Use of niraparib for treating brain cancer

Abstract

The present invention provides methods of administering niraparib for the treatment of primary brain cancer and metastatic brain cancer.

Description

Field of the Invention

[0001] The present invention provides methods of administering niraparib for treating primary brain cancer and metastatic brain cancer. Background of the Invention

[0003] Cancer is a serious public health problem. In 2020, an estimated 308,102 people worldwide will be diagnosed with a primary brain or spinal cord tumor. The 5-year survival rate for people with cancerous brain tumors or central nervous system tumors in the United States is nearly 36%. (Cancer Facts & Figures 2022, ACS website) In 2018 alone, 609,640 people died of cancer in the United States. American Cancer Society, Cancer Facts & Figures 2018 (available on the American Cancer Society website). Therefore, there is still a need for effective therapies to treat patients with cancer, including those with primary and metastatic brain cancer. Summary of the invention

[0004] The present disclosure relates to methods of treating primary or metastatic brain cancer in a human subject in need thereof, the method comprising administering to the human subject an effective dose of niraparib or a pharmaceutically acceptable salt thereof.

[0005] The present disclosure also provides niraparib or a pharmaceutically acceptable salt thereof for use in treating primary or metastatic brain cancer in a human subject in need thereof.

[0006] The present disclosure also provides the use of niraparib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating primary or metastatic brain cancer in a human subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 A summary of the phase 0 clinical protocol for niraparib in the treatment of newly diagnosed glioblastoma (HGG; high-grade glioma) and recurrent IDH1 / 2 + ATRX (WHO II-IV glioma) is shown.

[0008] Figure 2 A summary of the protocol to quantify the effects of P-gp and BCRP in limiting CNS penetration of niraparib is shown.

[0009] Figure 3 A summary of results quantifying the effects of P-gp and BCRP in limiting CNS penetration of niraparib is shown.

[0010] Figure 4 A summary of the clinical regimen of niraparib in newly diagnosed glioblastoma (HGG; high-grade glioma) Group A is shown.

[0011] Figure 5 A summary of the patient demographics and patient safety profile of the Arm A phase 0 and extension studies of niraparib in newly diagnosed glioblastoma (HGG; high-grade glioma) is shown.

[0012] Figure 6 A summary of free niraparib levels in non-enhancing tumor tissues in Group A Cohorts 1 and 2 is shown.

[0013] Figure 7 A summary of free niraparib levels in non-enhancing tumor tissue in Group A Cohorts 1 and 2 is shown, with the average of the 300 mg and 200 mg doses for Cohort 1 and the 300 mg dose for Cohort 2.

[0014] Figure 8 Total and free tumor / plasma ratios for niraparib A cohorts 1 and 2 in non-enhancing and enhancing tumor tissues are shown.

[0015] Fig. 9 Functional pharmacodynamic data for niraparib are shown, including comparison of PAR levels after ex vivo irradiation with untreated samples.

[0016] Fig.10 A summary of clinical outcomes for newly diagnosed glioblastoma is shown, with median PFS expressed in months. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present disclosure particularly relates to methods of treating brain cancer in a human subject in need thereof, the methods comprising administering to the human subject an effective amount of niraparib or a pharmaceutically acceptable salt thereof.

[0019] The present disclosure also relates particularly to a method of treating primary or metastatic brain cancer in a human subject in need thereof, the method comprising administering to the human subject an effective amount of niraparib or a pharmaceutically acceptable salt thereof.

[0020] The present disclosure also relates to methods of treating central nervous system (CNS) cancer in a human subject in need thereof, the method comprising administering to the human subject an effective dose of niraparib or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, a method of treating brain cancer in a human subject in need thereof comprises:

[0022] (i) administering an effective dose of niraparib or a pharmaceutically acceptable salt thereof to a human subject;

[0023] (ii) removal of brain cancer / tumor;

[0024] (iii) determine the concentration of niraparib in brain cancer / tumors;

[0025] (iv) if it is determined in step (iii) that sufficient niraparib is present, administering niraparib or a pharmaceutically acceptable salt thereof; and

[0026] (v) optionally further administering niraparib or a pharmaceutically acceptable salt thereof as maintenance therapy.

[0027] In some embodiments, the human subject is treated with niraparib or a pharmaceutically acceptable salt thereof for 4 days in step (i).

[0028] In some embodiments, the sufficient amount of niraparib present in step (iii) is a free concentration of niraparib > 5 times the biochemical IC50 value of niraparib. In some embodiments, 5 times the biochemical IC50 value of niraparib is 19 nM. In some embodiments, 5 times the biochemical IC50 value of niraparib is about 19 nM.

[0029] In some embodiments, the human subject is also treated with radiotherapy in step (iv), particularly stereotactic radiotherapy. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof and radiotherapy are administered for about 6-7 weeks. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy to treat brain cancer. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy to treat unmethylated MGMT gliomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy to treat unmethylated MGMT glioblastomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy to treat unmethylated gliomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy to treat unmethylated gliomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is used as an additional therapy to radiotherapy for the treatment of unmethylated glioblastomas.

[0030] In some embodiments, after treatment with niraparib or a pharmaceutically acceptable salt thereof and the radiation therapy in step (iv), the human subject further receives maintenance treatment with niraparib or a pharmaceutically acceptable salt thereof without receiving the radiation therapy in step (v).

[0031] In some embodiments, the human subject is also treated with radiation therapy, particularly stereotactic radiation therapy. In some embodiments, the radiation therapy may include, but is not limited to, one or more of the following:

[0032] •External radiation therapy uses a machine to send radiation through the body to reach metastatic tumors.

[0033] Whole-brain radiation therapy targets the entire brain and can hit multiple tumors or any metastatic disease that cannot be seen on MRI scans.

[0034] Stereotactic radiosurgery (e.g., CyberKnife) targets high doses of radiation to the specific shape of a tumor, sparing surrounding healthy tissue from unnecessary radiation exposure.

[0035] Proton therapy uses protons (rather than X-rays) to treat metastatic brain tumors. Like stereotactic radiosurgery, proton therapy minimizes damage to healthy tissue surrounding the tumor.

[0036] •Brachytherapy involves implanting radioactive material into the tumor to prevent further growth.

[0037] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct to radiation therapy to treat brain cancer. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct to radiation therapy to treat unmethylated MGMT glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct to radiation therapy to treat unmethylated MGMT glioblastoma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct to radiation therapy to treat unmethylated glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct to radiation therapy to treat unmethylated glioblastoma.

[0038] In some embodiments, the brain cancer is a primary or metastatic brain cancer. In some embodiments, the primary or metastatic brain cancer is newly diagnosed. In some embodiments, the primary brain cancer is newly diagnosed. In some embodiments, the metastatic brain cancer is newly diagnosed.

[0039] In some embodiments, the human subject receives preoperative niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the human subject receives preoperative niraparib or a pharmaceutically acceptable salt thereof before surgical resection. In some embodiments, the human subject receives preoperative niraparib or a pharmaceutically acceptable salt thereof before surgical resection, and the concentration of niraparib in the brain cancer tumor is measured after resection. In some embodiments, the human subject receives preoperative niraparib or a pharmaceutically acceptable salt thereof for 4 days before surgical resection. In some embodiments, the final preoperative dose is administered 3-5 hours or 8-10 hours before tumor resection.

[0040] In some embodiments, the brain cancer is a primary brain cancer.

[0041] In some embodiments, the brain cancer is glioma.

[0042] In some embodiments, the brain cancer is high-grade glioma.

[0043] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0044] In some embodiments, the brain cancer is an unmethylated glioma. In some embodiments, the brain cancer is an unmethylated glioblastoma.

[0045] In some embodiments, the administration of niraparib or a pharmaceutically acceptable salt thereof and radiotherapy begins after resection of a primary brain cancer tumor. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy in the treatment of brain cancer. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy in the treatment of unmethylated MGMT gliomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy in the treatment of unmethylated MGMT glioblastomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy in the treatment of unmethylated gliomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy in the treatment of unmethylated gliomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy to radiotherapy in the treatment of unmethylated glioblastomas.

[0046] In some embodiments, the radiation therapy is about 60 Gy (unit gray). In some embodiments, the radiation therapy is about 10 Gy (unit gray).

[0047] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof and radiation therapy are administered for about 6-7 weeks.

[0048] In some embodiments, the human subject further receives maintenance treatment with niraparib or a pharmaceutically acceptable salt thereof, without receiving radiation therapy, following treatment with niraparib or a pharmaceutically acceptable salt thereof and radiation therapy.

[0049] In some embodiments, the human subject further receives maintenance treatment with niraparib or a pharmaceutically acceptable salt thereof, without receiving radiation therapy, following treatment with niraparib or a pharmaceutically acceptable salt thereof and radiation therapy.

[0050] In some embodiments, the human subject, following treatment with niraparib or a pharmaceutically acceptable salt thereof and radiation therapy, further receives maintenance treatment with niraparib or a pharmaceutically acceptable salt thereof, without radiation therapy, until disease progression.

[0051] In some embodiments, about 4 weeks following treatment with niraparib or a pharmaceutically acceptable salt thereof and radiation therapy, the human subject further receives maintenance treatment with niraparib or a pharmaceutically acceptable salt thereof without receiving radiation therapy.

[0052] In some embodiments, the administration of niraparib or a pharmaceutically acceptable salt thereof is performed after a previous treatment. In some embodiments, the administration of niraparib or a pharmaceutically acceptable salt thereof is not performed after a previous treatment. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional treatment to radiation therapy.

[0053] In some embodiments, the dosage of niraparib or a pharmaceutically acceptable salt thereof is equivalent to 200 mg or 300 mg of niraparib free base. In some embodiments, the dosage of niraparib or a pharmaceutically acceptable salt thereof is equivalent to about 300 mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a single daily dose. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the daily dose of niraparib or a pharmaceutically acceptable salt thereof is equivalent to 200 mg or 300 mg of niraparib free base. In some embodiments, the daily dose of niraparib or a pharmaceutically acceptable salt thereof is equivalent to about 300 mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 200 mg of niraparib free base.

[0054] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as niraparib mesylate monohydrate.

[0055] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

[0056] In some embodiments, the dose of niraparib or a pharmaceutically acceptable salt thereof is administered daily.

[0057] In some embodiments, the primary brain cancer is selected from the group consisting of anaplastic astrocytoma, glioblastoma, glioblastoma multiforme, meningioma, pituitary carcinoma, schwannoma, oligodendroglioma, ependymoma, medulloblastoma, astrocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+) ATRX mutant glioma, malignant glioma, and primitive neuroectodermal tumor of the brain.

[0058] In some embodiments, the primary brain cancer is a WHO grade IV tumor.

[0059] In some embodiments, the primary brain cancer is glioblastoma. In some embodiments, the metastatic brain cancer is glioblastoma. In some embodiments, the central nervous system cancer is glioblastoma.

[0060] In some embodiments, the glioblastoma is a recurrent glioblastoma. In some embodiments, the glioblastoma is a newly diagnosed glioblastoma. In some embodiments, the newly diagnosed or recurrent glioblastoma is associated with an IDH-mutation and an ATRX deletion. In some embodiments, the glioblastoma is a primary glioblastoma.

[0061] In some embodiments, the human subject is newly diagnosed with glioblastoma and MGMT promoter hypermethylation. In some embodiments, the human subject has an unmethylated MGMT tumor. In some embodiments, the human subject has an unmethylated MGMT promoter. In some embodiments, the human subject has an unmethylated MGMT glioma. In some embodiments, the human subject has an unmethylated MGMT glioblastoma. In some embodiments, the human subject has an unmethylated glioma. In some embodiments, the human subject has an unmethylated glioblastoma. In some embodiments, the human subject has an unmethylated glioblastoma.

[0062] In some embodiments, the primary brain cancer is a glioma. In some embodiments, the metastatic brain cancer is a glioma. In some embodiments, the central nervous system cancer is a glioma. In some embodiments, the glioma is a recurrent glioma.

