boluses, powders, granules, and pastes for application to the tongue. The pharmaceutical composition may also be referred to as a drug.

[0118] As used herein, the term "niraparib" refers to the free base compound ((3S)-3-[4-{7-(aminocarbonyl)-2H-indazole-2-yl}phenyl]piperidine), a salt form containing a pharmaceutically acceptable salt of ((3S)-3-[4-{7-(aminocarbonyl)-2H-indazole-2-yl}phenyl]piperidine (e.g., ((3S)-3-[4-{7-(aminocarbonyl)-2H-indazole-2-yl}phenyl]piperidine tosylate), or their solvates or hydrates (even if This means any of the following: ((3S)-3-[4-{7-(aminocarbonyl)-2H-indazole-2-yl}phenyl]piperidine tosylate monohydrate, etc. In some embodiments, such forms may be individually referred to as “niraparib free base,” “niraparib tosylate,” and “niraparib tosylate monohydrate,” respectively. Unless otherwise specified, the term “niraparib” includes all forms of the compound (3S)-3-[4-{7-(aminocarbonyl)-2H-indazole-2-yl}phenyl]piperidine.

[0119] As used herein, the terms “maintenance therapy” or “maintenance treatment” refer to treatment given to prevent disease recurrence. For example, maintenance therapy may prevent or minimize the growth of cancer that has substantially decreased or been eliminated after initial treatment (cancer treatment). Maintenance therapy may be continuous treatment, for example, administered in multiple doses at intervals such as daily, every other day, weekly, every two weeks, every three weeks, every four weeks, or every six weeks. In some embodiments, maintenance therapy may be continued for a predetermined length of time. In some embodiments, maintenance therapy may be continued until unacceptable toxicity occurs and / or disease progression occurs. During the course of maintenance therapy, treatment may be interrupted when toxicity occurs as specified by adverse events. If the toxicity has adequately resolved to baseline or grade 1 or less within 28 days, the patient may restart treatment with niraparib, which may include a reduction in dose level if prevention is not considered feasible.

[0120] As used herein, overall survival (OS) is defined as the time from the start of treatment to death from any cause. For use as an endpoint in clinical trials, it is defined as the time from randomization to death from any cause and is measured for population treatment purposes.

[0121] As used herein, “Objective Response Rate (ORR)” is defined as the percentage of patients with a given reduction in tumor size and the shortest time to response. The response period is typically measured from the time of the initial response until tumor progression is documented. Generally, ORR can be defined as the sum of partial and complete responses.

[0122] When used herein, "time to first follow-up treatment" (TFST) "To first subsequent therapy" is defined as the period from the date of randomization in the current trial to the date on which the first subsequent treatment regimen (e.g., anti-cancer therapy) is initiated.

[0123] As used herein, “time to second subsequent therapy” (TSST) is defined as the time from the date of randomization in the current trial to the date on which a second subsequent therapy regimen (e.g., anti-cancer therapy) is initiated.

[0124] As used herein, "chemotherapy-free interval" (CFI) is defined as the time from the last dose of the last anti-cancer treatment (e.g., platinum-based chemotherapy) to the start of the next anti-cancer treatment. Ovarian cancer

[0125] Ovarian cancer begins when healthy cells in the ovary change and grow uncontrollably, forming a mass called a tumor. Tumors can be cancerous or benign. Cancerous tumors are malignant, meaning they can grow and spread to other parts of the body. Benign tumors mean that the tumor can grow but will not spread. Non-cancerous ovarian tumors can be treated by removing the ovary, or the part of the ovary in which the tumor is located. Ovarian cysts form on the surface of the ovary and, unlike non-cancerous tumors, usually heal on their own without treatment. Simple ovarian cysts are not cancerous. They often occur during a normal menstrual cycle. Types of ovarian cancer include epithelial carcinoma, germ cell tumor, or stromal tumor.

[0126] Epithelial carcinomas account for 85-90% of ovarian cancers. Historically, they were thought to originate on the surface of the ovary, but new evidence suggests that at least some ovarian cancers originate in specific cells within the fallopian tubes. The fallopian tubes are small tubes that connect a woman's ovaries to her uterus and are part of the female reproductive system. All women have two fallopian tubes, one on each side of the uterus. Cancer cells that originate in the fallopian tubes can reach the ovarian surface relatively quickly. The term "ovarian cancer" is often used to describe epithelial cancers that originate in the ovaries, in the fallopian tubes, and in the endometrium of the abdominal cavity, the so-called peritoneum. Germ cell tumors. This is a rare form of ovarian cancer that occurs in the egg-producing cells of the ovary. This type of tumor occurs more frequently in women between the ages of 10 and 29. Stromal tumors. This rare form of ovarian cancer occurs in the connective tissue cells that hold the ovaries together and are also the tissue that occasionally produces a female hormone called estrogen. More than 90% of these tumors are granulosa cell tumors in adults or infants. Granulosa cell tumors may secrete estrogen, which can cause abnormal vaginal bleeding at the time of diagnosis.

[0127] In 2012, the estimated number of epithelial ovarian cancer cases in women in the United States was approximately 22,280 (15,500 deaths), while in Europe in 2012, it was estimated at 65,538 (42,704 deaths). At diagnosis, most women present with advanced disease, which is a major cause of the high mortality rate. Initial chemotherapy consists of either taxane-based or platinum-based chemotherapy, or a combination of both. Approximately 75% of patients respond to frontline therapy, but 70% of these eventually relapse within 1–3 years. Despite the high response rate at the onset of the disease, there is a significant unmet need due to the high recurrence rate. Attempts to improve standard two-agent chemotherapy (carboplatin and paclitaxel) by adding a third cytotoxic agent (topotecan, gemcitabine, or doxil) have been unsuccessful (du Bois et al, 2006 and Pfisterer et al, 2006). A major challenge in the near future will be selecting patients with advanced ovarian cancer who will benefit most from targeted therapies in setting up frontline maintenance therapy. Maintenance therapy following a response to initial chemotherapy may offer clinical benefits by slowing the side effects of disease progression, delaying the need for toxic chemotherapy, and extending overall survival. However, there is currently no widely accepted standard of treatment for setting up maintenance therapy for ovarian cancer.

[0128] Given the lack of successful treatment strategies, researchers at the Cancer Genome Atlas (TCGA) comprehensively measured genomic and epigenetic abnormalities in clinically annotated HGS-OvCa samples to identify molecular factors that influence pathophysiology, affect outcomes, and constitute components of therapeutic targets (TCGA, 2011). Ovarian tumors are characterized by dysfunction in DNA repair, such as BRCA mutations. BRCA1 and BRCA2 were initially identified as tumor suppressor genes, and their deficiency was associated with an increased incidence of certain malignancies, including ovarian cancer. BRCA abnormalities are noted in 34% of ovarian cancers and are caused by a combination of germline mutations, sporadic mutations, and promoter hypermethylation. BRCA plays a crucial role in DNA repair, including homologous recombination. This study estimated that more than half of high-grade serous ovarian cancers arose from deficiencies in DNA repair. Tumor cells with BRCA abnormalities / homologous recombination disorders (HRD) inhibit DNA repair pathways, offering opportunities for therapeutic interventions using agents that leverage the synthetic lethal mechanisms of cancer treatment. Recent studies suggest that HR abnormalities in epithelial ovarian cancer (EOC) are not solely due to germline BRCA1 and BRCA2 mutations (Hennessy, 2010; TCGA, 2011; Byler Dann, 2012). The Cancer Genome Atlas Research Network reported that approximately half of the roughly 500 EOCs in its dataset had deficiencies in at least one HR pathway gene. The role of poly(ADP-ribose) polymerase (PARP)

[0129] Poly(ADP-ribose) polymerase (PARP) is a family of enzymes that cleave NAD+, release nicotinamide, and subsequently add ADP-ribose units to form ADP-ribose polymers. Therefore, activation of PARP enzymes can lead to a decrease in cellular NAD+ levels (e.g., PARP as an NAD+ consumer) and mediate cellular signaling via ADP-ribosylation of downstream targets. PARP-1 is a zinc finger DNA-binding enzyme that is activated by binding to double-strand or single-strand break sites on DNA. Anti-alkylating agents are known to reduce NAD+ content in tumor cells, and the discovery of PARP explains these phenomena. (Parp Inhibitors and Cancer Therapy. Curtin N. in Poly ADP Ribosylation. ed. Alexander Burke, Lands Bioscience and Springer Bioscience, 2006:218-233). Anti-alkylating agents induce DNA strand breaks, which activate PARP-1. This activation is part of the DNA repair pathway. PARP-1-mediated poly-ADP-ribosylation of nucleoproteins converts DNA damage into intracellular signals, which can activate DNA repair (e.g., via the base excision repair (BER) pathway) or, in cases of excessive and inefficient DNA damage, can induce cell death.

[0130] The role of PARP enzymes in the DNA damage response (e.g., DNA repair in response to genotoxic stress) has led to compelling suggestions that PARP inhibitors could be useful anticancer agents. Numerous studies have investigated the activity of PARP inhibitors as cancer treatments, either alone or in combination with other agents. PARP inhibitors may be particularly effective in treating cancers resulting from germline abnormalities or sporadic abnormalities in the homologous recombination DNA repair pathway, such as cancers caused by deficiencies in BRCA-1, BRCA-2, and / or ATM. Furthermore, co-administration of genotoxic chemotherapeutic agents and PARP inhibitors may enhance the killing effect of such chemotherapeutic agents by suppressing BER (Behavioral and Emission Reduction).

[0131] Preclinical ex vivo and in vivo studies have suggested that PARP inhibitors exhibit selective cytotoxicity against tumors with homozygous inactivation of either the BRCA-1 or BRCA-2 gene, which are known to be important in the homologous recombination (HR) DNA repair pathway. In cancers with HR defects, the biological basis for the use of PARP-1 inhibitors as monotherapies is the need for PARP-1 and PARP-2 for base excision repair (BER) of damaged DNA. When a single-strand DNA break site is formed, PARP-1 and PARP-2 bind and are activated at the lesion site, catalyzing the addition of a long-chain polymer of ADP-ribose (PAR chain) on several chromatin-associated proteins, including histones, PARP itself, and various DNA repair proteins. This leads to chromatin relaxation and rapid recruitment of DNA repair factors to access and repair the DNA break site. Normal cells repair up to 10,000 DNA defects daily, and single-strand breaks are the most common form of DNA damage. Cells with defects in the BER pathway enter S phase with unrepaired single-strand breaks. These existing single-strand breaks are converted to double-strand breaks as the replication mechanism passes through them. Double-strand breaks present during S phase are preferentially repaired by the error-free HR pathway. Cells unable to use HR (i.e., due to inactivation of genes required for HR, such as BRCA-1 or BRCA-2) may accumulate stagnant replication forks during S phase and repair damaged DNA using error-prone non-homologous end joining (NHEJ). Both the inability to complete S phase (due to stagnant replication forks) and the error-prone NHEJ repair are thought to contribute to cell death.

[0132] While we do not wish to be bound by theory, it is hypothesized that treatment with PARP inhibitors offers a novel opportunity to selectively kill a subset of cancer cells with abnormalities in DNA repair pathways. For example, tumors arising in patients with germline BRCA mutations have a defective homologous recombination DNA repair pathway, and their reliance on BER, a pathway inhibited by PARP inhibitors, would be increased for maintaining genomic integrity. Non-BRCA abnormalities in homologous recombination DNA repair genes may also increase the susceptibility of tumor cells to PARP inhibitors. This concept of inducing death by using a PARP inhibitor that inhibits one DNA repair pathway in tumors that already have abnormalities in complementary DNA repair pathways is called synthetic lethality.

[0133] Germline mutations in the BRCA-1 and BRCA-2 genes are found in the majority of patients with hereditary ovarian or breast cancer. Somatic BRCA-1 / 2 mutations and inactivation of the BRCA-1 and BRCA-2 genes by other mechanisms, including gene silencing through promoter hypermethylation, occur in a significant portion of several sporadic cancers. Particularly with respect to ovarian cancer, somatic BRCA-1 or BRCA-2 mutations are found in 10%–15% of all epithelial ovarian carcinomas (EOCs), and a sharp decrease in BRCA-1 expression is observed in a significant portion of sporadic ovarian cancers. In summary, up to 40%–60% of ovarian cancers may be responsive to PARP inhibitors as a result of deficiencies in the BRCA-HR pathway, suggesting the high potential of this approach in ovarian cancer treatment.