[0063] In some embodiments, the glioma is an adult diffuse glioma. In some embodiments, the adult diffuse glioma is an astrocytoma (IDH-mutant), an oligodendroglioma (IDH-mutant and 1p / 19q co-deleted), or a glioblastoma (IDH-wild type).

[0064] In some embodiments, the glioma is a childhood diffuse low-grade glioma. In some embodiments, the childhood diffuse low-grade glioma is selected from diffuse astrocytoma (MYB or MYBL1 altered), angiocentric glioma, juvenile multiforme low-grade neuroepithelial tumor, or diffuse low-grade glioma (MAPK pathway altered).

[0065] In some embodiments, the glioma is a pediatric diffuse high-grade glioma. In some embodiments, the pediatric diffuse high-grade glioma is selected from diffuse midline glioma (H3 K27 altered), diffuse hemispheric glioma (H3 G34 mutant), diffuse high-grade glioma (H3 wild-type and IDH wild-type) or infantile hemispheric glioma.

[0066] In some embodiments, the glioma is a well-defined astrocytic glioma. In some embodiments, the well-defined astrocytic glioma is selected from pilocytic astrocytoma, high-grade astrocytoma with pilocytic features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma or astroblastoma (MN1 altered).

[0067] In some embodiments, the glioma is an progressive IDH1 or IDH mutant non-enhancing glioma. In some embodiments, the glioma is an unmethylated MGMT glioma. In some embodiments, the glioma is an unmethylated glioma.

[0068] In some embodiments, the human subject has recurrent high-grade glioma and a DNA damage repair defect.

[0069] In some embodiments, the primary brain cancer is an astrocytoma. In some embodiments, the metastatic brain cancer is an astrocytoma. In some embodiments, the central nervous system cancer is an astrocytoma. In some embodiments, the astrocytoma is a recurrent astrocytoma. In some embodiments, the astrocytoma is a newly diagnosed astrocytoma.

[0070] In some embodiments, the primary brain cancer is an oligodendroglioma. In some embodiments, the metastatic brain cancer is an oligodendroglioma. In some embodiments, the central nervous system cancer is an oligodendroglioma. In some embodiments, the astrocytoma is a recurrent oligodendroglioma. In some embodiments, the oligodendroglioma is a newly diagnosed oligodendroglioma.

[0071] In some embodiments, the human subject exhibits a free concentration of niraparib>5 times the biochemical IC50 value of niraparib in brain cancer tumor tissue. In some embodiments, the human subject exhibits a free concentration of niraparib>5 times the biochemical IC50 value of niraparib in non-enhanced or enhanced brain cancer tumor tissue. In some embodiments, the human subject exhibits a free concentration of niraparib>5 times the biochemical IC50 value of niraparib in non-enhanced brain cancer tumor tissue. In some embodiments, the human subject exhibits a free concentration of niraparib>5 times the biochemical IC50 value of niraparib in enhanced brain cancer tumor tissue. In some embodiments, the free concentration of niraparib in non-enhanced or enhanced tumor tissue of brain cancer is measured after niraparib treatment before surgery. In some embodiments, the free concentration of niraparib in tumor tissue is measured after resection. In some embodiments, the free concentration of niraparib is measured in brain tumor tissue samples collected during surgery. In some embodiments, human subjects show a free concentration of niraparib in the gadolinium non-enhanced area of ​​brain cancer tumors>5 times the biochemical IC50 value of niraparib. In some embodiments, the free concentration of niraparib in the gadolinium non-enhanced area of ​​brain cancer tumors is measured after preoperative niraparib (300mg QD) treatment 4 days before planned resection (i.e. 3-5 hours or 8-12 hours after the last dose). In some embodiments, the free concentration of niraparib in the gadolinium non-enhanced area of ​​brain cancer tumors is measured after preoperative niraparib (200mg QD) treatment 4 days before planned resection (i.e. 3-5 hours or 8-12 hours after the last dose). In some embodiments, the free concentration of niraparib is measured in brain tumor tissue samples collected during surgery.

[0072] In some embodiments, 5 times the biochemical IC50 value of niraparib is 19 nM. In some embodiments, 5 times the biochemical IC50 value of niraparib is about 19 nM.

[0073] In some embodiments, the brain / plasma ratio of niraparib is about 0.5. In some embodiments, the tumor / plasma ratio of niraparib is about 4. In some embodiments, the tumor / plasma ratio of niraparib is about 8. In some embodiments, the tumor / plasma ratio is measured in non-enhanced tumor tissue. In some embodiments, the tumor / plasma ratio is measured in enhanced tumor tissue. In some embodiments, the tumor / plasma ratio of niraparib is about 4 in non-enhanced tumor tissue. In some embodiments, the tumor / plasma ratio of niraparib is about 8 in enhanced tumor tissue.

[0074] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents known to be useful for treating cancer.

[0075] In some embodiments, the one or more additional active agents are temozolomide, bevacizumab, or a combination thereof. In some embodiments, the one or more additional active agents include temozolomide, bevacizumab, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0076] In some embodiments, the one or more additional active agents is temozolomide.

[0077] In some embodiments, the one or more additional active agents is atezolizumab. In some embodiments, the one or more additional active agents include atezolizumab or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the one or more additional active agents is pembrolizumab. In some embodiments, the one or more additional active agents include pembrolizumab or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the one or more additional active agents is tovorafenib. In some embodiments, the one or more additional active agents include tovorafenib or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the one or more additional active agents is dostarlimab. In some embodiments, the one or more additional active agents include dostarlimab or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the human subject or cancer is in complete or partial response to platinum-based chemotherapy.

[0082] In some embodiments, the cancer is platinum-insensitive.

[0083] In some embodiments, the cancer is platinum-sensitive.

[0084] In some embodiments, the cancer is homologous recombination deficiency (HRD) negative.

[0085] In some embodiments, the patient is characterized as having a deleterious or suspected deleterious mutation in BRCA1 and / or BRCA2.

[0086] In some embodiments, the primary or metastatic brain cancer is recurrent.

[0087] In some embodiments, the cancer is brain cancer.

[0088] In some embodiments, the brain cancer is a primary brain cancer.

[0089] In some embodiments, the brain cancer is glioma.

[0090] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0091] In some embodiments, the brain cancer is an unmethylated glioma. In some embodiments, the brain cancer is an unmethylated glioblastoma.

[0092] In some embodiments, niraparib administration is initiated after resection of a metastatic brain cancer tumor.

[0093] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as maintenance therapy.

[0094] In some embodiments, the dosage of niraparib or a pharmaceutically acceptable salt thereof is equivalent to 200 mg or 300 mg of niraparib free base. In some embodiments, the dosage of niraparib or a pharmaceutically acceptable salt thereof is equivalent to about 300 mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a single daily dose. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the daily dose of niraparib or a pharmaceutically acceptable salt thereof is equivalent to 200 mg or 300 mg of niraparib free base. In some embodiments, the daily dose of niraparib or a pharmaceutically acceptable salt thereof is equivalent to about 300 mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 200 mg of niraparib free base.

[0095] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as niraparib mesylate monohydrate.

[0096] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

[0097] In some embodiments, the dose of niraparib or a pharmaceutically acceptable salt thereof is administered daily.

[0098] In some embodiments, the primary brain cancer is selected from the group consisting of anaplastic astrocytoma, glioblastoma, glioblastoma multiforme, meningioma, pituitary carcinoma, schwannoma, oligodendroglioma, ependymoma, medulloblastoma, astrocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+) ATRX mutant glioma, malignant glioma, and primitive neuroectodermal tumor of the brain.

[0099] In some embodiments, the primary recurrent brain cancer is a WHO grade II-IV tumor.

[0100] In some embodiments, the primary recurrent brain cancer is an IDH1 / 2(+) ATRX mutant glioma.

[0101] In some embodiments, the cancer is brain cancer.

[0102] In some embodiments, the brain cancer is a primary brain cancer.

[0103] In some embodiments, the brain cancer is glioma.

[0104] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0105] In some embodiments, the brain cancer is an unmethylated glioma. In some embodiments, the brain cancer is an unmethylated glioblastoma.

[0106] In some embodiments, the human subject exhibits a chromosomal fusion in the C-circle assay with a cutoff Ct value of 35. In some embodiments, the chromosomal fusion in the C-circle assay is measured after preoperative niraparib (300 mg QD) treatment 4 days prior to planned resection (ie, 3-5 hours or 8-12 hours after the last dose).

[0107] In some embodiments, the brain / plasma ratio of niraparib is about 0.5.

[0108] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents known to be useful for treating cancer.

[0109] In some embodiments, the one or more additional active agents are temozolomide, bevacizumab, or a combination thereof. In some embodiments, the one or more additional active agents include temozolomide, bevacizumab, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0110] In some embodiments, the one or more additional active agents is temozolomide. In some embodiments, the one or more additional active agents include temozolomide or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the one or more additional active agents is atezolizumab. In some embodiments, the one or more additional active agents include atezolizumab or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the one or more additional active agents is pembrolizumab. In some embodiments, the one or more additional active agents include pembrolizumab or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the one or more additional active agents is tovorafenib. In some embodiments, the one or more additional active agents include tovorafenib or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the one or more additional active agents is dotalizumab. In some embodiments, the one or more additional active agents include dotalizumab or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the human subject or cancer is in complete or partial response to platinum-based chemotherapy.

[0116] In some embodiments, the cancer is platinum-insensitive.

[0117] In some embodiments, the cancer is platinum-sensitive.

[0118] In some embodiments, the cancer is homologous recombination deficiency (HRD) negative.

[0119] In some embodiments, the human subject or the cancer is not tested for homologous recombination deficiency (HRD) status prior to administration of niraparib or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the human subject or the cancer is not tested for BRCA1 and / or BRCA2 mutations prior to administration of niraparib or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the cancer is brain cancer.

[0122] In some embodiments, the brain cancer is a primary brain cancer.

[0123] In some embodiments, the brain cancer is glioma.

[0124] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0125] In some embodiments, the brain cancer is an unmethylated glioma. In some embodiments, the brain cancer is an unmethylated glioblastoma.

[0126] In some embodiments, the metastatic brain cancer has spread from a primary site of lung cancer, breast cancer, colon cancer, kidney cancer, and melanoma.

[0127] In some embodiments, the metastatic brain cancer is asymptomatic or actively progressive brain metastasis.

[0128] In some embodiments, the metastatic brain cancer is caused by a lung cancer selected from a solid tumor, squamous cell carcinoma of the lung, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and lung adenocarcinoma.

[0129] In some embodiments, the metastatic brain cancer is caused by a breast cancer selected from a solid tumor, ductal carcinoma in situ (DCIS; intraductal carcinoma), invasive breast cancer (ILC or IDC; invasive lobular carcinoma or invasive ductal carcinoma), triple-negative breast cancer (TNBC), and inflammatory breast cancer.

[0130] In some embodiments, the metastatic brain cancer is caused by a kidney cancer selected from solid tumors, renal clear cell carcinoma, renal papillary carcinoma, kidney chromophobe cancer, kidney renal cell carcinoma, urothelial carcinoma, renal sarcoma, Wilms tumor, and renal lymphoma.

[0131] In some embodiments, the metastatic brain cancer is caused by a colon cancer selected from colorectal cancer, squamous cell carcinoma, gastrointestinal neuroendocrine tumors, solid tumors, and adenocarcinoma.

[0132] In some embodiments, the metastatic brain cancer is caused by a melanoma selected from the group consisting of superficial spreading melanoma, nodular melanoma, lentigo maligna, acral lentiginous melanoma, choroidal melanoma, conjunctival melanoma, iris melanoma, and mucosal melanoma.

[0133] In some embodiments, niraparib is administered after resection of a metastatic brain cancer tumor.

[0134] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as maintenance therapy.

[0135] In some embodiments, the dosage of niraparib or a pharmaceutically acceptable salt thereof is equivalent to 200 mg or 300 mg of niraparib free base. In some embodiments, the dosage of niraparib or a pharmaceutically acceptable salt thereof is equivalent to about 300 mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a single daily dose. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the daily dose of niraparib or a pharmaceutically acceptable salt thereof is equivalent to 200 mg or 300 mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 300 mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 200 mg of niraparib free base.

[0136] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as niraparib mesylate monohydrate.

[0137] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

[0138] In some embodiments, the dose of niraparib or a pharmaceutically acceptable salt thereof is administered daily.

[0139] In some embodiments, the brain / plasma ratio of niraparib is about 0.5.

[0140] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents known to be useful for treating cancer.

[0141] In some embodiments, the one or more additional active agents are temozolomide, bevacizumab, or a combination thereof. In some embodiments, the one or more additional active agents include temozolomide, bevacizumab, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0142] In some embodiments, the one or more additional active agents is temozolomide. In some embodiments, the one or more additional active agents include temozolomide or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the one or more additional active agents is atezolizumab. In some embodiments, the one or more additional active agents include atezolizumab or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the one or more additional active agents is pembrolizumab. In some embodiments, the one or more additional active agents include pembrolizumab or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the one or more additional active agents is tovorafenib. In some embodiments, the one or more additional active agents include tovorafenib or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the one or more additional active agents is dotalizumab. In some embodiments, the one or more additional active agents include dotalizumab or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the human subject or cancer is in complete or partial response to platinum-based chemotherapy.

[0148] In some embodiments, the cancer is platinum-insensitive.

[0149] In some embodiments, the cancer is platinum-sensitive.

[0150] In some embodiments, the cancer is homologous recombination deficiency (HRD) negative.

[0151] In some embodiments, the cancer is brain cancer.

[0152] In some embodiments, the brain cancer is a primary brain cancer.

[0153] In some embodiments, the brain cancer is glioma.

[0154] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0155] In some embodiments, the brain cancer is an unmethylated glioma. In some embodiments, the brain cancer is an unmethylated glioblastoma.

[0156] I. Definitions

[0157] References in this specification to "one embodiment" or "an embodiment" or "some embodiments" or "an embodiment" mean that the particular features, structures, or characteristics described in connection with the embodiment are included in at least one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" or "in some embodiments" or "in an embodiment" appearing in various places in this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0158] As used herein, the term "administration" generally refers to administering a composition to a subject or system. One of ordinary skill in the art will appreciate the various routes that may be used to administer to a subject (e.g., a human subject) where appropriate. In some embodiments, administration may involve intermittent administration (e.g., multiple administrations at intervals) and / or regular administration (e.g., each dose is spaced apart by a common time period).

[0159] The term "dosage form" or "unit dosage form" as used herein refers to a physically discrete unit of an active agent (e.g., a therapeutic agent or a diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of an active agent. In some embodiments, such an amount is a unit dose (or its entire portion) suitable for administration according to a regimen that has been determined to be associated with a desired or beneficial result when administered to a relevant population (i.e., a treatment regimen). One of ordinary skill in the art will appreciate that the total amount of a therapeutic composition or medicament administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0160] As used herein, the term "protocol" refers to a group of unit doses (usually more than one), which are administered individually to a subject, usually at intervals of one or more time periods. In some embodiments, a given therapeutic agent is administered according to a protocol, which may involve one or more doses. In some embodiments, the protocol includes multiple doses, each dose being separated from other doses in time. In some embodiments, each dose is separated from each other by a time period of the same length. In some embodiments, the protocol includes multiple doses, wherein each dose is separated by a time period of different lengths. In some embodiments, the protocol includes multiple doses of the same amount. In some embodiments, the protocol includes multiple doses of different amounts. In some embodiments, the protocol includes at least one dose, wherein the dose comprises a unit dose of a therapeutic agent. In some embodiments, the protocol includes at least one dose, wherein the dose comprises two or more unit doses of a therapeutic agent. For example, a dose of 300 mg can be administered as a single 300 mg unit dose or as two 150 mg unit doses. In some embodiments, when implementing the protocol in a relevant population, the protocol is associated with or produces an expected or beneficial result (i.e., a therapeutic protocol). In some embodiments, the regimen includes dosages throughout the treatment period to achieve the desired or beneficial results or until disease progression or unacceptable adverse effects occur.

[0161] The terms "patient", "subject" or "test subject" as used herein refer to any organism to which one or more compounds described herein are administered according to the present invention for, 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; etc.). In preferred embodiments, the subject is a human. In some embodiments, the subject may suffer from and / or be susceptible to a disease, disorder and / or condition (e.g., cancer, such as brain cancer). In some embodiments, the patient is a person who has been diagnosed with primary or metastatic brain cancer. In some embodiments, the patient suffers from a glioblastoma. In some embodiments, the patient suffers from a WHO grade II-IV glioma. In some embodiments, the WHO grade II-IV glioma is recurrent. In some embodiments, the patient suffers from an IDH1 / 2 (+) ATRX mutant glioma. In some embodiments, the IDH1 / 2 (+) ATRX mutant glioma is recurrent. As used herein, a "patient population" or "subject population" refers to a plurality of patients or subjects.

[0162] As used herein, "therapeutically effective amount" or "effective dose" refers to the amount of therapeutic agent that produces the desired effect. In some embodiments, the term refers to an amount sufficient to treat the disease, disorder and / or condition when applied to a population suffering from or susceptible to a disease, disorder and / or condition according to a regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and / or severity of one or more symptoms of a disease, disorder and / or condition and / or delays its onset. One of ordinary skill in the art will appreciate that the term "therapeutically effective amount" does not actually require successful treatment in a particular individual. On the contrary, a therapeutically effective amount can be an amount that provides a specific desired pharmacological response in a large number of subjects when applied to a patient with such treatment needs. In some embodiments, a therapeutically effective amount can refer to an amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). One of ordinary skill in the art will appreciate that in some embodiments, a therapeutically effective amount of a specific agent or therapy can be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective drug may be formulated and / or administered in multiple doses, for example, as part of a treatment regimen.

[0163] As used herein, "chemotherapeutic agent" refers to a chemical agent that inhibits cancer cell proliferation, growth, life span and / or metastatic activity. In some embodiments, the chemotherapeutic agent is a platinum-based agent, such as a platinum agent. In some such embodiments, the platinum agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatinum tetranitrate, phenoplatin, picoplatin or satraplatin.

[0164] "Homologous recombination" as used herein refers to the process of nucleotide sequence exchange between different DNA chains. Homologous recombination is involved in a variety of different biological processes. For example, homologous recombination is part of the DNA repair process (such as the double-strand break repair pathway and the synthesis-dependent strand annealing pathway), and also occurs during eukaryotic meiosis / gametogenesis. "Homologous recombination deficiency", "homologous recombination repair deficiency", "homologous repair deficiency" or "HRD" as used herein refers to the weakening or impairment of the homologous recombination process. This impairment may be caused by chromosomal aberrations or mutations in one or more genes involved in DNA repair. The reduction or impairment of the homologous recombination process can also be measured by evaluating epigenetic changes (i.e., hypermethylation) of the HRR gene promoter. For example, methylation of the BRCA1 and RAD51C promoters leads to inhibition of gene transcription and is associated with sensitivity to PARP inhibitors.

[0165] Reduction or impairment of the homologous recombination process can also be measured by the RAD51 focus formation assay: the absence of RAD51 focus formation indicates a defect in the homologous recombination pathway.

[0166] A reduction or impairment in the homologous recombination process can also be measured by HRR, BRCA1, and BRCA2 protein expression: Abnormally reduced protein levels of BRCA1, BRCA2, and other HRR genes may indicate a defect in the homologous recombination pathway.

[0167] As used herein, "BRCA mutation" or "mutation of BRCA" refers to an alteration or difference in the sequence of at least one copy of either or both BRCA1 or BRCA2 genes relative to an appropriate reference sequence (e.g., a wild-type reference sequence and / or a sequence present in a non-cancerous cell of a subject). Mutations in BRCA1 / 2 genes may result in BRCA1 / 2 deficiencies, which may include, for example, loss or reduction of expression or function of the BRCA gene and / or encoded protein. Such mutations may also be referred to as "harmful mutations" or may be suspected of being harmful mutations. A BRCA mutation may be a "germline BRCA mutation," which indicates that it is inherited from one or both parents. Germline mutations affect every cell in an organism and are passed on to offspring. BRCA mutations may also be acquired during a person's lifetime, i.e., spontaneously appear in any cell ("somatic cell") in the body at any time during the patient's life (i.e., non-inherited), and are interchangeably referred to herein as "sporadic BRCA mutations" or "somatic BRCA mutations." Genetic testing is feasible and known to those skilled in the art.

[0168] As used herein, the term "gene involved in DNA repair" refers to any gene involved in DNA repair in a cell. Components of the HR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM-000051), RAD51 (NM-002875), RAD51LI (NM-002877), RAD51C (NM-002876), RAD51L3 (NM-002878), DMC1 (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA1 (NM-007295), BRCA2 (NM-000059), RAD50 (NM-005732), MRE11A (NM-005590), NBS1 (NM-002485), ADPRT (PARP-1), ADPRTL2, (PARP2) CTPS, RPA, RPAI, RPA2, RPA3, XPD, ERCCI, XPF, MMS19, RAD51p, RAD51D, DMC1, XRCCR, XRCC3, RAD54, NB51, W RN, BLMKU70, RU8O, ATR, CHKI, CHK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, RAD1, RAD9, BARD1 (NM_000465), PALB2 (NM_024675), BLM (NM_000057), and BRIP1 (NM_032043). Other proteins involved in the HR-dependent DNA DSB repair pathway include regulatory factors such as EMSY (Cell (2003) 115:523-535).

[0169] 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 relates to the use of niraparib to treat cancer patients regardless of DNA repair status.

[0170] The term "progression-free survival" as used herein refers to the period of time during which a subject with a disease (e.g., cancer) survives without a significant deterioration in the disease state. Progression-free survival can be assessed as a period of time during which tumor growth does not progress and / or the patient's disease state is not determined to be a progressive disease. In some embodiments, the progression-free survival of a subject with cancer is assessed by assessing tumor (lesion) size, tumor (lesion) number, and / or metastasis.

[0171] As used herein, "progression-free survival 2" (PFS2) is defined as the period from treatment randomization to the earlier assessed date of progression on the next anticancer therapy following study treatment or death from any cause. In some embodiments, determination of progression can be assessed by clinical and / or radiological assessment.

[0172] The term "progression" or "progressive disease" (PD) of tumor growth used herein with respect to cancer states refers to an increase in the sum of the diameters of target lesions (tumors). In some embodiments, the progression of tumor growth refers to an increase of at least 20% in the sum of the diameters of target lesions, with the minimum sum in the study as a reference (including the baseline sum if the baseline sum is the smallest in the study). In some embodiments, in addition to a relative increase of 20%, the sum of the diameters of target lesions must also show an absolute increase of at least 5 mm. The appearance of one or more new lesions can also be considered for determining the progression of tumor growth.

[0173] The term "partial remission" or "PR" used herein refers to a slowing down of the tumor progression of the subject, with the baseline diameter sum as a reference, and the reduction of the target lesion diameter sum is used to indicate the reduction of the subject's tumor progression. In some embodiments, PR refers to a reduction of at least 30% in the diameter sum or target lesion with the baseline diameter sum as a reference. The exemplary method for assessing partial remission is determined by the RECIST guidelines. See EA Eisenhauer et al., "New response evaluation criteria insolid tumors: Revised RECIST guidelines (version 1.1)", Eur. J. of Cancer, 45: 228-247 (2009).

[0174] As used herein, "stable" or "disease stability" (SD) of tumor growth refers to neither shrinking to a degree sufficient to achieve PR nor increasing to a degree sufficient to achieve PD. In some embodiments, stable refers to a change (increase or decrease) of the target lesion diameter summation with reference to the baseline diameter summation being less than 30%, 25%, 20%, 15%, 10% or 5%. An exemplary method for assessing the stability of tumor growth or disease stability is determined by RECIST guidelines. See EA Eisenhauer et al., "New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1)", Eur. J. of Cancer, 45: 228-247 (2009).