[0134] The HR pathway is complex, and several genes other than BRCA-1 and BRCA-2 are required for either sensing or repairing DNA double-strand breaks via the HR pathway. Therefore, it is not surprising that PARP inhibitors also exhibit selective cytotoxicity against cancer cells with abnormalities in DNA repair proteins other than BRCA-1 and BRCA-2, including RecA homologs (RAD51 and RAD54), X-ray repair complementing defective repair in Chinese hamster cells (XRCC2 and XRCC3), DSS1, replication protein A1 (RPA1), ataxia telangiectasia mutated (ATM), ATM and Rad3-related (ATR), checkpoint kinases (CHK1, CHK2), Nijmegen breakage syndrome 1 (NBS1), and components of the Fanconi anemia repair pathway. Some of these genes are known to be mutated or downregulated in different sporadic tumors, and therefore may be "addicted" to not only HR-mediated DNA repair but also possibly non-HR-mediated DNA repair, and thus respond to PARP inhibitors. More recently, tumor cells with PTEN- gene deletions have also been shown to be sensitive to PARP inhibitors, possibly as a result of HR deficiency.

[0135] The therapeutic potential of PARP inhibitors is further expanded by observations that PARP-1 inhibitors not only possess monotherapy activity in HR-deficient tumors, but are also effective in preclinical models when used in combination with cisplatin, carboplatin, alkylating and methylating agents, radiotherapy, and topoisomerase I inhibitors. In contrast to the logical interpretation of monotherapy that PARP inhibition alone is sufficient to induce cell death (due to endogenous DNA damage) in HR-deficient cancers, PARP is required for the repair of DNA damage induced by standard cytotoxic chemotherapy. While the specific role of PARP is unknown in some cases, PARP-1 is known to be required to release trapped topoisomerase I / irinotecan complexes from DNA. Temozolomide-induced DNA damage is repaired via the BER pathway, which requires PARP to recruit repair proteins. Combination therapies that enhance cytotoxic agents or exert synergistic effects with cytotoxic agents without significantly increasing toxicity would bring significant benefits to patients with ovarian cancer and other cancer types.

[0136] Therapies using PARP inhibitors (e.g., PARP-1 / 2 inhibitors) offer a novel opportunity to selectively kill subsets of cancer cell types by exploiting defects in DNA repair. Human cancers exhibit genomic instability and increased mutation rates due to inherent defects in DNA repair. These abnormalities make cancer cells more dependent on remaining DNA repair pathways, and targeting these pathways is expected to have a greater impact on tumor cell survival than on normal cell survival. While PARP inhibitors offer the potential of cancer treatments, the clinical efficacy of these compounds is not yet clear. In particular, the results regarding the clinical outcomes of different PARP inhibitors (e.g., PARP-1 / 2 inhibitors) as cancer treatments are unclear and even contradictory in some cases. For example, an analysis of clinical trial results evaluating the PARP inhibitor olaparib shows inconsistencies in long-term outcomes for overall survival in patients with ovarian cancer. For example, an analysis of three clinical trials revealed that when average olaparib was used in addition to conventional treatment, it slowed the progression of platinum-sensitive epithelial ovarian cancer in women with germline BRCA mutations compared to placebo or no treatment, but there was no significant change in overall survival. Furthermore, the olaparib trial revealed that serious adverse events occurred more frequently in the olaparib group compared to the control group. Wiggins et al., (2015) “Poly(ADP-ribose)polymerase(PARP) inhibitors for the treatment of ovarian cancer” cancer.”Cochrane Database of Systematic See Reviews, Issue 5, Art. No.: CD007929. Another clinical trial using the PARP inhibitor veliparib was conducted with a relatively small sample size, but it failed to demonstrate any effect of veliparib on the progression of ovarian cancer. Thus, the field has failed to establish the clinical efficacy of these PARP inhibitors, and there remains a need to identify, characterize, and / or develop PARP inhibitors as effective cancer treatments. This disclosure satisfies this need. In particular, this disclosure provides niraparib compositions and techniques for achieving effective cancer treatment, especially for cancers of the female reproductive system (e.g., ovarian cancer). In some embodiments, this disclosure provides niraparib compositions and / or methods for achieving the progression-free survival rates and / or hazard ratios described herein. In some embodiments, the compositions and / or methods provided achieve such effects with a treatment emergent adverse event rate (TEAE) that is higher than that observed with comparable placebo treatment, not exceeding about three times, or not exceeding two times in some embodiments. The provided composition and / or method achieves such an effect with a severe TEAE rate that is higher than that observed with comparable placebo treatment, not exceeding approximately 5 times, not exceeding approximately 4.5 times, or not exceeding approximately 4 times.

[0137] Platinum-sensitive recurrent ovarian cancer still represents a medical unmet need. Both the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO) guidelines recommend retreatment with platinum-based combination chemotherapy if recurrence occurs more than six months after the initial response to platinum-based therapy. Paclitaxel and carboplatin are the most frequently used regimens for recurrent platinum-responsive patients. However, most patients who recur and are treated with a second round of platinum-based chemotherapy do not receive any further treatment after their response to that chemotherapy. This is because there are no approved products for maintenance use after chemotherapy in the United States. The standard of care in the United States is "watchful waiting."

[0138] Unfortunately, the efficacy of platinum-based chemotherapy diminishes over time. PFS and complete platinum-free intervals generally shorten after each subsequent treatment, eventually leading to platinum-resistant or refractory tumors. Furthermore, due to the cumulative toxicity of platinum-based agents and taxanes, patients generally do not receive more than six cycles of platinum-based chemotherapy per treatment cycle. There is a need for new agents that can prolong responsiveness to platinum-based chemotherapy, reduce the risk of recurrence or death, and extend the complete platinum-free interval.

[0139] The poly(ADP-ribose) polymerase (PARP) family of proteins consists of more than 15 different enzymes that are involved in various cellular functions, including cell cycle regulation, transcription, and DNA damage repair. BRCA1, BRCA2, and PALB2 are important proteins for error-free homologous recombination repair, or repair of double-strand DNA breaks via the HRR pathway. If the genes for any of these proteins mutate, the changes can lead to errors in DNA repair, ultimately potentially causing cancer, such as breast or ovarian cancer.

[0140] PARP-1 is the most abundant and best-characterized protein in this group and is essential for the repair of single-strand DNA breaks via the base excision repair pathway. If the break remains unrepaired until DNA replication occurs (which must precede cell division), the subsequent replication itself can cause the formation of double-strand breaks. Effective inhibition of PARP-1 leads to the accumulation of single-strand breaks, which ultimately result in double-strand breaks. Normally, such double-strand breaks are repaired by homologous recombination (HR), but in cells with defective HR, PARP inhibition can lead to chromosomal instability, cell cycle arrest, and subsequent apoptosis. DNA is damaged thousands of times during each cell cycle, and this damage should be repaired. If a large amount of damage occurs at once, the altered genes can lead to cell death. Normal cells, which do not replicate DNA as frequently as cancer cells and do not have either mutated BRCA1 or BRCA2, still have homologous repair mechanisms, which allow normal cells to survive PARP inhibition. PARP inhibitors function by inhibiting PARP enzyme activity, which can disrupt DNA damage repair and ultimately lead to cell death. They also work by positioning PARP proteins at DNA damage sites, which is thought to be associated with antitumor activity. The trapped PARP protein-DNA complex is highly toxic to cells because it interferes with DNA replication.

[0141] Typically, PARP proteins are released from DNA once the DNA binding and repair processes have progressed. Evidence exists that when the protein binds to a PARP inhibitor, it becomes trapped on the DNA. These trapped PARP-DNA complexes are more toxic to cells than unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity. Therefore, while we are not bound by any single theory, at least two mechanisms exist: PARP inhibitor-repair inhibition and PARP trapping.

[0142] In tumors with mutations in BRCA1 and BRCA2, breast cancer-related genes that encode proteins essential for normal hemoglobin (HR) function, HR has been observed to be unable to repair double-strand breaks. The use of small molecule PARP inhibitors exploits this genetic vulnerability in DNA damage repair and is an example of synthetic lethality. In this case, inhibiting both pathways simultaneously leads to cell death, while inhibiting only one of the pathways is not lethal. Promising preclinical results of PARP inhibitors in the treatment of BRCA-mutated tumor cells have provided a strong rationale for conducting clinical trials of these agents in patient populations most likely to carry these mutations, such as patients with breast or ovarian cancer. This therapeutic strategy is now recognized as monotherapy for treating patients with BRCA-mutated advanced ovarian cancer, following recent accelerated approvals by the U.S. Food and Drug Administration (FDA) for the PARP inhibitors olaparib and rucaparib. Surprisingly, this invention demonstrates that PARP inhibition is effective in extending progression-free survival in human cancer patients, with or without the presence of BRCA1 or BRCA2 mutations. Niraparib was the first PARP inhibitor to demonstrate this capability, but the results can be achieved with other PARP inhibitors as well. Niraparib and other such PARP inhibitors are examined below.

[0143] Niraparib, (3S)-3-[4-{7-(aminocarbonyl)-2H-indazole-2-yl}phenyl]piperidine, is an orally available, potent inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP)-1 and -2. See WO2008 / 084261 (published July 17, 2008) and WO2009 / 087381 (published July 16, 2009). The entirety of each of these is incorporated herein by reference. Niraparib can be prepared according to Scheme 1 of WO 2008 / 084261.

[0144] In some embodiments, niraparib can be prepared as a pharmaceutically acceptable salt. Those skilled in the art will recognize that such salt forms may exist as solvated or hydrated polymorphs. In some embodiments, niraparib is prepared in the form of a hydrate.

[0145] In some embodiments, niraparib is prepared in the form of a tosylate. In some embodiments, niraparib is prepared in the form of a tosylate monohydrate.

[0146] Niraparib crystalline tosylate monohydrate is being developed as a monotherapy agent for tumors with deficiencies in the homologous recombination (HR) deoxyribonucleic acid (DNA) repair pathway, and as a sensitizer in combination with cytotoxic agents and radiotherapy.

[0147] Niraparib is a potent and selective inhibitor of PARP-1 and PARP-2, exhibiting a 50% inhibitory concentration (IC) compared to the control. 50 The concentrations are 3.8 nM and 2.1 nM, respectively, and are at least 100 times more selective than other PARP-family species. Niraparib inhibits PARP activity stimulated as a result of DNA damage induced by the addition of hydrogen peroxide in various cell lines, and its IC 50 And the 90% inhibitory concentration (IC) of the control. 90 These values ​​are approximately 4 nM and 50 nM, respectively.

[0148] Niraparib exhibits selective antiproliferative activity against cancer cell lines with silencing of BRCA-1 or BRCA-2, or carrying BRCA-1 or BRCA-2 mutations, compared to wild-type counterparts. The antiproliferative activity of niraparib against BRCA-deficient cells results in cell cycle arrest at G2 / M, followed by apoptosis. Niraparib also exhibits selective cytotoxicity against selected Ewing sarcoma, acute lymphoblastic leukemia (ALL), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) cell lines, as well as tumor cell lines carrying homozygous inactivation of the ATM gene. Niraparib shows weak activity against normal human cells. It demonstrated potent antitumor activity in in vivo studies using BRCA-1 mutant breast cancer (MDA-MB-436), BRCA-2 mutant pancreatic cancer (CAPAN-1), ATM-mutated mantle cell lymphoma (GRANTA-519), serous ovarian cancer (OVCAR3), colorectal cancer (HT29 and DLD-1), patient-induced Ewing sarcoma, and a mouse TNBC xenograft model.

[0149] Target binding has also been demonstrated by measuring PARP activity in tumor homogenates from tumor xenograft experiments. Inhibition of PARP activity has also been measured in peripheral blood mononuclear cells (PBMCs) of mice administered niraparib. Niraparib has been shown to induce cell cycle arrest, particularly arrest at the G2 / M phase of the cell cycle. Therefore, in some embodiments, the present invention provides a method for inducing cell cycle arrest in tumor cells, the method comprising administering niraparib to patients in need. In some embodiments, the present invention provides a method for inducing cell cycle arrest at the G2 / M phase of tumor cells, the method comprising administering niraparib to patients in need. In some embodiments, the present invention provides a method for inducing cell cycle arrest at the G2 / M phase of BRCA-1 and / or BRCA-2 deficient cells, the method comprising administering niraparib to patients in need.