[0175] As used herein, the term "complete remission" or "CR" is used to represent that all or substantially all target lesions disappear. In some embodiments, CR refers to the target lesion diameter summation being reduced by 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% (i.e., lesion disappears) with reference to the baseline diameter summation. In some embodiments, CR represents that the total lesion diameter remaining after treatment is less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less. The exemplary method for assessing complete remission is determined by RECIST guidelines. See EA Eisenhauer et al., "New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1.)", Eur. J. of Cancer, 45:228-247 (2009).

[0176] As used herein, the "hazard ratio" (or "HR", when used in calculations of the treatment effect of niraparib, e.g., HR0.38) refers to an expression of the ratio of the risk or chance of an event occurring in the treatment group to the event occurring in the control group. The hazard ratio can be determined by the Cox model, which is a survival data regression method that provides estimates of the hazard ratio and its confidence interval. The hazard ratio is an estimate of the ratio of the hazard rates of the treatment group to the control group. The hazard rate is the probability that the event in question will occur in the next time interval if it has not yet occurred divided by the length of that interval. The assumption of proportional hazards regression is that the hazard ratio remains constant over time.

[0177] As used herein, "HGG" refers to high-grade glioma.

[0178] "MGMT" used herein is O-6-methylguanine-DNA methyltransferase, which is a gene encoding a DNA repair enzyme. "MGMT unmethylated" or "unmethylated MGMT" used herein refers to the absence of DNA methylation in the promoter region of the MGMT gene associated with cancer (i.e., glioma or glioblastoma). "Highly methylated MGMT promoter", "MGMT promoter high methylation" or "methylated MGMT promoter" used herein refers to the presence of DNA methylation in the promoter region of the MGMT gene associated with cancer (i.e., glioma or glioblastoma). "MGMT status" used herein refers to the methylation status of MGMT, i.e., the positive state is related to the methylation of the MGMT gene promoter, and the negative state is related to the unmethylated MGMT gene promoter.

[0179] As used herein, the term "treatment" (also referred to as "treat" or "treating") refers to the administration of any therapy that partially or completely reduces, ameliorates, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be directed to subjects who do not show signs of the relevant disease, disorder, and / or condition and / or subjects who only show early signs of the disease, disorder, and / or condition. Alternatively or in addition, such treatment may be directed to subjects who show one or more established signs of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who have been diagnosed with the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects known to have one or more susceptibility factors that are statistically correlated with an increased risk of development of the relevant disease, disorder, and / or condition. In some embodiments, "niraparib treatment" includes administering niraparib or a pharmaceutically acceptable salt thereof to a human subject in need thereof.

[0180] The term "pharmaceutically acceptable salt" as used herein refers to salts that are suitable for contact with human and lower animal tissues within the scope of reasonable medical judgment, and do not produce excessive toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0181] The term "pharmaceutical composition" as used herein refers to a composition in which an active agent is formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment regimen, and when applied to a relevant population, the active agent shows a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical composition can be specifically formulated for administration in solid or liquid form, including those pharmaceutical compositions suitable for oral administration, such as irrigating agents (aqueous or non-aqueous solutions or suspensions), tablets (such as those for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes for the tongue. Pharmaceutical composition may also refer to a drug.

[0182] As used herein, the term "niraparib" refers to any free base compound ((3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine), a salt form (including a pharmaceutically acceptable salt) of (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine (e.g., (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine methanesulfonate), or a solvate or hydrate form thereof (e.g., (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine methanesulfonate monohydrate). In some embodiments, these forms may be individually referred to as "niraparib free base," "niraparib methanesulfonate," and "niraparib methanesulfonate monohydrate," respectively. Unless otherwise indicated, the term "niraparib" includes all forms of the compound (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine.

[0183] As used herein, "intraoperative" is defined as occurring during a surgical procedure. In some embodiments, the surgical procedure is the removal of brain tumor tissue.

[0184] As used herein, "post-resection" refers to events that occur after resection of brain tumor tissue.

[0185] As used herein, "preoperative" or "pre-surgery" refers to events that occur before surgery. In some embodiments, the surgery is the removal of brain tumor tissue. In some embodiments, "preoperative niraparib" or "niraparib before surgery" refers to the administration of niraparib to a human subject prior to resection. For example, niraparib is administered to a patient determined to have brain cancer within a period of time prior to resection (e.g., up to 7 days prior to resection, or 4 days prior to resection).

[0186] As used herein, the term "maintenance therapy" or "maintenance treatment" is a treatment for preventing disease recurrence. For example, maintenance therapy can prevent or minimize the growth of cancer after significantly reducing or eliminating cancer after initial therapy (cancer treatment). Maintenance therapy can be a continuous treatment, wherein multiple doses are administered at intervals (e.g., every day, every other day, every week, every two weeks, every three weeks, every four weeks, or every six weeks). In some embodiments, maintenance therapy can last for a predetermined length of time. In some embodiments, maintenance therapy can be sustainable until unacceptable toxicity and / or disease progression occurs. During maintenance therapy, once toxicity indicated by adverse events occurs, treatment may be interrupted. If toxicity is appropriately reduced to baseline or grade 1 or lower within 28 days, the patient can restart treatment with niraparib, and if prevention is not feasible, it may include a dose reduction.

[0187] As used herein, overall survival ("OS") is defined as the time from the start of treatment to death from any cause. For use as a clinical trial endpoint, OS is defined as the time from randomization to death from any cause and is measured in the intention-to-treat population.

[0188] "Objective response rate (ORR)" as used herein is defined as the proportion of patients whose tumors shrink to a predetermined amount and for the shortest duration. Duration of response is usually measured from the time of initial response until tumor progression is recorded. Typically, ORR can be defined as the sum of partial response plus complete response.

[0189] As used herein, "time to first subsequent treatment" (TFST) is defined as the date of randomization to the start date of the first subsequent treatment regimen (eg, anticancer therapy) in the current study.

[0190] As used herein, "time to second subsequent treatment" (TSST) is defined as the date of randomization to the start date of the second subsequent treatment regimen (eg, anticancer treatment) in the current study.

[0191] As used herein, a "chemotherapy-free interval" (CFI) is defined as the time from the last dose of the last anticancer therapy (eg, platinum-based chemotherapy) to the start of the next dose of the anticancer therapy.

[0192] As used herein, "stereotactic radiation therapy" is highly focused radiation therapy that concentrates a high intensity radiation dose on the tumor while limiting the radiation dose to surrounding organs.

[0193] Niraparib is an oral, selective inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and 2. Niraparib has the following structure:

[0194] .

[0195] The chemical name of niraparib mesylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide-4-methylbenzenesulfonate hydrate (1:1:1), and its chemical structure is as follows:

[0196]

[0197] The empirical molecular formula of niraparib is C 26 H 30N4O5S, with a molecular weight of 510.61 g / mol. The niraparib mesylate monohydrate drug substance is a white to off-white, non-hygroscopic crystalline solid. The solubility of niraparib is independent of pH below pKa 9.95, and the solubility of the free base in water is 0.7 mg / mL to 1.1 mg / mL in the physiological pH range. Certain solid forms of niraparib are described in WO 2018 / 183354, which is incorporated herein by reference in its entirety.

[0198] Methods for preparing niraparib include those described in WO 2014 / 088983; WO 2014 / 088984; WO 2018 / 200517, US 8,071,623; US 8,436,185; US 62 / 489,415 filed April 24, 2017; and Jones et al., J. Med. Chem., 52:7170-7185, 2009, each of which is incorporated herein by reference in its entirety.

[0199] Niraparib showed PARP 1 and 2 inhibition, IC 50 = 3.8 and 2.1 nM, respectively, and in whole-cell assays, it inhibited PARP activity, EC 50 =4 nM, and inhibited the proliferation of cancer cells with mutant BRCA-1 and BRCA-2, CC 50 In the range of 10-100 nM (see Jones et al., Journal Medicinal Chemistry, 2009, 52, 7170-7185). Methods for administering niraparib to cancer patients are also described in WO2018 / 005818, which is incorporated herein by reference in its entirety. Exemplary dosage forms comprising niraparib are described in, for example, WO 2018 / 183349 and WO 2019 / 067634, each of which is incorporated herein by reference in its entirety.

[0200] II. Combination therapy

[0201] In one embodiment, the method of the present invention can be used in combination with one or more other therapeutic agents (or in combination with one or more other active agents) known to be useful for treating cancer, including immunotherapy (e.g., immune checkpoint inhibitors), cell and gene therapy, chemotherapy, or radiotherapy. The term one or more other therapeutic agents used herein includes any compound or therapeutic agent known or showing favorable properties when administered to a patient in need of cancer treatment. In addition, it is not important whether the compound is administered in the same dosage form, for example, one compound can be administered by injection and another compound can be administered orally. In some embodiments, the method of the present invention is used as an additional therapy for radiotherapy in cancer treatment. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy for radiotherapy in brain cancer treatment. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is used as an additional therapy for radiotherapy for the treatment of unmethylated MGMT gliomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is used as an additional therapy for radiotherapy for the treatment of unmethylated MGMT glioblastomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an additional therapy for radiotherapy in the treatment of unmethylated gliomas. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct to radiation therapy in the treatment of unmethylated glioblastoma.

[0202] The term "co-administration" as used herein refers to simultaneous administration or separate sequential administration of niraparib or a pharmaceutically acceptable salt thereof as described herein and one or more other active agents (including chemotherapy and radiotherapy) known to be useful for treating cancer in any manner. The term one or more other active agents used herein includes any compound or therapeutic agent known or showing favorable properties when administered to a patient in need of cancer treatment. Preferably, if the administration is not simultaneous, the compounds are administered at close times to each other. In addition, it is not important whether the compounds are administered in the same dosage form, for example, one compound can be administered by injection and another compound can be administered orally.

[0203] Generally, in the cancer treatment of the present invention, any anti-tumor drug that is active to the sensitive tumor being treated can be co-administered.Co-administration is defined as including administration together with one or more other agents.The one or more other active agents (or one or more additional active agents) can be selected from any known cancer therapy, including small molecule therapy, antibody therapy, antibody drug conjugate (ADC) therapy and cell and gene therapy. Examples of anti-tumor drugs include but are not limited to chemotherapeutics, immunomodulators and immunostimulatory adjuvants. Examples of such agents can be found in Cancer Principles and Practice of Oncology, 11th edition (November 29, 2018), Lippincott Williams & Wilkins Publishers, compiled by VT Devita, TS Lawrence and SA Rosenberg (Editors). One of ordinary skill in the art will be able to discern which drug combinations are useful according to the specific characteristics of the drug and the cancer involved. Typical anti-tumor drugs used in the present invention include, but are not limited to, anti-microtubule or anti-mitotic agents; platinum coordination complexes; alkylating agents; antibiotic agents; topoisomerase I inhibitors; topoisomerase II inhibitors; antimetabolites; hormones and hormone analogs; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; heat shock protein inhibitors; cancer metabolism inhibitors; and cancer gene therapy agents.

[0204] As used herein, "immunomodulator" refers to any substance that affects the immune system, including monoclonal antibodies. Niraparib or a pharmaceutically acceptable salt thereof of the present invention may be regarded as an immunomodulator. Niraparib or a pharmaceutically acceptable salt thereof of the present invention may be regarded as an immunomodulator. Immunomodulators may be used as anti-tumor drugs for treating cancer. For example, immunomodulators include, but are not limited to, antibodies or other antagonists of CTLA-4, such as ipilimumab (YERVOY®) and tremelimumab; PD-1, such as dostarlimab, nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®) and cemiplimab (LIBTAYO®); and TIM-3, such as cobolimab. In some embodiments, immunomodulators include ipilimumab, tremelimumab, dostarlimab, nivolumab, pembrolizumab, cemiplimab, cobolimab, or a pharmaceutically acceptable salt thereof. Other immunomodulators include, but are not limited to, antibodies or other antagonists of PD-L1, OX-40, LAG3, TIM-3, 41BB, and GITR.

[0205] In one embodiment, the other active agent (or additional active agent) can be selected from one described in, for example, WO2018 / 208968, WO2018 / 213732, and WO2020 / 051142. For example, the PD-1 inhibitor is such as dotalimumab or pembrolizumab. In some embodiments, the PD-1 inhibitor is dotalimumab. In some embodiments, the PD-1 inhibitor includes dotalimumab, pembrolizumab, or a pharmaceutically acceptable salt thereof. In some embodiments, the PD-1 inhibitor includes dotalimumab or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the other active agent (or additional active agent) is a type II pan-RAF-kinase inhibitor. Type II pan-RAF-kinase inhibitors such as CCT3833 / BAL3833, LY3009120, lifirafenib, belvarafenib, TAK-580, JZP815, and tovorafenib are being studied for, e.g., patients with solid tumors, advanced or metastatic tumors, advanced or refractory solid tumors, NRAS advanced melanoma, gliomas, colorectal cancer, primary brain tumors, brain metastases of solid tumors, malignant gliomas, pediatric low-grade gliomas (pLGG), and recurrent or progressive solid tumors. In some embodiments, the type II pan-RAF-kinase inhibitor includes CCT3833 / BAL3833, LY3009120, lifirafenib, bevafenib, TAK-580, JZP815, tovorafenib, or a pharmaceutically acceptable salt thereof. In some embodiments, the type II pan-RAF-kinase inhibitor is tovorafenib. In some embodiments, the type II pan-RAF-kinase inhibitor includes tovorafenib, or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the active agent (or additional active agent) is an alkylating chemotherapeutic agent. In some embodiments, the alkylating chemotherapeutic agent is temozolomide. In some embodiments, the alkylating chemotherapeutic agent includes temozolomide or a pharmaceutically acceptable salt thereof. In some embodiments, temozolomide is co-administered to a human subject with radiotherapy. In some embodiments, the human subject has a positive MGMT state. In some embodiments, the human subject has a negative MGMT state. In some embodiments, temozolomide is co-administered to a human subject with radiotherapy, wherein the human subject has a positive MGMT state. In some embodiments, temozolomide is co-administered to a human subject with radiotherapy, wherein the human subject has a negative MGMT state. In some embodiments, the human subject suffers from a newly diagnosed glioblastoma and MGMT promoter hypermethylation. In some embodiments, the human subject suffers from an unmethylated MGMT glioma. In some embodiments, the human subject suffers from an unmethylated MGMT glioblastoma. In some embodiments, temozolomide is co-administered with radiotherapy to a human subject, wherein the human subject suffers from newly diagnosed glioblastoma and MGMT promoter hypermethylation. In some embodiments, when brain cancer is diagnosed as having cells (particularly glioblastoma cells) with methylated MGMT promoters, it is useful to treat with alkylating chemotherapeutic agents (e.g., temozolomide). Therefore, in some embodiments, temozolomide is co-administered with radiotherapy to a human subject, wherein the human subject has a methylated MGMT promoter. In some embodiments, temozolomide is administered as a pharmaceutically acceptable salt.

[0208] In some embodiments, the cancer is brain cancer.

[0209] In some embodiments, the brain cancer is a primary brain cancer.

[0210] In some embodiments, the brain cancer is glioma.

[0211] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0212] In some embodiments, the brain cancer is an unmethylated glioma. In some embodiments, the brain cancer is an unmethylated glioblastoma.

[0213] In one embodiment, when brain cancer is metastatic, the other active agent (or additional active agent) can be selected from chemotherapy and immunotherapy, wherein the chemotherapy is selected from trastuzumab and erlotinib, and wherein the immunotherapy is selected from atezolizumab, ipilimumab, pembrolizumab and nivolumab. In some embodiments, chemotherapy is tovorafenib. In some embodiments, immunotherapy is pembrolizumab. In some embodiments, immunotherapy is atezolizumab. In some embodiments, immunotherapy is dotalimumab. In some embodiments, chemotherapy is selected from trastuzumab, erlotinib and pharmaceutically acceptable salts thereof, and immunotherapy is selected from atezolizumab, ipilimumab, pembrolizumab, nivolumab and pharmaceutically acceptable salts thereof. In some embodiments, chemotherapy includes tovorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, immunotherapy includes pembrolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, immunotherapy includes atezolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the immunotherapy comprises dotarimab or a pharmaceutically acceptable salt thereof.

[0214] In one embodiment, the other active agent (or additional active agent) may be selected from temozolomide and bevacizumab. In one embodiment, the other active agent (or additional active agent) comprises temozolomide, bevacizumab or a pharmaceutically acceptable salt thereof.

[0215] In one embodiment, the other active agent (or additional active agent) may be temozolomide. In one embodiment, the other active agent (or additional active agent) comprises temozolomide or a pharmaceutically acceptable salt thereof.

[0216] In one embodiment, the other active agent (or additional active agent) can be atezolizumab. In one embodiment, the other active agent (or additional active agent) includes atezolizumab or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the other active agent (or additional active agent) can be pembrolizumab. In some embodiments, the other active agent (or additional active agent) includes pembrolizumab or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the other active agent (or additional active agent) can be tovorafenib. In some embodiments, the other active agent (or additional active agent) includes tovorafenib or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the other active agent (or additional active agent) can be dotalizumab. In some embodiments, the other active agent (or additional active agent) includes dotalizumab or a pharmaceutically acceptable salt thereof.

[0220] The anti-tumor drugs selected for use in combination with niraparib or a pharmaceutically acceptable salt thereof include, but are not limited to, abarelix, abemaciclib, abiraterone, afatinib, aflibercept, doxorubicin, alectinib, alemtuzumab, arsenic trioxide, asparaginase, axitinib, AZD-9291, belinastat, bendamustine, bevacizumab, blinatumomab, bosutinib, brentuximab vedotin), cabazitaxel, cabozantinib, capecitabine, ceritinib, clofarabine, cobimetinib, crizotinib, daratumumab, dasatinib, degarelix, denosumab, decizumab, docetaxel, elotuzumab, entinostat, enzalutamide, epirubicin, eribulin, filgrastim, flumatinib, fulvestrant, furquintinib, gemtuzumab ozogamicin, ibritumomab, ibrutinib, idelalisib, imatinib, irinotecan, ixabepilone, ixazomib, lenalidomide, lenvatinib, ylvaline leucovorin, nitrogen mustard, necimab, nelarabine, netupitant, nilotinib, obinutuzumab, olaparib, omacitabine, osimertinib, oxaliplatin, paclitaxel, palbociclib, palonosetron, panitumumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, plerixafor, pomalidomide, ponatinib, pralatrexate, quizartinib, radium-223, ramucirumab, regorafenib, rolapitant, rucaparib, sipuleucel-T, sonidegib, sunitinib, talimogene laherparepvec, tipiracil, topotecan, trabectedin, trifluridine, triptorelin, uridine, vandetanib, velaparib, vemurafenib, venetoclax, vincristine, vismodegib, zoledronic acid and pharmaceutically acceptable salts thereof.

[0221] III. Brain Cancer and Research Principles

[0222] The World Health Organization (WHO) classifies brain tumors into four categories based on their severity, as shown in Table A below.

[0223] Table A. Brain cancer – WHO grade

[0224]

[0225] Table B provides a non-limiting list of genes that may be altered or mutated in glioblastoma (GBM).

[0226] Table B. Example list of genes that may be altered or mutated in glioblastoma

[0227]

[0228] Primary brain tumors are among the top ten causes of cancer-related death in the United States, accounting for approximately 1.4% of all cancers and 2.4% of all cancer-related deaths. Approximately 14 per 100,000 people in the United States are diagnosed with primary brain tumors each year, and approximately 6 to 8 per 100,000 people are diagnosed with WHO grade III or IV primary brain tumors. Almost all grade II gliomas will progress to high-grade gliomas (grade III / IV). Glioblastoma multiforme (GBM, WHO grade IV glioma) is the most commonly reported malignant brain tumor histology in the National Cancer Database (29.6%). Patients with WHO grade III or IV gliomas have a poor prognosis, with an average survival of 12-16 months after diagnosis. Although conventional treatments such as surgery, radiotherapy, and temozolomide can delay tumor progression and prolong patient survival, these tumors commonly recur and lead to patient death. Despite this, the alkylating agent temozolomide remains the only effective adjuvant chemotherapy for patients with glioblastoma. Phase 0 trials identify promising new drugs through “humanized” preclinical studies. There are multiple design variations under Phase 0 trials to achieve a range of possible research goals. These studies include: (1) determining whether the mechanism of action (MOA) defined in nonclinical models can be achieved in humans; (2) improving biomarker testing using human tumor tissue; (3) developing novel imaging probes and evaluating their distribution, binding properties, and on-target effects in humans; (4) evaluating the human pharmacodynamics (PD) and / or pharmacokinetics (PK) of 2 or more analogs to select the most promising candidates for further development; (5) determining the dose range and dosing sequence of the biomodulator for combination with established chemotherapy; and (6) providing human PK-PD relationship data for the drug prior to Phase 1 testing. For CNS oncology studies, PK analysis refers to measuring the concentration of the study drug in brain tumor tissue, while PD analysis refers to quantifying the molecular / cellular targets affected by the study drug.

[0229] Phase 0 clinical trials are challenging for patients with brain tumors not only because of trial logistics but also because the non-therapeutic nature of such studies has an inhibitory effect on patient recruitment. Phase 0 trials with an extension phase apply the Phase 0 strategy to patients with brain tumors but incorporate PK and / or PD-dependent triggers to allow Phase 0 patients to enter an exploratory extension phase. In doing so, this strategy becomes attractive to potential brain tumor patients because it provides them with confidence that there is biological evidence that their tumor can be remitted if they choose to receive treatment. For these patients who enter the extension phase, they (and their providers) are motivated by the biological rationale that links the experimental treatment to their individual case. Interestingly, our institutional experience with Phase 0 and Phase 0+ extension studies demonstrates this advantage, with patient recruitment rates increasing from 14% to 35% since transitioning to the latter model in 2016 (Tien et al., 2019).

[0230] Less than 1% of all published brain tumor clinical trials include PK and PD endpoints to assess tissue effects after the first drug exposure. However, few studies have examined tissue from these patients after long-term drug treatment, even though 19% of patients with high-grade gliomas undergo, for example, 3 or more tumor resections. Using the proposed study paradigm, patients are scheduled for re-resection due to tumor recurrence after receiving a therapeutic dose of an experimental drug, which provides an important opportunity for longitudinal tissue analysis. In this population, enhancing and non-enhancing tumor tissue from rapidly relapsing and slowly relapsing tumors can be compared to determine the role of targeted and off-target pathways in tumor escape. To control for interindividual variability in CNS drug penetration, putative resistance mechanisms can also be examined in matched tissue specimens from the initial, second (stage 0), and third (progression from the extension phase) resections. In addition to characterizing resistance mechanisms, the planned identification of tissue biomarker signatures associated with sensitivity to experimental drugs can inform future clinical trial design. For patients who complete phase 0 of the study and have adequate evidence of tumor penetration (i.e., a “positive” PK endpoint), the observed differences in PD effects provide an opportunity to distinguish between biological responders (i.e., patients with positive PK and PD endpoints) and nonresponders (i.e., patients with positive PK endpoints and negative PD endpoints). Using a variety of molecular and genetic techniques, a panel of tumor biomarker combinations that predict pharmacodynamic sensitivity to investigational drugs can be developed for prospective studies. In summary, these longitudinal studies of human brain tumors exposed to experimental therapies can provide actionable evidence for future strategies.

[0231] Therefore, the FDA's initial proposed Phase 0 clinical trial mechanism was designed for the general drug development community. However, brain tumor drug development has unique research limitations due to the lack of predictive animal models, high risk of tumorigenesis, inappropriate microdosing, challenges with the BBB, and potential confounding effects of neurosurgical anesthesia. Adapting the Phase 0 trial paradigm for patients with neuro-oncology is an effective way to obtain direct evidence of drug delivery and target modulation. Specific modifications included in the proposal include: (1) abandoning microdosing in favor of high-dose regimens, (2) incorporating CSF into PK and PD analyses, and (3) adding an expansion component for patients with significant PK and / or PD responses. In some embodiments, patients in the expansion phase have primary brain cancer. In some embodiments, patients in the expansion component have primary brain cancer. In some embodiments, patients in the expansion phase have secondary brain cancer. In some embodiments, patients in the expansion component have secondary brain cancer.