[0150] Olaparib acts as an inhibitor of the poly-ADP-ribose polymerase (PARP) enzyme and is therefore named a PARP inhibitor. Its chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazine-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazine-1(2H)-one. Clinical trials of olaparib were initiated in breast cancer, ovarian cancer, and colorectal cancer. Preliminary activity was observed in ovarian cancer, with 7 out of 17 patients with BRCA1 or BRCA2 mutations responding, and 11 out of 46 patients without these mutations responding. However, an interim analysis of a phase II trial investigating the use of olaparib to maintain progression-free survival or responsiveness after successful platinum-based chemotherapy suggested that the reported progression-free survival benefit was unlikely to translate to an overall survival benefit for population treatment purposes. However, planned analyses of a subset of patients with BRCA mutations have shown a clear advantage of using olaparib (Ledermann et al., New England Journal of Medicine, 366;15(2012); Lancet Oncol. 15(8):852-61). Olaparib is approved as monotherapy at a recommended dose of 400 mg twice daily in patients with advanced ovarian cancer with germline BRCA mutations (gBRCAmut) who have previously received three or more lines of chemotherapy. BRCA1 / 2 mutations can genetically predispose individuals to certain types of cancer and make them resistant to other forms of cancer treatment. However, these cancers sometimes possess unique vulnerabilities, and the cancer cells become increasingly dependent on PARP to repair their own DNA and continue to divide. This means that drugs that selectively inhibit PARP may be beneficial if the cancer is sensitive to this treatment. Therefore, clinical data on olaparib showed that PARP inhibitors are not beneficial in extending progression-free survival in the treatment of cancers characterized by the absence of BRCA1 or BRCA2 mutations.

[0151] Similarly, rucaparib acts as an inhibitor of the poly-ADP-ribose polymerase (PARP) enzyme and is also named a PARP inhibitor. Its chemical name is 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indole-6-one((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hepta-1-yl)methanesulfonate. It is also approved as monotherapy for the treatment of patients with advanced ovarian cancer associated with adverse BRCA mutations (germline and / or somatic) who have been treated with two or more prior chemotherapy agents. The efficacy of rucaparib was investigated in 106 patients with advanced BRCA-mutated ovarian cancer that had progressed after two or more prior chemotherapy agents in two multicenter, single-arm, open-label clinical trials, Trial 1 and Trial 2. All 106 patients received 600 mg of rucaparib orally twice daily as monotherapy until disease progression or unacceptable toxicity occurred. Independent radiological response assessment was 42% (95% CI [32,52]), and the median duration of response (DOR) was 6.7 months (95% CI [5.5,11.1]). Physician-assessed overall response (ORR) was 66% (52 / 79; 95% CI [54,76]) in platinum-sensitive patients, 25% (5 / 20; 95% CI [9,49]) in platinum-resistant patients, and 0% (0 / 7; 95% CI [0,41]) in platinum-refractory patients. ORR was similar for patients with BRCA1 or BRCA2 gene mutations. Therefore, clinical data on rucaparib showed that PARP inhibitors are not beneficial in extending progression-free survival in the treatment of cancers characterized by the absence of BRCA1 or BRCA2 mutations.

[0152] Similarly, talazoparib acts as an inhibitor of the poly-ADP-ribose polymerase (PARP) enzyme and is also known as a PARP inhibitor. It is currently being evaluated in clinical trials for the treatment of patients with gBRCA mutations in breast cancer (i.e., advanced breast cancer in patients whose BRCA gene contains germline mutations). The primary objective of this trial is to compare the progression-free survival (PFS) of patients treated with talazoparib as monotherapy with that of patients treated at the physician's discretion as defined in the protocol.

[0153] Similarly, veliparib acts as an inhibitor of the poly-ADP-ribose polymerase (PARP) enzyme and is also named a PARP inhibitor. The chemical name of veliparib is 2-[(R)-2-methylpyrrolidine-2-yl]-1H-benzimidazole-4-carboxamide.

[0154] At the time of diagnosis of ovarian cancer, most women present with progressive disease, which is a major cause of high mortality. Patients with stage 2, 3, or 4 disease may undergo tumor reduction surgery if the tumor is resectable, followed by 4 to 8 cycles of chemotherapy. Initial chemotherapy can consist of either IV chemotherapy agents or a combination of IV and intraperitoneal (IP) chemotherapy agents. IV chemotherapy agents typically consist of a taxane (paclitaxel or docetaxel) and a platinum-based agent (cisplatin or carboplatin). Approximately 75% of patients respond to frontline therapy and are considered platinum-sensitive if they remain recurrence-free or disease-free for at least 6 months after treatment. However, up to 70% of patients eventually relapse within 1 to 3 years. Attempts to improve standard platinum-based dual chemotherapy by adding a third cytotoxic agent have failed, showing no improvement in either progression-free survival or overall survival, and resulting in increased toxicity (du Bois et al, 2006 and Pfisterer, 2006 et al). Even after a high response rate at the initial stage of the disease, a high relapse rate means there is a significant unmet need.

[0155] Researchers at the Cancer Genome Atlas (TCGA) validated clinically annotated HGS-OvCa samples and identified molecular factors that influence pathophysiology, affect outcomes, and constitute components of therapeutic targets (TCGA, 2011). Ovarian tumors are characterized by dysfunction in DNA repair, such as BRCA mutations. BRCA1 and BRCA2 have been identified as tumor suppressor genes, and their deficiency has been associated with an increased incidence of certain malignancies, including ovarian cancer. BRCA plays a crucial role in DNA repair, including homologous recombination. Tumor cells with BRCA abnormalities / homologous recombination abnormalities (HRD) are particularly sensitive to DNA damage. Niraparib inhibits PARP activity stimulated as a result of DNA damage and exhibits selective antiproliferative activity against cancer cell lines with BRCA-1 or BRCA-2 silenced, or carrying BRCA-1 or BRCA-2 mutations, compared to wild-type counterparts. The antiproliferative activity of niraparib against BRCA-deficient cells is a result of cell cycle arrest at G2 / M, followed by apoptosis. PARP inhibitors interfere with alt-NHEJ and BER, causing tumors with BRCA abnormalities to repair double-strand breaks using error-prone NHEJ. Non-BRCA abnormalities in homologous recombination DNA repair genes can also increase the sensitivity of tumor cells to PARP inhibitors. PARP inhibitors, including niraparib, are useful in treating individuals with tumors that carry mutations in the DNA repair pathway, such as individuals with germline BRCA mutations (gBRCAmut) that cause ovarian cancer.

[0156] In an attempt to address high recurrence rates, anti-PARP therapy may be administered as maintenance therapy in patients with recurrent and / or platinum-sensitive ovarian cancer, including fallopian tube and peritoneal cancer, as a way to extend the high initial response rate associated with frontline platinum-based chemotherapy agents, thereby extending progression-free survival and / or overall survival. Such extension of progression-free survival may result in a reduced hazard ratio for disease progression or death. Extended progression-free survival may offer several clinical benefits, including delayed disease symptoms, delayed toxic burden from chemotherapy, and delayed decline in quality of life. In another embodiment, patients with platinum-sensitive ovarian cancer are further characterized as having BRCA abnormalities and / or HRD (e.g., positive HRD status). In another embodiment, patients with recurrent and / or platinum-sensitive ovarian cancer are further characterized by the absence of germline BRCA mutations that are harmful or suspected to be harmful. In another embodiment, patients with recurrent and / or platinum-sensitive ovarian cancer are further characterized by the absence of either germline or sporadic BRCA mutations.

[0157] The present invention is based in part on the discovery that cancers characterized by wild-type or mutant BRCA1 and / or BRCA2 (BRCA genes) can be treated using PARP inhibitors, for example, in or without the presence of mutations in the BRCA genes. Accordingly, aspects of the present invention relate to a method for treating a cancer patient, the method comprising administering anti-PARP therapy to the patient regardless of the BRCA status of the patient or cancer, or regardless of the DNA repair status. In other aspects, the present invention relates to a method for treating a cancer patient, the method comprising administering anti-PARP therapy to the patient, in which case the therapy is initiated before determining the BRCA status or HRD status of the patient or cancer. In other aspects, the present invention relates to a method for treating a cancer patient, the method comprising administering anti-PARP therapy to the patient, in which case the therapy is initiated without determining the BRCA status or DNA repair status of the patient or cancer. In another embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients characterized by the absence of mutations in BRCA1 and / or BRCA2. In another embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients characterized by the absence of mutations in genes involved in DNA repair. In another embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients characterized by the absence of mutations in genes involved in homologous recombination. In an embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients having cancer characterized by the absence of mutations in BRCA1 or BRCA2. In an embodiment, the present invention relates to a method for treating cancer patients, the method comprising administering anti-PARP therapy to patients having cancer characterized by the absence of mutations in genes involved in homologous recombination.

[0158] In some embodiments, anti-PARP therapy is administered in doses equivalent to about 100 mg, about 200 mg, or about 300 mg of niraparib, a salt thereof, or a derivative thereof. In some embodiments, anti-PARP therapy is administered in doses equivalent to about 100 mg of niraparib, a salt thereof, or a derivative thereof. In some embodiments, anti-PARP therapy is administered in doses equivalent to about 200 mg of niraparib, a salt thereof, or a derivative thereof. In some embodiments, anti-PARP therapy is administered in doses equivalent to about 300 mg of niraparib, a salt thereof, or a derivative thereof.

[0159] In some embodiments, anti-PARP therapy is administered in regimens determined to achieve i) extended progression-free survival compared to controls, ii) a reduced hazard ratio for disease progression or death compared to controls, iii) extended overall survival compared to controls, or iv) an overall response rate of at least 30%.

[0160] In some embodiments, anti-PARP therapy involves the administration of an agent that inhibits PARP-1 and / or PARP-2. In some embodiments, the agent is a small molecule, nucleic acid, polypeptide (e.g., antibody), carbohydrate, lipid, metal, or toxin. In relevant embodiments, the agent is ABT-767, AZD 2461, BGB-290, BGP 15, CEP 9722, E7016, E7449, fluzoparib, INO1001, JPI 289, MP 124, niraparib, olaparib, ONO2231, rucaparib, SC 101914, talazoparib, veliparib, WW 46, or salts thereof or derivatives thereof. In some related embodiments, the agent is niraparib, olaparib, lucaparib, thalazoparib, beriparib, or a salt or derivative thereof. In some embodiments, the agent is niraparib, or a salt or derivative thereof. In some embodiments, the agent is olaparib, or a salt or derivative thereof. In some embodiments, the agent is lucaparib, or a salt or derivative thereof. In some embodiments, the agent is thalazoparib, or a salt or derivative thereof. In some embodiments, the agent is beriparib, or a salt or derivative thereof.

[0161] In some embodiments, the method extends progression-free survival compared to the control. In some embodiments, the method reduces the hazard ratio for disease progression or death compared to the control. In some embodiments, the method extends overall survival compared to the control. In some embodiments, the method achieves an overall response rate of at least 30%. In some embodiments, the method achieves an improved progression-free survival compared to the control. In some embodiments, the method achieves an improved complete chemotherapy-free period compared to the control. In some embodiments, the method achieves an improved time to first subsequent therapy compared to the control. In some embodiments, the method achieves an improved time to second subsequent therapy compared to the control. In some embodiments, the method is determined not to have adverse effects on quality of life as determined by FOSI and / or EQ-5D-5L. In some embodiments, the method is determined so as not to affect the efficacy of subsequent treatment with chemotherapeutic agents (e.g., platinum-based agents such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin).

[0162] In some embodiments, such cancers are selected from gynecological cancers (i.e., cancers of the female reproductive system). In some embodiments, cancers of the female reproductive system include, but are not limited to, ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer. In some embodiments, gynecological cancers are associated with homologous repair deficiency (HRD) and / or BRCA1 / 2 mutations. In some embodiments, gynecological cancers are platinum-sensitive. In some embodiments, gynecological cancers respond to platinum-based therapy. In some embodiments, gynecological cancers develop resistance to platinum-based therapy. In some embodiments, gynecological cancers have previously shown partial or complete response to platinum-based therapy. In some embodiments, gynecological cancers are currently resistant to platinum-based therapy.

[0163] In one embodiment, the cancer is ovarian cancer, fallopian tube cancer, or peritoneal cancer. In another embodiment, the cancer is breast cancer.

[0164] In some embodiments, the cancer is recurrent cancer.