[0232] Primary brain cancers include, but are not limited to, anaplastic astrocytoma, glioblastoma, glioblastoma multiforme, meningioma, pituitary carcinoma, schwannoma, oligodendroglioma, ependymoma, medulloblastoma, astrocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+)ATRX mutant glioma, malignant glioma, and primitive neuroectodermal tumor of the brain.

[0233] In some embodiments, the patient suffers from glioblastoma (GBM). In some embodiments, one or more of the following genes are mutated or altered in the glioblastoma patient: isocitrate dehydrogenase (IDH), 6- Methylguanine-DNA methyltransferase (MGMT), epidermal growth factor receptor (EGFR), telomerase reverse transcriptase (TERT), chromosome 7p gain, chromosome 10q deletion, H3 histone, family 3A (H3F3A), fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK) or alpha thalassemia / mental retardation syndrome X-linked (ATRX). In some embodiments, the human subject suffers from unmethylated MGMT glioblastoma. In some embodiments, the human subject suffers from unmethylated glioblastoma.

[0234] Brain metastasis (also called secondary brain cancer) refers to the spread of cancer cells from the primary cancer site to the brain. Any cancer may spread to the brain, but the types most likely to cause brain metastasis are lung cancer, breast cancer, colon cancer, kidney cancer, and melanoma. Brain metastasis may form one or more tumors in the brain. In some embodiments, brain metastasis is asymptomatic. In some embodiments, brain metastasis is active and progressive brain metastasis.

[0235] In embodiments, the type of cancer causing brain metastasis is lung cancer (e.g., solid tumor). In embodiments, lung cancer is advanced lung cancer. In embodiments, lung cancer is metastatic lung cancer. In embodiments, lung cancer is squamous cell carcinoma of the lung. In embodiments, lung cancer is small cell lung cancer (SCLC). In embodiments, lung cancer is non-small cell lung cancer (NSCLC). In embodiments, lung cancer is lung adenocarcinoma. In embodiments, lung cancer is ALK translocation lung cancer (e.g., lung cancer with known ALK translocation). In embodiments, lung cancer is EGFR mutant lung cancer (e.g., lung cancer with known EGFR mutation). In embodiments, lung cancer is MSI-H lung cancer. In embodiments, lung cancer is MSS lung cancer. In embodiments, lung cancer is POLE mutant lung cancer. In embodiments, lung cancer is POLD mutant lung cancer. In embodiments, lung cancer is high TMB lung cancer. In embodiments, lung cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD") or characterized by homologous recombination repair (HRR) gene mutation or deletion.

[0236] In embodiments, the cancer type causing brain metastasis is breast cancer (e.g., solid tumor). In embodiments, breast cancer is ER positive breast cancer, ER negative breast cancer, PR positive breast cancer, PR negative breast cancer, HER2 positive breast cancer, HER2 negative breast cancer, BRCA1 / 2 positive breast cancer, BRCA1 / 2 negative cancer or triple negative breast cancer (TNBC). In embodiments, cancer is ductal carcinoma in situ (DCIS; intraductal carcinoma). In embodiments, cancer is invasive breast cancer (e.g., ILC or IDC; invasive lobular carcinoma or invasive ductal carcinoma). In embodiments, cancer is triple negative breast cancer (TNBC). In embodiments, cancer is inflammatory breast cancer. In some embodiments, breast cancer is metastatic breast cancer. In some embodiments, breast cancer is advanced breast cancer. In some embodiments, cancer is II phase, III phase or IV phase breast cancer. In some embodiments, cancer is IV phase breast cancer. In some embodiments, breast cancer is triple negative breast cancer. In embodiments, breast cancer is metastatic breast cancer. In embodiments, breast cancer is MSI-H breast cancer. In embodiments, breast cancer is MSS breast cancer. In embodiments, breast cancer is POLE mutant breast cancer. In embodiments, breast cancer is POLD mutant breast cancer. In embodiments, the breast cancer is a high TMB breast cancer.In embodiments, the breast cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD") or is characterized by a homologous recombination repair (HRR) gene mutation or deletion.

[0237] In embodiments, the cancer type causing brain metastasis is colon cancer (e.g., solid tumor). In embodiments, colon cancer is adenocarcinoma. In embodiments, the cancer type causing brain metastasis is colorectal (CRC) cancer (e.g., solid tumor). In embodiments, colorectal cancer is advanced colorectal cancer. In embodiments, colorectal cancer is adenocarcinoma. In embodiments, colorectal cancer is metastatic colorectal cancer. In embodiments, colorectal cancer is MSI-H colorectal cancer. In embodiments, colorectal cancer is MSS colorectal cancer. In embodiments, colorectal cancer is POLE mutant colorectal cancer. In embodiments, colorectal cancer is POLD mutant colorectal cancer. In embodiments, colorectal cancer is high TMB colorectal cancer. In embodiments, colorectal cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD") or is characterized by homologous recombination repair (HRR) gene mutation or deletion. In embodiments, colon cancer is selected from colorectal cancer, squamous cell carcinoma, gastrointestinal neuroendocrine tumors.

[0238] In embodiments, the type of cancer causing brain metastasis is renal cancer (e.g., a solid tumor). In embodiments, the renal cancer is renal clear cell carcinoma. In embodiments, the renal cancer is renal papillary carcinoma. In embodiments, the renal cancer is renal chromophobe cell carcinoma. In embodiments, the renal cancer is renal cell carcinoma. In embodiments, the renal cancer is urothelial carcinoma. In embodiments, the renal cancer is renal sarcoma. In embodiments, the renal cancer is Wilms tumor. In embodiments, the renal cancer is renal lymphoma.

[0239] In embodiments, the type of cancer causing brain metastasis is melanoma. In embodiments, the melanoma is superficial spreading melanoma. In embodiments, the melanoma is nodular melanoma. In embodiments, the melanoma is lentigo maligna melanoma. In embodiments, the melanoma is acral lentigo melanoma. In embodiments, the melanoma is choroidal melanoma. In embodiments, the melanoma is conjunctival melanoma. In embodiments, the melanoma is iris melanoma. In embodiments, the melanoma is mucosal melanoma. In embodiments, the melanoma is advanced melanoma. In embodiments, the melanoma is metastatic melanoma. In embodiments, the melanoma is MSI-H melanoma. In embodiments, the melanoma is MSS melanoma. In embodiments, the melanoma is POLE mutant melanoma. In embodiments, the melanoma is POLD mutant melanoma. In embodiments, the melanoma is high TMB melanoma.

[0240] Exemplary DNA repair pathways and their defects are described in the present disclosure and International Publication Nos. WO 2018 / 005818 and WO 2019 / 133697, each of which is incorporated herein by reference in its entirety. Exemplary DNA repair pathways include base excision repair (BER), direct repair (DR), double-strand break (DSB) repair, homologous recombination repair (HRR), mismatch repair (MMR), nucleotide excision repair (NER), and non-homologous end joining (NHEJ) repair; interruptions in these pathways can lead to the development and / or growth of cancer. See, e.g., Kelley et al., "Targeting DNA repair pathways for cancer treatment: what's new?", Future Oncol., 10(7): 1215–37 (2014).

[0241] In some embodiments, the patient receives PARP therapy (i.e., niraparib) regardless of cancer homologous repair deficiency (HRD status). In some embodiments, the patient receives niraparib or a pharmaceutically acceptable salt thereof, regardless of HRD status. In some embodiments, the patient is not tested for the presence of a BRCA mutation or for the presence of a homologous recombination deficiency (including the presence of a DNA repair defect) prior to administration of niraparib or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, administration of niraparib or a pharmaceutically acceptable salt thereof is initiated within 12 weeks after the first day of the last chemotherapy cycle.

[0243] In some embodiments, the patient receives niraparib, or a pharmaceutically acceptable salt thereof, independent of the determination of HRD status (eg, the patient receives niraparib, or a pharmaceutically acceptable salt thereof, independent of the determination of BRCA status).

[0244] In some embodiments, a patient's HRD status can be known prior to treatment.

[0245] In some embodiments, the HRD status of the patient is determined. Various testing strategies have been used to measure homologous recombination defects (HRD) in ovarian cancer (including fallopian tube cancer and peritoneal cancer) and are known in the art. Genetic variations of BRCA1 / 2 and other HRR-related genes can be sequenced to understand germline or somatic gene mutation status.

[0246] In some embodiments, the cancer is characterized by a defect in at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, or at least sixteen genes involved in the HRR pathway, and the gene is not BRCA1 or BRCA2. In some embodiments, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen genes involved in the HRR pathway, and any combination thereof.

[0247] In some embodiments, at least one defect in the HRR pathway is a monoallelic mutation of a gene (e.g., a monoallelic mutation of a gene other than BRCA1 or BRCA2). In some embodiments, the monoallelic mutations are independently germline mutations. In some embodiments, the monoallelic mutations are independently sporadic mutations.

[0248] In some embodiments, at least one defect in the HRR pathway is a biallelic mutation of a gene (e.g., a biallelic mutation of a gene other than BRCA1 or BRCA2). In some embodiments, the biallelic mutations are independently germline mutations. In some embodiments, the biallelic mutations are independently sporadic mutations.

[0249] Defects in the HRR pathway (e.g., defects in at least one non-BRCA1 or non-BRCA2 gene involved in the HRR pathway and / or defects in BRCA1 and / or BRCA2) can be identified using methods known in the art. For example, identification of defects in the HRR pathway can include determinations by standardized laboratory tests (e.g., also including those approved by relevant regulatory agencies).

[0250] In some embodiments, a pre-specified HRR gene set is used to identify defects in genes involved in the HRR pathway. In some embodiments, the pre-specified HRR gene set includes one or more, two or more, three or more, four or more, five or more, seven or more, eight or more, nine or more, ten or more, or eleven or more genes selected from ATM, ATR, BARD1, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, and RAD54L.

[0251] a. Surgical status and residual disease

[0252] In some embodiments, the high-risk patient has an inoperable cancer. In some embodiments, the inoperable cancer is a stage III cancer. In some embodiments, the inoperable cancer is a stage IV cancer.

[0253] In some embodiments, the platinum-based chemotherapy regimen also includes surgery.

[0254] In some embodiments, surgical treatment occurs prior to initiating a first line of platinum-based chemotherapy regimen (primary debulking surgery).

[0255] In some embodiments, high-risk patients have residual disease after cytoreductive surgery. In some embodiments, residual disease is observed after primary cytoreductive surgery.

[0256] In some embodiments, surgery is not able to completely remove the cancer cells and residual disease describes the cancer cells that remain after surgery.

[0257] In some embodiments, the residual disease is visible residual disease. In some embodiments, the residual disease is less than about 2.0 centimeters. In some embodiments, the residual disease is greater than about 0.1 centimeters. In some embodiments, the residual disease is greater than about 0.1 centimeters and less than about 2.0 centimeters. In some embodiments, the residual disease is greater than about 1.0 centimeters.

[0258] In some embodiments, the stage III cancer patient has visible residual disease after surgery.

[0259] In some embodiments, the stage IV cancer patient has visible residual disease after surgery.

[0260] b. Neoadjuvant chemotherapy (NACT)

[0261] In some embodiments, the patient has received neoadjuvant chemotherapy (NACT), wherein the patient begins receiving platinum chemotherapy prior to surgical treatment, and the surgical treatment is interval cytoreductive surgery performed prior to completion of the platinum chemotherapy.

[0262] In embodiments, patients receive two or more cycles of postoperative platinum-based therapy following interval cytoreductive surgery.

[0263] In some embodiments, the patient with stage III cancer has received NACT. In some embodiments, the patient has no residual disease. In some embodiments, the patient has residual disease (e.g., visible residual disease as described herein).