[0165] In one embodiment, niraparib is administered as maintenance therapy to patients with recurrent ovarian cancer (including fallopian tube cancer and peritoneal cancer), in which case the administration of niraparib results in an extension of progression-free survival. In one embodiment, niraparib is administered as monotherapy for maintenance treatment to patients with recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, in which case the patients are responsive to platinum-based chemotherapy agents. In one embodiment, niraparib is administered as monotherapy for maintenance treatment to patients with harmful or suspected harmful germline or somatic BRCA mutations or homologous recombination defects in recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, in which case the patients are responsive to platinum-based chemotherapy agents.

[0166] Such extensions of progression-free survival can result in a reduced hazard ratio for disease progression or death. Maintenance therapy is administered during the period between discontinuation of initial treatment aimed at delaying disease progression and intensive subsequent treatment, which may present tolerability issues for the patient. In another embodiment, patients with recurrent ovarian cancer are further characterized as having BRCA abnormalities or HRD. In another embodiment, patients with recurrent ovarian cancer are further characterized by the absence of germline BRCA mutations that are harmful or suspected to be harmful.

[0167] In one embodiment, niraparib is administered as maintenance therapy to patients with recurrent ovarian cancer (including fallopian tube and peritoneal cancer) who have achieved a complete or partial response after multiple platinum-based chemotherapy treatments, in which case the administration of niraparib results in an extension of progression-free survival. Such an extension of progression-free survival may result in a reduced hazard ratio for disease progression or death. Maintenance therapy is administered during the period between discontinuation of chemotherapy aimed at delaying disease progression and intensive subsequent treatments that may present tolerability issues for the patient. In another embodiment, patients with recurrent ovarian cancer are further characterized as having BRCA abnormalities or HRD. In yet another embodiment, patients with recurrent ovarian cancer are further characterized by the absence of harmful or suspected harmful germline BRCA mutations.

[0168] In another embodiment, a second approach to addressing the high recurrence rate of ovarian cancer is to select patients with advanced ovarian cancer who would benefit most from a specific targeted agent in a frontline or maintenance therapy setting. Thus, niraparib is administered as treatment in patients with advanced ovarian cancer, in which case such administration results in an extension of overall survival, and in this case the administration is either as treatment (for disease continuing after 1-4 lines of prior treatment) or as maintenance therapy (for patients with PR or CR to prior treatment). In another embodiment, patients with advanced ovarian cancer are further characterized as having BRCA abnormalities or HRD. In another embodiment, patients with recurrent ovarian cancer are further characterized by the absence of harmful or suspected harmful germline BRCA mutations.

[0169] In some embodiments, the present invention provides a method for administering niraparib to patients with recurrent or platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer, the method comprising administering niraparib in accordance with a regimen determined to achieve an extension of progression-free survival. In some embodiments, progression-free survival is longer in patients treated with niraparib compared to, for example, patients not treated with niraparib. In some embodiments, progression-free survival is longer in patients treated with niraparib than in patients treated with other cancer treatments, for example, treatment with a different PARP inhibitor.

[0170] In some embodiments, the extended progression-free survival is at least 9 months. In some embodiments, the progression-free survival is at least 12 months. In some embodiments, the progression-free survival is at least 15 months. In some embodiments, the progression-free survival is at least 18 months. In some embodiments, the progression-free survival is at least 21 months. In some embodiments, the progression-free survival is at least 24 months. In some embodiments, the progression-free survival is at least 27 months. In some embodiments, the progression-free survival is at least 30 months. In some embodiments, the progression-free survival is at least 33 months. In some embodiments, the progression-free survival is at least 36 months.

[0171] In some embodiments, the patient has germline mutations in BRCA1 and / or BRCA2 (gBRCA mut ) has. In some embodiments, the extended progression-free survival is at least 9 months. In some embodiments, the extended progression-free survival is at least 12 months. In some embodiments, the extended progression-free survival is at least 15 months. In some embodiments, the extended progression-free survival is at least 18 months. In some embodiments, the extended progression-free survival is at least 21 months. In some embodiments, the extended progression-free survival is at least 24 months. In some embodiments, the extended progression-free survival is at least 27 months. In some embodiments, the extended progression-free survival is at least 30 months. In some embodiments, the extended progression-free survival is at least 33 months. In some embodiments, the extended progression-free survival is at least 36 months.

[0172] In some embodiments, the patient is the absence of germline mutations in BRCA1 and / or BRCA2 (non-gBRCA). mutCharacterized by: In some embodiments, the patient has a tumor that is positive for homologous recombination deficiency. In some embodiments, the patient is negative for recombination deficiency. In some embodiments, the extended progression-free survival is at least 9 months. In some embodiments, the extended progression-free survival is at least 12 months. In some embodiments, the extended progression-free survival is at least 15 months. In some embodiments, the extended progression-free survival is at least 18 months. In some embodiments, the extended progression-free survival is at least 21 months. In some embodiments, the extended progression-free survival is at least 24 months. In some embodiments, the extended progression-free survival is at least 27 months. In some embodiments, the extended progression-free survival is at least 30 months. In some embodiments, the extended progression-free survival is at least 33 months. In some embodiments, the extended progression-free survival is at least 36 months.

[0173] In some embodiments, the patient is the absence of mutations in BRCA1 and / or BRCA2 (BRCA wtCharacterized by: In some embodiments, the patient has a tumor that is positive for homologous recombination deficiency. In some embodiments, the patient is negative for homologous recombination deficiency. In some embodiments, the extended progression-free survival is at least 9 months. In some embodiments, the extended progression-free survival is at least 12 months. In some embodiments, the extended progression-free survival is at least 15 months. In some embodiments, the extended progression-free survival is at least 18 months. In some embodiments, the extended progression-free survival is at least 21 months. In some embodiments, the extended progression-free survival is at least 24 months. In some embodiments, the extended progression-free survival is at least 27 months. In some embodiments, the extended progression-free survival is at least 30 months. In some embodiments, the extended progression-free survival is at least 33 months. In some embodiments, the extended progression-free survival is at least 36 months.

[0174] In some embodiments, the present invention provides a method for administering niraparib to patients with recurrent or platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer, the method comprising administering niraparib in accordance with a regimen determined to achieve a hazard ratio for disease progression or death. In some embodiments, the hazard ratio is improved in patients treated with niraparib compared to, for example, patients not treated with niraparib. In some embodiments, the hazard ratio is improved in patients treated with niraparib compared to patients treated with another cancer treatment, for example, treatment with a different PARP inhibitor.

[0175] In some embodiments, the hazard ratio for disease progression is about 0.3. In some embodiments, the hazard ratio for disease progression is about 0.4. In some embodiments, the hazard ratio for disease progression is about 0.45. In some embodiments, the hazard ratio for disease progression is about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.45. In some embodiments, the hazard ratio for disease progression is less than about 0.4. In some embodiments, the hazard ratio for disease progression is less than about 0.35. In some embodiments, the hazard ratio for disease progression is less than about 0.3.

[0176] In some embodiments, the patient has a germline mutation (gBRCA mut ) in BRCA1 and / or BRCA2. In some embodiments, the hazard ratio for disease progression is about 0.3. In some embodiments, the hazard ratio for disease progression is about 0.4. In some embodiments, the hazard ratio for disease progression is about 0.45. In some embodiments, the hazard ratio for disease progression is about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.45. In some embodiments, the hazard ratio for disease progression is less than about 0.4. In some embodiments, the hazard ratio for disease progression is less than about 0.35. In some embodiments, the hazard ratio for disease progression is less than about 0.3.

[0177] In some embodiments, the patient has a non - existence of germline mutations in BRCA1 and / or BRCA2 (non - gBRCA mut) characterized thereby. In some embodiments, the patient has a tumor with a positive homologous recombination deficiency state. In some embodiments, the patient has a negative recombination deficiency state. In some embodiments, the hazard ratio for disease progression is about 0.3. In some embodiments, the hazard ratio for disease progression is about 0.4. In some embodiments, the hazard ratio for disease progression is about 0.45. In some embodiments, the hazard ratio for disease progression is about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.45. In some embodiments, the hazard ratio for disease progression is less than about 0.4. In some embodiments, the hazard ratio for disease progression is less than about 0.35. In some embodiments, the hazard ratio for disease progression is less than about 0.3.

[0178] In some embodiments, the present invention provides a method of administering niraparib to a patient having recurrent and / or platinum-sensitive ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, the method comprising administering niraparib according to a regimen determined to achieve an extended overall survival period. In some embodiments, the extended overall survival period is longer in patients administered niraparib as compared to, for example, patients not administered niraparib. In some embodiments, the extended overall survival period is longer in patients administered niraparib as compared to patients receiving another cancer treatment, such as treatment with a different PARP inhibitor.

[0179] In some embodiments, the patient has at least (i) a germline mutation in BRCA1 or BRCA2, or (ii) a sporadic mutation in BRCA1 or BRCA2.

[0180] In some embodiments, the patient has high-grade serous ovarian cancer or high-grade serous histotype-predominant ovarian cancer.

[0181] In some embodiments, patients are further characterized by the absence of germline mutations in BRCA1 or BRCA2.

[0182] In some embodiments, patients are further characterized by the absence of sporadic mutations in BRCA1 or BRCA2.

[0183] In some embodiments, patients are further characterized by a negative BRCA1 / 2 status. In some embodiments, germline mutations in BRCA1 or BRCA2 are not detected in patient-derived samples.

[0184] In some embodiments, progression for the purpose of determining progression-free survival is determined by 1) tumor evaluation by CT / MRI showing disease progression in clear accordance with RECIST 1.1 criteria, and / or 2) additional diagnostic tests (e.g., histology / cytology, ultrasound, endoscopy, positron emission tomography) identifying new lesion sites.

[0185] In some embodiments, patients are characterized by having homologous recombination abnormalities. In some embodiments, patients are positive for homologous recombination abnormalities. Homologous recombination abnormalities can be established according to methods known to those skilled in the art. For example, in some embodiments, the recombination abnormality is established by determining the number of Indicator CA Regions in a patient sample. In some embodiments, the number of Indicator CA Regions includes at least two types selected from LOH indicator regions, TAI indicator regions, or LST indicator regions in at least two pairs of human chromosomes in cancer cells. In some embodiments, a CA region (any of the LOH region, TAI region, or LST region) is a CA indicator region (any of the LOH indicator region, TAI region, or LST region) if it is at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 megabases in length). In some embodiments, an LOH indicator region is longer than about 1.5, 5, 12, 13, 14, 15, 16, or 17 megabases (preferably 14, 15, or 16 megabases, more preferably 15 megabases), but shorter than the total length of each chromosome in which the LOH region is located. Alternatively, the total length of such LOH indicator regions combined may be determined. In some embodiments, the TAI indicator region is an allele-unbalanced TAI region that (a) extends to one of the telomere peripheries, (b) does not cross the centromere, and (c) is longer than 1.5, 5, 12, 13, 14, 15, 16, 17 megabases or more (preferably 10, 11, 12 megabases or more, more preferably 11 megabases or more). Alternatively, the total length of combined such TAI indicator regions may be determined. Since the LST concept already includes several minimum-sized regions (such minimum sizes are determined according to their ability to distinguish HRD from samples in which HDR is not impaired), the LST indicator region is identical to the LST region when used herein.Furthermore, the LST region score can be derived from the number of regions exhibiting LST as described above, or from the number of LST breakpoints. In some embodiments, the shortest length of a stable copy number region adjacent to an LST breakpoint is at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 megabases (preferably 8, 9, 10, or 11 megabases or more, more preferably 10 megabases), and the largest remaining region that is not removed is less than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, or 4 megabases (preferably 2, 2.5, 3, 3.5, or 4 megabases or less, more preferably less than 3 megabases). As used herein, a patient is determined to have a positive HRD condition if the patient-derived sample has many CA index regions or has a CA region score (as defined herein) that exceeds a reference value or threshold.

[0186] In some embodiments, the present invention provides a method for administering niraparib, the method comprising the following steps: Niraparib should be administered to the target population having one or more of the following characteristics, according to a regimen determined to achieve an extension of progression-free survival: BRCA mutation; Positive homologous recombination abnormality; or Presentation of response to prior treatment.

[0187] In some embodiments, the target population has a BRCA mutation. In some embodiments, the BRCA mutation is a germline BRCA mutation (gBRCA). mut ). In some embodiments, the BRCA mutation is a somatic (or sporadic) BRCA mutation (sBRCA). mut ). In some embodiments, the target population has a positive homologous recombination abnormality. In some embodiments, the target population has non-mutant BRCA1 / 2 "BRCA wt " or "BRCA wt This indicates ". Measurement of tumor response

[0188] Tumor response can be measured, for example, by the RECIST v1.1 guidelines. These guidelines are provided by EAEisenhauer, et al., “New response evaluation criteria in solid tumors: Revised RECIST Guidelines (Version 1.1),” Eur. J. of Cancer, 45:228-247 (2009), and are incorporated by reference throughout. These guidelines first require an estimate of the total tumor tissue volume at baseline, which is used as a comparison for subsequent measurements. Tumors can be measured using any imaging system known in the art, such as CT scans or X-rays. Measurable disease is defined by the presence of at least one measurable lesion site. In experiments where the primary endpoint is tumor progression (either time to progression or the rate of progression at a fixed date), the protocol must specify whether enrollment is limited to patients with measurable disease, or whether patients with only non-measurable disease are also eligible.

[0189] If two or more measurable lesion sites are present at baseline, all lesion sites representing all invasive organs, up to a total of five (and up to two lesion sites per organ), must be identified as target lesion sites, recorded, and measured at baseline (this means that in cases where a patient has only one or two invasive organ sites, up to two and four lesion sites may be recorded, respectively).

[0190] The target lesion site must be selected based on its size (the lesion site with the largest diameter), must be representative of all affected organs, and furthermore, must be capable of reproducible, repeatable measurements.

[0191] Lymph nodes are noteworthy even when they are normal anatomical structures and may be visualized by imaging even if they are not invaded by a tumor. Pathological lymph nodes that are defined as measurable and can be identified as target lesion sites must meet the P15mm short-axis criterion by CT scan. Only the short axes of these lymph nodes will contribute to the baseline total. The short axis of a lymph node is the diameter typically used by radiologists to determine whether a lymph node is invaded by a solid tumor. Lymph node size is usually reported as two diameters in the plane from which the image is acquired (for CT scans, this is almost always the axial plane; for MRI, the acquisition plane may be axial, sagittal, or coronal). The smaller of these measurements is the short axis.

[0192] For example, an abdominal lymph node reported as 20mm-30mm has a short axis of 20mm and is considered a malignant, measurable lymph node. In this example, 20mm must be recorded as the lymph node measurement. All other pathological lymph nodes (lymph nodes with a P of 10mm but with a short axis of <15mm) must be considered non-target lesion sites. Lymph nodes with a short axis of <10mm are considered non-pathological and should not be recorded or followed.

[0193] The sum of the diameters for all target lesion sites (the longest diameter for non-lymph node lesions and the short axis for lymph node lesions) will be calculated and reported as the baseline diameter sum. If lymph nodes are included in the sum, only the short axis will be added, as described above. The baseline diameter sum will be used as a reference for further characterizing any objective tumor regression in terms of the measurable dimensions of diseased sites.

[0194] All other lesion sites (or disease sites), including pathological lymph nodes, must be identified as non-target lesion sites and also documented at baseline. Measurements are not required, and these lesion sites must be tracked as “present,” “absent,” or, in rare cases, “obvious progression.” Furthermore, multiple non-target lesion sites, including those in the same organ, may be documented as single entries in the case record format (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). General Protocol

[0195] Where described herein, the methods provided include administering niraparib to a patient, subject, or subject population in accordance with a regimen that achieves any one or any combination of the following: extension of progression-free survival; reduction of the hazard ratio for disease progression or death; and / or extension of overall survival or prospective overall response rate. In some embodiments, niraparib is administered concurrently with or sequentially with an additional therapeutic agent, such as a chemotherapeutic agent (e.g., a platinum-based agent). In some embodiments, niraparib is administered before, during, or after the administration of a chemotherapeutic agent.

[0196] The concurrent or sequential administration of an additional therapeutic agent (e.g., a chemotherapeutic agent) and niraparib is referred to as "combination therapy". In combination therapy, niraparib may be administered to a subject in need thereof before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the chemotherapeutic agent. In some embodiments, niraparib and the chemotherapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 to 2 hours apart, 2 to 3 hours apart, 3 to 4 hours apart, 4 to 5 hours apart, 5 to 6 hours apart, 6 to 7 hours apart, 7 to 8 hours apart, 8 to 9 hours apart, 9 to 10 hours apart, 10 to 11 hours apart, 11 to 12 hours apart, less than 24 hours apart, or less than 48 hours apart.

[0197] In some embodiments, niraparib is administered to patients or a subject population that demonstrated a response to a prior treatment. In some embodiments, the patients or subject population demonstrated a response to a prior treatment with a chemotherapeutic agent. In some such embodiments, the chemotherapeutic agent is a platinum-based formulation.

[0198] In some embodiments, niraparib is administered as maintenance therapy after a complete or partial response to at least one platinum-based therapy. In some embodiments, at least one platinum-based therapy includes administering to patients in need a platinum-based agent selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenantriplatin, picoplatin, or satraplatin. In some embodiments, the response to the most recent platinum-based chemotherapy is a complete response. In some embodiments, the response to the most recent platinum-based chemotherapy is a partial response.

[0199] In some embodiments, the regimen comprises at least one oral dose of niraparib. In some embodiments, the regimen comprises multiple oral doses. In some embodiments, the regimen comprises once daily (QD) administration.

[0200] In some embodiments, the regimen comprises at least one 28-day cycle. In some embodiments, the regimen comprises multiple 28-day cycles. In some embodiments, the regimen comprises one 28-day cycle. In some embodiments, the regimen comprises two 28-day cycles. In some embodiments, the regimen comprises three 28-day cycles. In some embodiments, the regimen comprises consecutive 28-day cycles. In some embodiments, the regimen comprises administering an effective dose of niraparib daily until disease progression occurs or unacceptable toxicity occurs. In some embodiments, the regimen comprises administering a daily dose of at least 100, 200, or 300 mg of niraparib daily until disease progression occurs or unacceptable toxicity occurs.

[0201] In some embodiments, the oral dose is niraparib in an amount ranging from about 5 to about 400 mg. In some embodiments, the amount of niraparib is about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, or about 400 mg. In some embodiments, the amount of niraparib is about 300 mg of niraparib. In some embodiments, the regimen includes an administration of 300 mg of niraparib once daily.

[0202] In some embodiments, the oral dose is administered in one or more unit dosage forms. In some embodiments, the one or more unit dosage forms are capsules. In some embodiments, each unit dosage form contains about 5, about 10, about 25, about 50, or about 100 mg of niraparib. It should be understood that any combination of unit dosage forms can be combined to form a once-daily (QD) dose. For example, taking three 100 mg unit dosage forms once daily results in a once-daily dose of 300 mg of niraparib. In some embodiments, niraparib is administered as a single 300 mg unit dosage form. In some embodiments, niraparib is administered as a 300 mg QD. In some embodiments, niraparib is administered as 3 x 100 mg QDs (i.e., niraparib is administered as three 100 mg unit dosage forms). In some embodiments, niraparib is administered as 2 x 150 mg QDs (i.e., niraparib is administered as two 150 mg units). Pharmacokinetics

[0203] Pharmacokinetic data can be obtained using techniques known in this field. Due to inherent variations in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects, the appropriate pharmacokinetic and pharmacodynamic profile elements describing a particular composition may vary. Typically, pharmacokinetic and pharmacodynamic profiles are based on determining the mean parameters of a group of subjects. A group of subjects includes any reasonable number of subjects suitable for determining a representative mean, such as 5, 10, 16, 20, 25, 30, 35, or more. The mean is determined by calculating the average of the measurements of all subjects for each parameter measured.

[0204] In some embodiments, the pharmacokinetic parameters may be any parameters suitable for describing the compositions of the present invention. For example, in some embodiments, C max This includes approximately 500 ng / ml or more, approximately 550 ng / ml or more, approximately 600 ng / ml or more, approximately 700 ng / ml or more, approximately 800 ng / ml or more, approximately 880 ng / ml, approximately 900 ng / ml or more, approximately 100 ng / ml or more, approximately 1250 ng / ml or more, approximately 1500 ng / ml or more, approximately 1700 ng / ml or more, or any other C suitable for describing the pharmacokinetic profile of niraparib. max That is the case.

[0205] In some embodiments, where an active metabolite is formed in vivo after administration of the drug to the target, C max The levels are approximately 500 pg / ml or higher, approximately 550 pg / ml or higher, approximately 600 pg / ml or higher, approximately 700 pg / ml or higher, approximately 800 pg / ml or higher, approximately 880 pg / ml or higher, approximately 900 pg / ml or higher, approximately 1000 pg / ml or higher, approximately 1250 pg / ml or higher, approximately 1500 pg / ml or higher, approximately 1700 pg / ml or higher, or any other C suitable for describing the pharmacokinetic profile of the compound formed in vivo after administration of niraparib to the subject. max That is the case.

[0206] In some embodiments, T maxFor example, this could be approximately 0.5 hours or less, approximately 1.0 hour or less, approximately 1.5 hours or less, approximately 2.0 hours or less, approximately 2.5 hours or less, or approximately 3.0 hours or less, or any other time suitable for describing the pharmacokinetic profile of niraparib. max That is the case.

[0207] Generally, the AUC described herein is the area under the curve corresponding to the concentration of the analyte over a selected period after administration of a dose of the therapeutic agent. In some embodiments, such a period begins at dose administration (i.e., 0 hours after dose administration) and extends over approximately 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 40 hours, or longer after dose administration. In some embodiments, the AUC is the AUC obtained between 0 and 12 hours after administration of the dose described herein. In some embodiments, the AUC is the AUC obtained between 0 and 18 hours after administration of the dose described herein. In some embodiments, the AUC is the AUC obtained between 0 and 24 hours after administration of the dose described herein. In some embodiments, AUC is the AUC obtained between 0 and 36 hours after administration of the dose described herein.

[0208] AUC (0-inf) For example, AUC may be approximately 590 ng·h / mL or higher, approximately 1500 ng·h / mL or higher, approximately 2000 ng·h / mL or higher, approximately 3000 ng·h / mL or higher, approximately 3500 ng·h / mL or higher, approximately 4000 ng·h / mL or higher, approximately 5000 ng·h / mL or higher, approximately 6000 ng·h / mL or higher, approximately 7000 ng·h / mL or higher, approximately 8000 ng·h / mL or higher, approximately 9000 ng·h / mL or higher, or any other AUC co-int suitable for describing the pharmacokinetic profile of the therapeutic agent (e.g., niraparib). In some embodiments where an active metabolite is formed in vivo after administration of the therapeutic agent (e.g., niraparib) to the subject, AUC (0-inf)This could be, for example, approximately 590 pg·hr / mL or higher, approximately 1500 pg·hr / mL or higher, approximately 2000 pg·hr / mL or higher, approximately 3000 pg·hr / mL or higher, approximately 3500 pg·hr / mL or higher, approximately 4000 pg·hr / mL or higher, approximately 5000 pg·hr / mL or higher, approximately 6000 pg·hr / mL or higher, approximately 7000 pg·hr / mL or higher, approximately 8000 pg·hr / mL or higher, approximately 9000 pg·hr / mL or higher, or any other AUC suitable for describing the pharmacokinetic profile of the compound formed in vivo after administration of niraparib to the subject. (0-inf) That's fine.

[0209] Approximately one hour after administration, the plasma concentration of niraparib may be, for example, ≥140 ng / ml, ≥425 ng / ml, ≥550 ng / ml, ≥640 ng / ml, ≥720 ng / ml, ≥750 ng / ml, ≥800 ng / ml, ≥900 ng / ml, ≥1000 ng / ml, ≥1200 ng / ml, or any other niraparib plasma concentration.

[0210] In some embodiments, the patient population includes one or more subjects (target population) suffering from metastatic disease.

[0211] In some embodiments, the patient population includes one or more subjects who have cancer or are susceptible to cancer. In some such embodiments, the cancer is ovarian cancer, fallopian tube cancer, peritoneal cancer, or breast cancer. In some embodiments, the patient population includes one or more subjects who have cancer (for example, containing or consisting of subjects). For example, in some embodiments, the patient population with cancer may have previously been treated with chemotherapeutic agents, such as chemotherapeutic agents such as platinum-based agents.