[0264] In some embodiments, the patient with stage IV cancer has received NACT. In some embodiments, the patient has no residual disease. In some embodiments, the patient has residual disease (e.g., visible residual disease as described herein).

[0265] 1. First-line platinum-based chemotherapy

[0266] In some embodiments, platinum-based chemotherapy is a treatment cycle regimen using a platinum agent (e.g., any platinum agent described herein). In some embodiments, the administration of PARP therapy (e.g., niraparib) begins after all treatment cycles in the regimen are completed. In some embodiments, the platinum-based treatment regimen lasts for about 3-6 months. In some embodiments, the patient must start niraparib treatment within 12 weeks after the first day of the last cycle of chemotherapy (e.g., within 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, or 1 week after the first day of the last cycle of chemotherapy).

[0267] As used herein, a first-line platinum-based chemotherapy regimen is the first regimen a patient receives after being diagnosed with cancer.

[0268] In some embodiments, the patient receives a platinum-based chemotherapy regimen comprising multiple platinum-based chemotherapy cycles. A platinum-based chemotherapy cycle may refer to a period of treatment with a platinum-based chemotherapeutic agent followed by a period of rest (no treatment), repeated on a regular schedule (thereby constituting a platinum-based chemotherapy regimen).

[0269] In some embodiments, the platinum-based chemotherapy regimen comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve cycles of platinum chemotherapy. In some embodiments, the patient has received six or more cycles of platinum chemotherapy with a platinum-based chemotherapy regimen. In some embodiments, the patient has received nine or fewer cycles of platinum chemotherapy with a platinum-based chemotherapy regimen. In some embodiments, the patient has received 4-9 cycles of platinum chemotherapy with a platinum-based chemotherapy regimen; that is, the patient has received ≥4 and ≤9 cycles of platinum chemotherapy. In some embodiments, the patient has received 6-9 cycles of platinum chemotherapy with a platinum-based chemotherapy regimen; that is, the patient has received ≥6 and ≤9 cycles of platinum chemotherapy. In some embodiments, the patient has received 4-8 cycles of platinum chemotherapy with a platinum-based chemotherapy regimen; that is, the patient has received ≥4 and ≤8 cycles of platinum chemotherapy.

[0270] In some embodiments, the platinum-based chemotherapy regimen also includes surgical treatment. In some embodiments, cytoreductive surgery (primary cytoreductive surgery) is performed before platinum chemotherapy is administered to the patient described herein. In some embodiments, the patient has received NACT, wherein the patient has received one or more platinum chemotherapy cycles before cytoreductive surgery (interval cytoreductive surgery). In some embodiments, patients who receive NACT after cytoreductive surgery have received two or more (≥2) postoperative platinum chemotherapy cycles.

[0271] Exemplary platinum-based chemotherapeutic agents suitable for use in the methods described herein include cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthridine, picoplatin and / or satraplatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the first-line platinum-based chemotherapy comprises administration of cisplatin or carboplatin, or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the first-line platinum-based chemotherapy comprises administration of a second therapeutic agent in addition to the platinum chemotherapeutic agent.

[0273] In some embodiments, the first-line platinum-based chemotherapy includes administration of a second therapeutic agent, a taxane chemotherapeutic agent (eg, paclitaxel or docetaxel, or a pharmaceutically acceptable salt thereof).

[0274] In some embodiments, the first line of platinum-based chemotherapy comprises administration of a second therapeutic agent, bevacizumab. In some embodiments, the first line of platinum-based chemotherapy comprises administration of a second therapeutic agent, bevacizumab, or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the first-line platinum-based chemotherapy is administered as intraperitoneal chemotherapy.

[0276] 2. Response to first-line platinum-based chemotherapy

[0277] In some embodiments, administration of niraparib or a pharmaceutically acceptable salt thereof is initiated within 12 weeks after the first day of the last cycle of chemotherapy (eg, a platinum-based chemotherapy as described herein).

[0278] In some embodiments, the patient receiving the PARP therapy (eg, niraparib) has cancer that is in complete response to a first-line platinum-based chemotherapy regimen.

[0279] In some embodiments, the patient receiving PARP therapy (eg, niraparib) has a cancer that has had a partial response to a first-line platinum-based chemotherapy regimen.

[0280] In some embodiments, remission (e.g., complete remission or partial remission) is assessed prior to completion of a first-line platinum-based chemotherapy regimen. In some embodiments, remission (e.g., complete remission or partial remission) is assessed at any time after the second or third cycle of platinum-based chemotherapy. In some embodiments, remission is assessed after three or more (≥3) cycles of platinum chemotherapy.

[0281] Tumor response to platinum-based chemotherapy or to PARP therapy (eg, administration of niraparib after first-line platinum-based chemotherapy) can be assessed according to methods known in the art.

[0282] Tumor remission can be measured by, for example, assessing target lesions and / or non-target lesions including according to RECIST v 1.1 guidelines (including as described herein). The guideline is provided by EA Eisenhauer et al., " New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.), " Eur. J. of Cancer, 45: 228-247 (2009), which is incorporated herein by reference as a whole. The guideline first requires the estimation of the overall tumor burden at baseline, which is used as a comparator for subsequent measurements. Tumors can be measured by using any imaging system known in the art (such as by CT scanning or X-rays). Measurable disease is defined as the presence of at least one measurable lesion. In the study of primary endpoints with tumor progression (progression time or progression ratio of fixed date), the scheme must clearly specify whether to be limited to patients with measurable disease enrolled, or only patients with unmeasurable disease are also eligible to enroll.

[0283] When more than one measurable lesion is present at baseline, representative lesions from all affected organs (up to five lesions and two lesions per organ) should be identified as target lesions and recorded and measured at baseline (this means that in cases where patients have involvement of only one or two organ sites, a maximum of two and four lesions, respectively, should be recorded).

[0284] Target lesions should be selected based on their size (lesion with the longest diameter), should be representative of all involved organs, and should be amenable to reproducible measurement.

[0285] Lymph nodes deserve special mention because they are normal anatomical structures that can be seen on imaging even when there is no tumor involvement. Pathologic lymph nodes, defined as measurable and potentially identified as target lesions, must meet the P15mm short axis criteria on the CT scan. Only the short axis of these lymph nodes is counted in the baseline total. The short axis of a lymph node is the diameter that radiologists typically use to determine whether a lymph node is involved by a solid tumor. Lymph node size is typically reported in two dimensions in the plane in which the image was 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.

[0286] For example, an abdominal lymph node reported as 20 mm · 30 mm has a short axis of 20 mm and can be considered a malignant, measurable lymph node. In this example, 20 mm should be recorded as the lymph node measurement. All other pathological lymph nodes (those with a short axis of P10 mm but <15 mm) should be considered non-target lesions. Lymph nodes with a short axis of <10 mm are considered non-pathological lymph nodes and should not be recorded or tracked.

[0287] The sum of the diameters of all target lesions (longest diameter for non-nodal lesions, short axis for nodal lesions) will be calculated and reported as the baseline diameter sum. If lymph nodes are to be included in the sum, only the short axis will be added to the sum as described above. The baseline diameter sum will serve as a reference to further characterize any objective tumor regression in the measurable dimensions of the disease.

[0288] All other lesions (or disease sites), including pathological lymph nodes, should be identified as non-target lesions and also recorded at baseline. Rather than being measured, these lesions should be recorded as “present,” “absent,” or, in rare cases, “definitely progressive.” In addition, multiple non-target lesions involving the same organ may be recorded as a single item on the case record form (e.g., “multiple pelvic lymphadenopathy” or “multiple liver metastases”).

[0289] According to the RECIST v 1.1 efficacy criteria, the efficacy of target lesions can be evaluated as follows:

[0290] Complete remission (CR): All target lesions disappear. The short axis of any pathological lymph node (whether target or non-target) must be reduced to < 10 mm.

[0291] Partial response (PR): The sum of the diameters of target lesions is reduced by at least 30% based on the baseline sum of diameters.

[0292] Progressive Disease (PD): An increase of at least 20% in the sum of target lesion diameters, taking the smallest sum on study as reference (including the baseline sum if that is the smallest sum on study). In addition to a relative increase of 20%, the sum must also show an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

[0293] Stable disease (SD): Based on the smallest sum of diameters during the study period, there is neither enough shrinkage to meet the criteria for PR nor enough enlargement to meet the criteria for PD.

[0294] The efficacy of non-target lesions can be evaluated according to the RECIST v 1.1 efficacy criteria as follows:

[0295] Complete remission (CR): All non-target lesions disappear and tumor marker levels return to normal. All lymph nodes must be free of pathological size (short axis <10 mm)

[0296] Non-CR / non-PD: One or more non-target lesions persist and / or tumor marker levels remain above normal.

[0297] Progressive Disease (PD): Appearance of one or more new lesions and / or clear progression of existing non-target lesions. Clear progression should generally not exceed the target lesion status. It must represent a change in the overall disease status, not an increase in a single lesion.

[0298] 3. Platinum-sensitive and platinum-resistant cancers

[0299] Platinum-sensitive cancer is a cancer that does not come back or get worse for at least six months after treatment with platinum-based chemotherapy.

[0300] Platinum-resistant cancers are cancers that initially respond to platinum chemotherapy but recur or progress within about six months of treatment.

[0301] In some embodiments, the patient receiving niraparib receives treatment independent of the platinum-sensitive status of the cancer.

[0302] In some embodiments, the patient receiving niraparib receives a treatment that is independent of the determination of the platinum-sensitive status of the cancer.

[0303] In some embodiments, the patient receiving niraparib has a platinum-sensitive cancer.

[0304] In some embodiments, the patient receiving niraparib has a platinum-resistant cancer.

[0305] IV. General Experimental Protocol

[0306] As described herein, methods are provided comprising administering niraparib or a pharmaceutically acceptable salt thereof to a patient, subject, or population of subjects according to a regimen that achieves any one or a combination of the following: prolonging progression-free survival; reducing the hazard ratio for disease progression or death; and / or prolonging overall survival or a positive overall response rate.

[0307] In some embodiments, the methods described herein are effective as first-line maintenance therapy for brain cancer in patients who have received and completed only one platinum-based chemotherapy regimen.

[0308] In some embodiments, a method is useful for prolonging the effects of first-line platinum-based chemotherapy in a patient diagnosed with cancer (eg, brain cancer).

[0309] In some embodiments, the cancer is brain cancer.

[0310] In some embodiments, the brain cancer is a primary brain cancer.

[0311] In some embodiments, the brain cancer is glioma.

[0312] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0313] In some embodiments, the brain cancer is an unmethylated glioma. In some embodiments, the brain cancer is an unmethylated glioblastoma.

[0314] In some embodiments, the methods are useful for treating primary or metastatic brain cancer.

[0315] In some embodiments, suitable patients are newly diagnosed primary or metastatic brain cancer. In some embodiments, newly diagnosed primary or metastatic brain cancer patients have not received any cancer treatment (for example, newly diagnosed primary or metastatic brain cancer patients have not received any platinum-based chemotherapy, radiotherapy or any surgery). In some embodiments, the method includes administering only one platinum-based chemotherapy regimen to the patient. In some embodiments, the patient's cancer is relieved by chemotherapy, which is manifested as complete or partial relief. In some embodiments, the method includes orally administering an effective dose of niraparib to the patient every day before determining the sensitivity of the cancer to a platinum-based chemotherapy regimen. In some embodiments, cancer is sensitive to platinum. In some embodiments, cancer is resistant to platinum.

[0316] In some embodiments, a suitable patient diagnosed with primary or metastatic brain cancer has previously received and completed one platinum-based chemotherapy regimen. For example, a suitable patient diagnosed with primary or metastatic brain cancer has previously received and completed only one platinum-based chemotherapy regimen.

[0317] In some embodiments, suitable patients are patients with primary or metastatic brain cancer who are at high risk for disease progression.

[0318] In some embodiments, the primary or metastatic brain cancer is characterized by BRCA deficiency and / or HRD (eg, positive HRD status).