[0212] In some embodiments, this disclosure provides techniques that can remarkably achieve substantially identical niraparib PK profiles even when administered to patients in a fed or fasted state. Niraparib can be administered to patients in either a fasted or fed state. Specifically, it has been remarkably found that the bioavailability of niraparib is substantially similar in patients administered niraparib in either a fed or fasted state. In some embodiments, administering niraparib to patients in a fed or fasted state results in substantially bioequivalent niraparib plasma C max Values ​​are obtained. In some embodiments, when administered to patients in a feeding or fasting state, bioequivalent niraparib plasma T1 is obtained. max Values ​​are obtained. In some embodiments, administering niraparib to patients in a fed or fasted state yields bioequivalent plasma AUC values. Therefore, in some embodiments, niraparib is administered in either a fed or fasted state. In some embodiments, niraparib is administered in a fasted state. In other embodiments, niraparib is administered in a fed state.

[0213] In some embodiments, a unit dose of niraparib may be administered to a fasted patient. In some embodiments, a unit dose of niraparib may be administered to a fed patient. In some embodiments, administration in either a fed or fasted state is excluded. In some embodiments, a unit dose may be administered for therapeutic purposes in either a fed or fasted state, and the subject has a choice for each individual administration regarding whether to take it with food or without food. In some embodiments, a unit dose of niraparib may be administered immediately before food intake (i.e., within 30 or 60 minutes before food intake), with food, or immediately after food intake (e.g., within 30, 60, or 120 minutes after food intake). In some embodiments, for example, it may be administered at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours, or longer after food intake, or at any time in between. In some embodiments, the unit dose of niraparib is administered after an overnight fast. In some embodiments, the unit dose of the composition may be administered 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or more before food intake, or at any time in between. [Examples]

[0214] The following embodiments are provided for illustrative purposes only and are not intended to limit the claimed invention. Example 1. Treatment of platinum-sensitive ovarian cancer

[0215] In the NOVA study, patients with platinum-sensitive recurrent ovarian cancer who had responded to platinum-based therapy were prospectively randomized to receive either niraparib or placebo. Two cohorts were treated: a germline BRCA mutation-positive cohort (gBRCA). mut ) and non-germ cell lineage BRCA cohort (non-gBRCA) mut Therefore, NOVA's gBRCAmut The cohort was designed to prospectively evaluate the efficacy of placebo versus niraparib in patients with platinum-sensitive recurrent ovarian cancer who had responded to platinum-based therapy. Patients in this cohort were assessed using the FDA-approved Integrated BRACAnalysis test and were carriers of germline BRCA mutations. Non-gBRCA mut The patient tested negative in the FDA-approved Integrated BRACAnalysis test.

[0216] This is a double-blind, 2:1 randomized, evaluation trial of niraparib as maintenance therapy in patients with relapsed and / or platinum-sensitive ovarian cancer, specifically those with gBRCA. mut The patients had either a tumor with a high-grade serous tissue structure or a tumor with a high-grade serous tissue structure. This study compared maintenance therapy with niraparib with placebo and evaluated the efficacy of niraparib as maintenance therapy in patients with recurrent ovarian cancer, evaluated by extension of progression-free survival (PFS). The purpose of this study was to identify germline BRCA mutations (gBRCA mut A patient cohort having the above characteristics, and having a high-grade serous tissue structure or a high-grade serous-dominant tissue structure but not having the gBRCA mutation (non-gBRCA). mut Independently evaluated in the patient cohort. Non-gBRCA mut Some patients in the cohort have a specific DNA repair deficiency in gBRCA mut It has been reported that this phenomenon is shared with carriers, and this phenomenon is widely described as "BRCAness." (See Turner, N., A. Tutt, and A. Ashworth, Hallmarks of 'BRCAness' in sporadic cancers. Nat. Rev. Cancer 4(10), 814-9, (2004)). Recent studies have suggested that homologous recombination abnormalities (HRD) in epithelial ovarian cancer (EOC) are not simply due to germline BRCA1 and BRCA2 mutations. (Hennessy, B.T. et al. Somatic) mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly(ADP ribose) polymerase inhibitors in ovarian cancer.Journal of clinical oncology:official journal of the American Society of Clinical Oncology 28,3570-3576,(2010);TCGA ``Integrated genomic analyzes of ovarian carcinoma.'' Nature 474(7353),609-615,(2011); and Dann RB,DeLoia JA,Timms KM,Zorn KK,Potter J,Flake DD 2nd,Lanchbury JS,Krivak TC.BRCA 1 / 2 mutations and expression:Response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer.Gynecol (See Oncol. 125(3), 677-82, (2012)). Non-BRCA abnormalities in homologous recombination DNA repair genes can also increase the sensitivity of tumor cells to PARP inhibitors. Therefore, HRD is used and evaluated as a tumor biomarker classification.

[0217] Patients enrolled in this study had received at least two platinum-based regimens, had responded (completely or partially) to the last regimen, had no measurable disease area exceeding 2 cm after the last treatment, and had normal cancer antigen CA125 (or a reduction of more than 90%). Patients were assigned to one of two independent cohorts. One cohort had a harmful gBRCA mutation (gBRCA) according to the following criteria. mut One cohort has the gBRCA mutation (non-gBRCA), and the other has a high-grade serous tissue structure but does not have the gBRCA mutation (non-gBRCA). mut ) is: [Table 1]

[0218] Patients were also evaluated for their HRD status and further classified as either HRD-positive (HRDpos) or HRD-negative (HRDneg).

[0219] The study treatment was administered to patients on day 1 and thereafter at the end of each cycle (28 days) until the patient discontinued the study treatment. The study treatment was continuously administered orally once daily. Three 100 mg capsules were taken at the time of each dose. Patient visits were made at the end of each cycle (every 4 weeks ± 3 days). Tumor evaluation according to the Response evaluation criteria in solid tumors (RECIST) guidelines, via computed tomography (CT) or magnetic resonance imaging (MRI) scans of the abdomen / pelvis and clinically designated areas, was required at the end of every two cycles (8 weeks with a permitted visit period of ± 7 days from the visit date) until cycle 14, and thereafter at the end of every three cycles (12 weeks with a permitted visit period of ± 7 days from the visit date) until progression.

[0220] Patients were analyzed based on the extension of progression-free survival (PFS). More specifically, progression was determined if at least one of the following criteria was met: 1) Tumor evaluation by CT / MRI clearly shows progressive disease according to RECIST 1.1 criteria, 2) Additional diagnostic tests (e.g., histology / cytology, ultrasound, endoscopy, positron emission tomography) identify new lesion sites, or existing lesion sites indicate clear progressive disease and Gynecologic Cancer Intergroup (GCIG) criteria (Rustin et al.). 3) Definitive clinical signs and symptoms of PD ([i] refractory cancer-related pain, [ii] malignant bowel obstruction / worsening dysfunction, or [iii] obvious symptomatic worsening of ascites or pleural effusion, and CA-125 progression according to GCIG criteria) are determined to be applicable to the progression of CA-125 according to the Guidelines for Response Evaluation Criteria in Solid Tumors (RECIST), which are not related to non-malignant or iatrogenic causes. Solid tumors were assessed. This assessment was required at the end of every two cycles (8 weeks) until cycle 14 (56 weeks), and then at the end of every three cycles (12 weeks) until progression occurred.

[0221] Patients continued to receive the treatment assigned to them until the disease progressed, until unacceptable toxicity occurred, until death occurred, or until consent was withdrawn and / or until follow-up was lost. Interruption and / or dose reduction were made whenever there was toxicity of any grade deemed unacceptable to the patient. result

[0222] Niraparib is used by germline BRCA mutation carriers (gBRCA) regardless of HRD status. mut ) Among patients, not being a germline BRCA mutation carrier (non-gBRCA) mut ) among patients with homologous recombination disorder (HRD) tumors, and non-gBRCA mut In patients with this condition, overall, PFS was significantly extended compared to the control group. Non-gBRCA mutThe entire cohort also included patients with HRD-negative tumors. Analysis showed that the HRD-negative population also benefited from niraparib treatment. Determination of gBRCA status and HRD status may include determination by standardized experimental tests, such as the Myriad myChoice® HRD test, or by tests approved by the relevant regulatory authorities.

[0223] In all populations, median PFS was significantly longer in patients treated with niraparib than in patients treated with placebo. (Non-gBRCA) mut Both of the cohort's primary efficacy groups (HRD-positive and overall) demonstrated a significant therapeutic effect of niraparib compared to placebo (HR 0.38 and HR 0.45, respectively; HR = hazard ratio). The entire population showed a consistent, long-term therapeutic effect of niraparib, as evidenced by the Kaplan-Meier curves (see Figures 1–4). Importantly, the same consistent, long-term benefits of niraparib treatment were observed in all exploratory subgroups validated within this cohort. (Non-gBRCA) mut In the cohort, the HRD-positive group consisted of patients with somatic cell tumor BRCA mutations (HRDpos / sBRCA). mut ) and patients with wild-type BRCA (HRDpos / BRCA wt ) included. Importantly, the treatment benefit observed within the HRD-positive group was not simply HRDpos / sBRCA mut This means that it was not derived from the effects within the subgroup. HRDpos / BRCA wt The subgroup also demonstrated consistent long-term benefits from niraparib treatment compared to the overall HRD-positive group. The hazard ratio was 0.38 (Figure 6).

[0224] Germline BRCA mutation carriers (gBRCA mutAmong patients with gBRCA, the niraparib group successfully achieved a statistically significant difference over the control group in terms of the primary endpoint, PFS. The hazard ratio was 0.27. The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months in the control group (p<0.0001). Figure 1 shows the results for patients treated with niraparib and placebo. mut The PFS curves for patients are shown. These results were far superior to those of Trial 19 (N Engl J Med. 2012;366(15):1382-1392), which evaluated the activity of the PARP inhibitor olaparib versus placebo in a similar patient population with a trial design similar to NOVA. Trial 19 reported median PFS of 11.2 months and 4.3 months in the olaparib group and the control group in patients with BRCA mutations. (Non-gBRCA) mut In patients whose tumors were determined to be HRD-positive using the Myriad myChoice® HRD test, the niraparib group successfully achieved a statistically significant difference over the control group in terms of the primary endpoint, PFS. The hazard ratio was 0.38. The median PFS for patients with HRD-positive tumors treated with niraparib was 12.9 months, compared to 3.8 months in the control group (p<0.0001). Figure 2 shows the results for non-gBRCA treated with niraparib and placebo. mut The PFS curve for HRD-positive patients is shown.

[0225] Niraparib is used in the entire non-germline BRCA mutation cohort, including both HRD-positive and HRD-negative tumor patients (non-gBRCA). mut ) also showed a statistically significant difference. The niraparib group successfully achieved a statistically significant difference over the control group in terms of the primary endpoint, PFS. The hazard ratio was 0.45. The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months in the control group (p<0.0001). Figure 3 shows the results for non-gBRCA patients treated with niraparib and placebo. mutThe PFS curves for patients (including both HRD-positive and HRD-negative patients) are shown.

[0226] Niraparib is used in patients with HRD-negative tumors who have non-germline BRCA mutations (non-gBRCA mutations). mut ) also showed a statistically significant difference in patients. The niraparib group successfully achieved a statistically significant difference over the control group in terms of the primary endpoint, PFS. The hazard ratio was 0.58. The median PFS for patients treated with niraparib was 6.9 months, compared to 3.8 months in the control group (p<0.0226). Non-germline BRCA mutations (non-gBRCA) with HRD-negative tumors. mut Figure 4 shows the PFS for patients with the following condition.

[0227] Mixed study population (2 cohorts mixed, gBRCA) mut and non-gBRCA mut In an exploratory pooled analysis examining the effects of niraparib, PFS was longer with niraparib than with placebo. The median PFS for all patients treated with niraparib was 11.3 months compared to 4.7 months in patients treated with placebo, with an HR of 0.38, 95% CI of 0.303, 0.488, and p<0.0001 (Figure 5). Furthermore, gBRCA mut and non-gBRCAmut cohort, non-gBRCA mut As observed in the Kaplan-Meier (KM) curves from analyses of subgroups within the cohort and mixed cohorts, the treatment effects were substantial, long-lasting, and consistent.

[0228] Tables 1-3 below summarize progression-free survival for various patient cohorts. "NR" means "not reached." "95% CI" means 95% confidence interval. Non-gBRCA mut An exploratory analysis of biomarker-related subgroups within the cohort was conducted. The subgroup analyzed was HRDpos / somatic BRCA. mut HRDpos / BRCA wt , and HRDneg. Table 1: Progression-free survival (major) [Table 2] Table 2: Progression-free survival, non-gBRCA [Table 3] Table 3: Treatment efficacy of niraparib and placebo in the NOVA patient population. [Table 4]

[0229] The most common (>10%) grade 3 / 4 adverse events occurring during treatment among all patients treated with niraparib were thrombocytopenia (28.3%), anemia (24.8%), and neutropenia (11.2%). Adverse events were managed by dose adjustments among all patients. The MDS / AML rates were similar in the ITT population, at 1.3% in the niraparib group and 1.2% in the control group. No patients died during the study treatment.

[0230] In this study, non-gBRCA mut Both of the primary efficacy groups in the cohort (HRD-positive and overall) showed a significant niraparib treatment effect compared to placebo (each with respect to HR (HR 0.38 and HR 0.45; Table 3). Both populations demonstrated consistent, long-term therapeutic benefits of niraparib, as evident from the Kaplan-Meier curves. The same consistent, long-term therapeutic benefits of niraparib were observed in all exploratory subgroups examined within this cohort.

[0231] Non-gBRCA mut In the cohort, the HRD-positive group consisted of patients with somatic cell tumor BRCA mutations (HRDpos / sBRCA). mut ) and patients with wild-type BRCA (HRDpos / BRCA wt ) included. The treatment benefit observed within the HRD-positive group was simply HRDpos / sBRCA. mut It was not derived from the effects in the subgroup. HRDpos / BRCAwt The subgroup also demonstrated consistent long-term benefits from niraparib treatment compared to the overall HRD-positive group. The hazard ratio was 0.38 (Figure 6).

[0232] It should be noted that gBRCA mut The HR observed in the cohort (0.27) is HRDpos / sBRCA mut The HR observed in the subgroup was identical, demonstrating a consistent niraparib treatment effect across the entire cohort and in two independent patient populations with similar tumor biological backgrounds (Figure 7).

[0233] All estimated hazard ratios are less than 1, and therefore, gBRCA mut Cohort (Figure 12A), non-gBRCA mut HRD-positive group in Cohort P (Figure 12B), and all non-gBRCA mut Regarding the cohort (Figure 12C), the study suggests an extension of progression-free survival in patients treated with niraparib. Subgroup analysis within non-gBRCAmut cohorts

[0234] As mentioned above, non-gBRCA mut The cohort includes patients in the following three groups: HRD-positive patients, HRD-negative patients, and patients whose tumor HRD status could not be determined (HRDnd). Furthermore, the HRD-positive group includes two additional subgroups: women with somatic BRCA mutation tumors (sBRCA). mut ) and women with HRD-positive tumors resulting from non-BRCA-related deficiencies in the HR pathway (HRDpos / BRCA wt )

[0235] Non-gBRCA mut Within the HRD-positive cohort, 47 patients had sBRCAmut tumors, and 115 had BRCA tumors. wt The patients had tumors. The results of the PFS analysis for these two subgroups of patients are shown in Figures 7 and 6.

[0236] HRDpos / sBRCA mutAmong patients with [condition], the median PFS in the niraparib group was 20.9 months (95% CI: 9.7, NE), compared with 11.0 months (95% CI: 2.0, NE) in the placebo group (11.0 months). The HR was 0.27 (95% CI: 0.081, 0.903) (p = 0.0248). (See Figure 7). sBRCA mut Since the HR was 0.27 in the subgroup, the HR of 0.27 observed in the gBRCA mut cohort is supported.

[0237] HRDpos / BRCA wt Among patients with [condition], the median PFS in the niraparib group was 9.3 months (95% CI: 5.8, 15.4), compared with 3.7 months (95% CI: 3.3, 5.6) in the placebo group. Since the HR was 0.38 (95% CI: 0.231, 0.628) (p = 0.0001), a stable treatment effect for HRD patients is shown even without the presence of sBRCA mutations. (See Figure 6).

[0238] Non-gBRCA mut The entire cohort also included patients with HRD-negative tumors, and exploratory analysis showed that this population also benefited from niraparib treatment (HR 0.58). In the Kaplan-Meier curve (Figure 4), a consistent long-term effect of niraparib is shown, although at a low level, compared with placebo. The impact and persistence of the niraparib effect are important for the evaluation of PFS benefit. For example, the probability of remaining progression-free at 12 months was 27% in the niraparib group compared with 7% in the placebo group. At 18 months, patients treated with niraparib were estimated to have more than twice the progression-free survival compared with placebo-treated patients (19% vs. 7%; Table 3). This benefit for 20 - 25% of recurrent ovarian cancer patients is important in cancer treatment and a surprising advance.

[0239] Treatment interruption and / or dose reduction could be performed at any time when the patient experienced toxicity of any grade deemed unacceptable. Treatment should be interrupted for any non-hematological adverse event (AE) of grade 3 or 4 according to NCI CTCAE v.4.02, if the clinical investigator believed the event was related to the administration of the study drug. If the toxicity had adequately resolved to baseline or grade 1 or lower within 28 days, the patient could restart treatment with the study drug; however, if prevention was not deemed feasible, the dose level should be reduced according to Table 4. If the event recurred at the same or a more severe grade, the patient's treatment was interrupted again. Further dose reductions were required even after the event had resolved. Up to two dose reductions were permitted for all patients. Table 4: Dose reduction for non-hematological toxicity [Table 5]

[0240] If the toxicity requiring treatment discontinuation did not completely resolve or decrease to NCI CTCAE grade 1 or lower during a maximum discontinuation period of 28 days, and / or if the patient had already undergone up to two dose reductions (down to the minimum dose of 100 mg QD), the patient needed to permanently discontinue treatment with the study drug.

[0241] No deaths were reported during treatment in this study. Most patients in both treatment groups, including all patients treated with niraparib and 96% of patients treated with placebo, experienced at least one TEAE (Thirdly Evolved Endocrine Emission). The high rate of TEAEs in the placebo group suggests the influence of previous chemotherapy and the lingering effects of pre-existing ovarian cancer in the patients.

[0242] Overall, the incidence of treatment-related TEAEs was 98% in the niraparib group and 71% in the placebo group. Given the higher incidence of treatment-related TEAEs in patients receiving placebo, it is difficult to conclude that the events were related to the study treatment, highlighting the importance of including a placebo group in safety assessments for this population.

[0243] The incidence of TEAEs in niraparib-treated patients and placebo-treated patients was as follows: TEAEs with CTCAE Grade 3 or higher, 74% and 23%; SAEs, 30% and 15%; TEAEs leading to treatment discontinuation, 69% and 5%; TEAEs leading to dose reduction, 67% and 15%; and TEAEs leading to treatment discontinuation, 15% and 2%. The TEAEs most frequently reported in the niraparib group were consistent with the known safety profiles of niraparib and other PARP inhibitors. The majority of universal TEAEs were reported at a higher incidence in the niraparib group than in the placebo group. Disease-related symptoms were excluded, including abdominal pain and bloating, as well as other pain-related symptoms including back pain, arthralgia, and myalgia.

[0244] Grade 3 or 4 TEAEs were frequent, but dose adjustments were effective in reducing the frequency of these events during the treatment period. The incidence of thrombocytopenia over time is an example of the effectiveness of dose adjustments. Figure 8 shows the mean platelet count over time for the entire niraparib-treated population. Platelet counts were collected weekly during the first cycle. The first four time points were C1D1, C1D8, C1D15, and C1D21. Subsequent time points were day 1 of all remaining cycles. The mean platelet count decreased considerably by day 15. However, after this point, the platelet count continued to increase and returned to almost baseline by roughly cycle 4.

[0245] Importantly, efficacy was not compromised in patients titrated to lower dose levels. To assess the potential impact of dose reduction on niraparib efficacy, an analysis of PFS was conducted based on the last prescribed dose and the dose administered for the longest duration for each patient. Note that only patients who received at least one dose of niraparib were included in these analyses. The results of the KM analysis of niraparib doses based on the longest duration are presented in Figure 9.

[0246] The most common dose for the longest duration was 200 mg in both the gBRCA mut (74 out of 136, 54%) and non-gBRCA mut (107 out of 231, 46%) cohorts. The dose for the longest duration was 300 mg in 25 (18%) and 73 (32%) patients in the gBRCA mut cohort and non-gBRCA mut cohort, respectively. And the dose for the longest duration was 100 mg in 37 (27%) and 51 (22%) patients, respectively.

[0247] Figures 9 and 10 show the KM plots of PFS by the dose of niraparib for the longest duration for the gBRCA mut cohort and non-gBRCA mut cohort, respectively. As shown, PFS for all three doses was consistent across the overall population, indicating that patients who required dose reduction did not experience a decrease in efficacy compared to those who maintained a starting dose of 300 mg. Secondary efficacy analysis of niraparib

[0248] Secondary efficacy endpoints included time to first subsequent treatment (TFST), time to second subsequent treatment (TSST), progression-free survival 2 (PFS2), chemotherapy-free interval (CFI), and overall survival (OS). Niraparib was more effective than placebo across most of the evaluated secondary efficacy endpoints (Figure 11). Secondary endpoints such as PFS2, OS, and CFI were analyzed using stratified log-rank tests. Treatment HRs and their 95% CIs were estimated using a stratified Cox proportional hazards model. Maintenance treatment with niraparib significantly improved chemotherapy-free interval and time to first subsequent treatment in patients in both cohorts. Patients treated with placebo needed to initiate subsequent treatment earlier than patients treated with niraparib, regardless of biomarker status (Figures 11, 13, and 14). Progression-free survival (P2) was significantly longer in patients treated with niraparib in both cohorts. gBRCA mut In the cohort, progression-free survival 2 was 25.8 months in the niraparib group compared to 19.5 months in the placebo group (hazard ratio, 0.48; 95% CI, 0.280~0.821; P=0.0062) for all non-gBRCA mut In the cohort, median PFS2 was 18.64 months with niraparib compared to 15 months with placebo; hazard ratio, 0.649; 95% CI 0.494, 0.964; P=0.0293). Time to second subsequent treatment was also a secondary endpoint, but this analysis could not be performed because too few patients received a second treatment at the data cutoff (gBRCA). mut In the cohort, niraparib was effective in 34 / 138 cases, placebo in 26 / 65 cases, and non-gBRCA mut In the cohort, the rates were 90 / 234 for niraparib and 53 / 116 for placebo.

[0249] Regarding the efficacy of the following line of treatment, a mixed trial population (a mixed gBRCA population of two cohorts) mut and non-gBRCA mut In a pooled analysis examining the PFS2-PFS1 ratio, PFS2-PFS1 was similar between patients treated with niraparib and those treated with placebo (see Figure 15).

[0250] gBRCA mut , non-gBRCA mut Table 5 below presents a summary of the secondary efficacy analysis of the mixed patient cohort. "HR" represents the hazard ratio, and "95% CI" represents the 95% confidence interval. Table 5 - Secondary efficacy analysis - gBRCA mut Cohort, non-gBRCA mut PFS2, time to subsequent treatment, and overall survival in cohorts and mixed patient cohorts. [Table 6]

[0251] Secondary endpoints include CFI, TFST, TSST, and PFS2, and gBRCA mut and non-gBRCA mut In both cohorts, the niraparib treatment group showed a more sustained therapeutic effect. Furthermore, no adverse effects of niraparib treatment on overall survival (OS) were observed.

[0252] The incidence of TEAEs in patients treated with niraparib and placebo was as follows: MDS / AML occurred in 1.4% (5 out of 367) of patients treated with niraparib and 1.1% (2 out of 179) of patients treated with placebo. No patients experienced grade 3 or 4 bleeding events, although one patient had grade 3 petechiae and hematoma concurrent with pancytopenia. No grade 5 events occurred. Grade 3 or higher hematological treatment-related TEAEs were manageable through dose individualization. Subgroup analysis based on response to the last platinum-based chemotherapy.

[0253] Platinum resistance was evaluated in patients treated with placebo. Platinum resistance was defined as a response duration to platinum of less than 6 months to the most recent (final) platinum regimen. The estimated probability of disease progression 6 months after the last dose of the most recent platinum treatment was calculated using the Kaplan-Meier method. 181 patients were randomized to placebo (65 of whom had gBRCA). mut And 116 of them were non-gBRCA mut ). gBRCA mut , non-gBRCA mut The estimated platinum resistance rates for the combined cohort were 42%, 53%, and 49%, respectively. See Figure 16. Therefore, approximately half of the patients in the trial developed platinum resistance to the final line of chemotherapy. Disease progression at 12 months was also evaluated for each cohort. A summary of disease progression at 6 months and within 12 months is shown in Table 6. Table 6 - Estimated proportion of placebo patients with disease progression (PD) less than 6 months or less than 12 months after the last platinum-based therapy. [Table 7]

[0254] Patients were stratified based on their response to their most recent platinum-based treatment (CR or PR). gBRCA mut 49% of patients in the cohort (niraparib: 67 / 138, placebo: 32 / 65), non-gBRCA mut Approximately 49% of the cohort patients (niraparib: 117 / 234 [50%]; placebo: 56 / 116 [48%]) were enrolled in the NOVA trial having a partial response (PR) after their most recent platinum-based chemotherapy. At the time of unblinding, gBRCA mut The cohort consisted of 30 (45%) niraparib patients and 23 (72%) placebo patients, as well as non-gBRCA patients. mutIn the cohort, 65 (56%) of niraparib patients and 45 (80%) of placebo patients experienced a progression-free survival (PFS) event. The hazard ratio (95% CI) for PFS was calculated for patients who achieved a partial response (PR) to their most recent platinum-based regimen, compared to gBRCA. mut In this case, 0.24 (0.131-0.441), non-gBRCA mut The response rate in the cohort was 0.35 (0.230-0.532). The response rate in patients who achieved a partial response to their most recent platinum-based chemotherapy treatment is comparable to the overall NOVA trial results mentioned above.

[0255] Placebo-treated patients were further stratified based on their response to the last two platinum-based therapies. The characteristics of these placebo-treated patients are shown in Table 7. In the non-gBRCAmut cohort, a higher proportion of patients with PD less than 6 months (platinum-resistant) had a partial response (PR) after both the last and second-to-last platinum-based chemotherapy compared to patients with PD of 6 months or more (platinum-sensitive). (39.7% and 14.6% for the second-to-last treatment, and 65.5% and 22.9% for the last treatment). Table 7 - Characteristics of placebo-treated patients at baseline [Table 8]

[0256] Patients treated with placebo were also stratified according to the number of previous treatment lines they had received (2 and 3 or more), and the results are shown in Figure 17. Patients who experienced disease progression (PD) less than 6 months after their last chemotherapy had received more lines of platinum-based therapy in the past (Figure 17, panels A and B) and a higher total number of chemotherapy lines (Figure 17, panels C and D) than patients who experienced PD more than 6 months after their most recent platinum-based chemotherapy. Outcomes reported by patients

[0257] Patient-reported outcomes were measured using the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI) and the EQ-5D-5L Health Utility Index (HUI) scores. Patient-reported outcomes (PROs) were collected every other cycle from cycle 14 to post-progression at screening visits. A mixed-action growth curve model was constructed to model the association between treatment and PRO scores for each measure. Responder rates were assessed using the minimally important difference threshold and the change from baseline. The association between health status and patient-reported health outcomes was assessed through a cross-sectional analysis of adjusted EQ-5D-5L Health Utility Index (HUI) scores. Compliance rates were high and similar between the two treatment groups: niraparib: FOSI completion rates ranged from 75.0% to 97.1%. The placebo-FOSI completion rate ranged from 77.6% to 97.4%. PRO was gBRCA mut Cohort, non-gBRCA mut In both cohorts, niraparib and placebo were similar throughout the entire study period. See Figure 18. No significant difference in mean PRO scores was observed between niraparib and placebo in either cohort. The responder proportion analysis also showed similar results for non-gBRCA in cycle 2. mut Except for the cohort, no significant differences were observed. Adjusted HUI scores were similar in both groups at baseline, but the mean adjusted pre-progression HUI score tended to be higher in the niraparib group (gBRCA). mut In the cohort, 0.812 and 0.803; non-gBRCA mutIn the cohort, the ratios were 0.845 and 0.828. Hematological toxicity did not have an adverse effect on the patients' overall health benefit. These data support that patients with recurrent ovarian cancer treated with niraparib after a complete or partial response to platinum-based chemotherapy can maintain their quality of life while being treated with niraparib (e.g., while receiving niraparib maintenance therapy). conclusion

[0258] This study is the first to demonstrate clear activity of PARP inhibitors in the patient population best defined by platinum sensitivity. These data support the extension of PARP inhibitor applications beyond cancers with BRCA mutations, demonstrating the efficacy of niraparib in both HRD-positive ovarian cancer and non-gBRCA ovarian cancers, including HRD-negative ovarian cancer. Once-daily administration of niraparib significantly extended progression-free survival in all three primary efficacy groups: the gBRCAmut cohort, the subgroup of patients prospectively defined as having HRD-positive tumors within the non-gBRCAmut cohort, and patients in the entire non-gBRCAmut cohort. As clearly shown in the Kaplan-Meier curves, the therapeutic effect of niraparib was clinically significant, consistent, and long-lasting in all three primary efficacy groups. Furthermore, secondary endpoints such as complete chemotherapy-free time, time to first subsequent treatment, and progression-free survival 2 were also statistically significant and clinically meaningful for the niraparib treatment groups in both cohorts. Importantly, patient-reported outcomes showed that niraparib maintenance therapy was at least as favorable as placebo. In summary, these data strongly support the use of niraparib in patient populations that are not receiving any alternative treatment.

[0259] Exploratory analyses and the resulting Kaplan-Meier curves demonstrate that niraparib treatment, regardless of biomarker status, provides consistent long-term benefits to patients compared to placebo in all exploratory subgroups, and yields findings consistent with the results for the primary efficacy population. While there was variability in the response to niraparib among different biomarker populations, significantly improved progression-free survival was observed in patients with tumors lacking BRCA mutations and without homologous recombination defects (HRD-negative).

[0260] Secondary endpoints were improved with niraparib, as indicated by significantly extended PFS2, CFI, and TFST. Furthermore, niraparib did not affect the efficacy of subsequent treatment lines, suggesting an extension of clinical benefit. Niraparib significantly improved outcomes in patients with recurrent ovarian cancer following a partial or complete response to platinum-based chemotherapy regimens, regardless of BRCA mutation or HRD status.

[0261] The adverse event profile of niraparib was manageable and tolerable for long-term administration following response to platinum-based chemotherapy. The 300 mg dose was appropriate for most patients and tolerable given the life-threatening nature of the disease. This dose can be adapted to individual patients if necessary, significantly reducing the need to discontinue treatment due to side effects. Overall, there were no deaths during treatment, and approximately 85% of patients maintained niraparib treatment throughout the study period, further suggesting that side effects were tolerable and manageable. Adverse events could be routinely monitored using standard assessment methods for hematological experimental parameters, which are common in patients undergoing anti-cancer treatment. The incidence of myelodysplastic syndrome and / or acute myeloid leukemia was very low (1%), and the ratios were similar in the niraparib and placebo groups.

[0262] Niraparib is a daily oral treatment that significantly improves progression-free survival without compromising quality of life, regardless of biomarker status, extends the response to platinum-based chemotherapy, and delays the need for additional platinum-based chemotherapy with associated cumulative toxicity in patients with recurrent ovarian cancer. Niraparib treatment has shown dramatic effects in a broad patient population, and the benefits of this PARP inhibitor will be extended to non-BRCA ovarian cancer patients with platinum-sensitive, recurrent ovarian cancer who have responded to platinum-based chemotherapy. Example 2. Food effects of chiraparib

[0263] A 14-day open-label, two-treatment crossover secondary trial evaluated the effect of a high-fat diet on exposure to niraparib (single dose).

[0264] Patients with ovarian cancer were randomized to either Group A or Group B, regardless of platinum sensitivity or tumor burden, with 6 patients assigned to each group. In Group A, patients fasted for at least 10 hours prior to a single 300 mg dose of niraparib (no food or drink other than water). After administration, patients remained fasted for at least 2 hours. In Group B, patients fasted for at least 10 hours prior to consuming a high-fat meal. Within 5 minutes of finishing the meal, a single 300 mg dose of niraparib was administered orally, and patients were allowed to resume fasting for at least 4 hours. After a 7-day PK evaluation and washout period, on day 8, all patients received a second single dose of niraparib under opposite conditions (fasting and high-fat diet). The 6 patients in Group A received the single dose of niraparib after the high-fat meal, while the patients in Group B received the second single dose of niraparib under fasting conditions. After completing a 14-day supplemental study on food effects, patients resumed daily administration of 300 mg QD of niraparib on cycle 1 / 1 day, approximately two weeks after the start of the main study.

[0265] While some aspects of the present invention have been described above, it should be noted that various modifications, refinements, and improvements will be readily apparent to those skilled in the art. Such modifications, refinements, and improvements are intended to be part of this disclosure and to be within the spirit and scope of the present invention. Accordingly, the above description and drawings are for illustrative purposes only, and the present invention is described in more detail by the following claims.

[0266] Example 3. DNA repair gene Table 8 is a list of DNA repair genes. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] References: du Bois, A, Floquet A, Kim JW, Rau J, Del Campo JM, Friedlander M, Pignata S, Fujiwara K, Vergote I, Colombo, N, Mirza MR, Monk BJ, Wimberger P, Ray-Coquard I, Zang R, Padilla ID, Baumann KH, Kim JH, and Harter P. Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): Results 一项国际多组织试验(AGO - OVAR16)的 Pfisterer, J., M. Plante, I. Vergote, A. du Bois, H. Hirte, A. J. Lacave, U. Wagner, A. Stahle, G. Stuart, R. Kimmig, S. Olbricht, T. Le, J. Emerich, W. Kuhn, J. Bentley, C. Jackisch, H. J. Luck, J. Rochon, A. H. Zimmermann, E. Eisenhauer, O. Ago, C. T. G. Ncic和G. C. G. Eortc(2006年)。“吉西他滨联合卡铂与卡铂治疗铂敏感复发性卵巢癌患者的疗效比较:AGO - OVAR、NCIC CTG和EORTC GCG的多组织试验。”《临床肿瘤学杂志》24(29): 4699 - 4707。 TCGA(2011年)。“卵巢癌的综合基因组分析。”《自然》474: 609 - 615。 Equal

[0267] In the specification and claims, articles such as "a" and "an," as used herein, should be understood to include multiple referents unless otherwise clearly indicated. A claim or description containing "or" between one or more members of a group is deemed to satisfy the case where one, two or more, or all members of the group are present in, used in, or otherwise related to a given product or process, unless otherwise specified or clearly indicated by the context. The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or process. The present invention also includes embodiments in which two or more, or all members of the group, are present in, used in, or otherwise related to a given product or process. Furthermore, the present invention should be understood to include all modifications, combinations, and rearrangements introduced in other claims that depend on the same basic claim (or any other claim, if relevant) and are not clearly indicated or clearly indicated to a person skilled in the art unless otherwise suggested or if a contradiction or inconsistency does not arise. Where elements are presented as a list (e.g., a Markush group or similar form), it should be understood that subgroups of each element are also disclosed, and any element may be excluded from such group. Generally, where the present invention or an aspect of the present invention is considered to include a particular element, characteristic, etc., it should be understood that a particular embodiment or aspect of the present invention consists of, or essentially consists of, such element, characteristic, etc. For the sake of simplicity, these embodiments are not specifically described in much detail in each example herein. It should also be understood that any embodiment or aspect of the present invention may be expressly excluded from the claims, whether or not specific exclusions are enumerated in the specification. Published documents, websites, or other reference materials cited herein that describe the background of the present invention or provide additional details relating to its implementation are incorporated herein by reference.

Claims

1. A composition for use in the treatment of cancer in a human patient, comprising a poly[ADP-ribose] polymerase inhibitor, wherein the patient is characterized by having received prior treatment with platinum-based therapy, the composition is administered without determining the BRCA gene status and homologous recombination repair disorder (HRD) status of the patient or cancer, and the therapeutic agent is niraparib, and the composition is for maintenance therapy after complete or partial response to at least one platinum-based therapy.

2. The composition according to claim 1, wherein the therapeutic agent is niraparib prepared in the form of a tosylate monohydrate.

3. The composition according to claim 1 or 2, wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and breast cancer.

4. The composition according to any one of claims 1 to 3, wherein the cancer is a recurrent cancer.

5. The composition according to claim 3, or claim 4, which references claim 3, wherein the ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is platinum-sensitive at the start of treatment.

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