[0319] In some embodiments, the primary or metastatic brain cancer is characterized by the absence of a deleterious or suspected deleterious germline BRCA mutation.

[0320] In some embodiments, the primary or metastatic brain cancer is characterized by the absence of a BRCA mutation (whether germline or sporadic).

[0321] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with an additional therapeutic agent (e.g., a chemotherapeutic agent). In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered before, during, or after the administration of a chemotherapeutic agent. The simultaneous or sequential administration of niraparib or a pharmaceutically acceptable salt thereof with an additional therapeutic agent (e.g., a chemotherapeutic agent) is referred to as "combination therapy." In combination therapy, niraparib or a pharmaceutically acceptable salt thereof can be administered prior to (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) administration of the chemotherapeutic agent to a subject in need thereof. In some embodiments, the dosing interval of niraparib or a pharmaceutically acceptable salt thereof and the chemotherapeutic agent is 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 7 hours, 7 hours to 8 hours, 8 hours to 9 hours, 9 hours to 10 hours, 10 hours to 11 hours, 11 hours to 12 hours, no more than 24 hours, or no more than 48 hours.

[0322] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered to a patient or subject population that has responded to a first-line platinum-based chemotherapy regimen.

[0323] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as a first-line maintenance therapy to patients who have a complete or partial response to a first-line platinum-based chemotherapy regimen. The methods described herein are suitable for treating patients diagnosed with primary or metastatic brain cancer and prolonging the effect of a first-line platinum-based chemotherapy regimen (e.g., as described herein).

[0324] In some embodiments, administration of niraparib or a pharmaceutically acceptable salt thereof is initiated within 12 weeks after the first day of the last cycle of chemotherapy (eg, a platinum-based chemotherapy as described herein).

[0325] In some embodiments, PARP therapy (e.g., administered after a first-line platinum-based chemotherapy regimen) comprises at least one oral dose of niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the regimen comprises multiple oral doses. In some embodiments, the regimen comprises once daily (QD) dosing.

[0326] In some embodiments, the PARP treatment 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 daily administration of an effective dose of niraparib or a pharmaceutically acceptable salt thereof until disease progression or unacceptable toxicity occurs. In some embodiments, the regimen comprises taking a daily dose of at least 100, 200, or 300 mg of niraparib or a pharmaceutically acceptable salt thereof daily until disease progression or unacceptable toxicity occurs.

[0327] In some embodiments, the oral dose is an amount of niraparib in the range of 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.

[0328] In some embodiments, the amount of niraparib is about 100 mg. In some embodiments, the regimen comprises administering 300 mg of niraparib once daily.

[0329] In some embodiments, the amount of niraparib is about 100 mg. In some embodiments, the regimen comprises administering 200 mg of niraparib once daily.

[0330] In some embodiments, the amount of niraparib is about 300 mg niraparib. In some embodiments, the regimen comprises administering 300 mg niraparib once daily.

[0331] In some embodiments, the starting dose of niraparib treatment is based on the patient's baseline weight or baseline platelet count. In some embodiments, niraparib is administered to patients with a baseline weight ≥77 kg and a baseline platelet count ≥150,000 μL in an amount equivalent to about 300 mg of niraparib free base per day. In some embodiments, niraparib is administered to patients with a baseline weight <77 kg or a baseline platelet count <150,000 μL in an amount equivalent to about 200 mg of niraparib free base per day. Additional dose adjustments for study treatment will not be based on changes in the patient's weight during study participation. For those patients who were started at a dose of about 200 mg of niraparib once daily, an increase in the dose of niraparib to about 300 mg of niraparib once daily is allowed if no treatment interruption or discontinuation occurs within the first 2 cycles of treatment. For any dose modification, the amount of the unit dosage form (e.g., capsule or tablet) administered will be modified accordingly.

[0332] In some embodiments, the oral dose is administered in one or more unit dosage forms. In some embodiments, one or more unit dosage forms are capsules. In some embodiments, one or more unit dosage forms are tablets. 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 unit dosage form combination can be combined to form a once-daily (QD) dose. For example, three 100 mg unit dosage forms are taken once a day, so that about 300 mg of niraparib is administered once a day. In some embodiments, niraparib is administered in a single 300 mg unit dosage form. In some embodiments, niraparib is administered in 300 mg QD. In some embodiments, niraparib is administered in 3 x100 mg QD (i.e., niraparib is administered in three 100 mg unit dosage forms). In some embodiments, niraparib is administered in 2 x 150 mg QD (i.e., niraparib is administered in two 150 mg unit dosage forms).

[0333] In some embodiments, niraparib is administered as niraparib free base. In some embodiments, niraparib is administered as a pharmaceutically acceptable salt of niraparib. In some embodiments, niraparib is administered as niraparib mesylate monohydrate. In some embodiments, the amount of niraparib in a dose is based on the weight of the free base of the pharmaceutically acceptable salt. In some embodiments, the amount of niraparib in a dose is based on the weight of the pharmaceutically acceptable salt.

[0334] In some embodiments, the oral dose of niraparib is administered in a 7-day dosing, 7-day resting regimen. In some embodiments, the 7-day dosing, 7-day resting regimen includes 3 or more cycles. In some embodiments, the 7-day dosing, 7-day resting regimen includes 4 cycles. In some embodiments, the oral dose of niraparib is 45 mg / kg. In some embodiments, the oral dose of niraparib is administered in combination with one or more additional active agents known to be useful for treating cancer. In some embodiments, the oral dose of niraparib is administered in combination with an additional active agent known to be useful for treating cancer. In some embodiments, the oral dose of niraparib and an additional active agent are administered in a 7-day dosing, 7-day resting regimen, respectively. In some embodiments, the 7-day dosing, 7-day resting regimen includes 3 or more cycles. In some embodiments, the 7-day dosing, 7-day resting regimen includes 4 cycles. In some embodiments, niraparib is administered in the first, third, fifth, and seventh weeks of the regimen, and an additional active agent is administered in the second, fourth, sixth, and eighth weeks of the regimen. In some embodiments, the oral dose of niraparib is 45 mg / kg, and the oral dose of an additional active agent is 60 mg / kg. In some embodiments, one or more additional active agents are temozolomide, bevacizumab, or a combination thereof. In some embodiments, one or more additional active agents include temozolomide, bevacizumab, a pharmaceutically acceptable salt, or a combination thereof. In some embodiments, one or more additional active agents are temozolomide. In some embodiments, one or more additional active agents include temozolomide or a pharmaceutically acceptable salt thereof. In some embodiments, one or more additional active agents are atezolizumab. In some embodiments, one or more additional active agents include atezolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, one or more additional active agents are pembrolizumab. In some embodiments, one or more additional active agents include pembrolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, one or more additional active agents are tovorafenib. In some embodiments, one or more additional active agents include tovorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, one or more additional active agents are dotalimumab. In some embodiments, the one or more additional active agents include dotarimab or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, dose interruptions (no more than 28 days) or dose reductions may be permitted based on treatment side effects. For patients starting at about 300 mg niraparib per day, dose reductions to about 200 mg niraparib per day and subsequently to about 100 mg niraparib per day are permitted.

[0336] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 6 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 9 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 12 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 15 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 18 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 21 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 24 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 27 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 30 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 33 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 36 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 39 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 42 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 45 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 48 months.

[0337] In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 9-12 months. In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 12-15 months. In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 15-18 months. In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 18-21 months. In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 21-24 months. In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 24-27 months. In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 27-30 months. In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 30-33 months. In some embodiments, the administration time of niraparib or a pharmaceutically acceptable salt thereof is at least about 33-36 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 36-39 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 39-42 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 42-45 months. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered for at least about 45-48 months.

[0338] In some embodiments, the method prolongs progression-free survival compared to a control. In some embodiments, the method reduces the risk ratio of disease progression or death compared to a control. In some embodiments, the method prolongs overall survival compared to a control. In some embodiments, the method achieves an overall remission rate of at least 30%. In some embodiments, the method achieves an improved progression-free survival 2 compared to a control. In some embodiments, the method achieves an improved chemotherapy-free interval compared to a control. In some embodiments, the method achieves an improved first subsequent treatment time compared to a control. In some embodiments, the method achieves an improved second subsequent treatment time compared to a control. In some embodiments, it has been determined by FOSI and / or EQ-5D-5L that these methods will not adversely affect quality of life. In some embodiments, it has been determined that the method will not affect the effectiveness of subsequent chemotherapeutic agents (e.g., platinum agents, including but not limited to cisplatin, carboplatin, oxaliplatin, nedaplatin, tetranitrate triplatin, pheniplatin, picoplatin or satraplatin) treatment.

[0339] This extension of progression-free survival can result in a reduced risk ratio for disease progression or death. Maintenance therapy is performed during the interval between stopping the first-line platinum-based chemotherapy regimen or radiotherapy (the purpose is to delay disease progression) and subsequent intensive treatment (which may bring tolerance problems to patients). In another embodiment, patients with primary or metastatic brain cancer are further characterized as having BRCA deficiency or HRD. In some embodiments, the patient suffers from glioblastoma. In some embodiments, the patient suffers from WHO grade II-IV glioma. In some embodiments, the patient suffers from IDH1 / 2 (+) ATRX mutant glioma.

[0340] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as maintenance therapy to patients with primary or metastatic brain cancer who have complete remission or partial remission after administration and completion of only one platinum-based chemotherapy treatment, wherein the administration of niraparib or a pharmaceutically acceptable salt thereof results in an extension of progression-free survival. This extension of progression-free survival may result in a reduced risk ratio for disease progression or death. This first-line maintenance therapy is performed during the interval between stopping chemotherapy (for the purpose of delaying disease progression) and subsequent intensive therapy (which may cause tolerance problems for patients). In some embodiments, a further feature of a primary or metastatic brain cancer patient is that there is no harmful or suspected harmful germline BRCA mutation. In some embodiments, the patient suffers from glioblastoma. In some embodiments, the patient suffers from WHO grade II-IV glioma. In some embodiments, the patient suffers from IDH1 / 2 (+) ATRX mutant glioma.

[0341] In some embodiments, the present invention provides a method of administering niraparib or a pharmaceutically acceptable salt thereof to a patient with primary or metastatic brain cancer, the method being unrelated to the sensitivity of the cancer to platinum. In some embodiments, the method comprises administering niraparib or a pharmaceutically acceptable salt thereof according to a determined regimen to achieve an extended progression-free survival. In some embodiments, for example, compared with patients who have not received niraparib or a pharmaceutically acceptable salt thereof, the progression-free survival of patients receiving niraparib or a pharmaceutically acceptable salt thereof is longer. In some embodiments, the progression-free survival of patients receiving niraparib or a pharmaceutically acceptable salt thereof is longer than that of patients receiving alternative cancer therapies (e.g., therapies using different PARP inhibitors). In some embodiments, the patient suffers from primary or metastatic brain cancer before the administration of niraparib or a pharmaceutically acceptable salt thereof, which brain cancer exhibits partial remission to platinum-based chemotherapy (e.g., primary or metastatic brain cancer that is platinum-sensitive or platinum-resistant that exhibits partial remission to platinum-based chemotherapy). In some embodiments, the patient has a primary or metastatic brain cancer that has demonstrated a complete response to platinum-based chemotherapy (e.g., a platinum-sensitive or platinum-resistant primary or metastatic brain cancer that has demonstrated a complete response to platinum-based chemotherapy) prior to administration of niraparib or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the present invention provides a method of administering niraparib or a pharmaceutically acceptable salt thereof to a patient with platinum-sensitive primary or metastatic brain cancer, the method comprising administering niraparib or a pharmaceutically acceptable salt thereof according to a determined regimen to achieve an extended progression-free survival. In some embodiments, for example, compared with patients who do not receive niraparib or a pharmaceutically acceptable salt thereof, the progression-free survival of patients receiving niraparib or a pharmaceutically acceptable salt thereof is longer. In some embodiments, the progression-free survival of patients receiving niraparib or a pharmaceutically acceptable salt thereof is longer than that of patients receiving alternative cancer therapies (e.g., therapies using different PARP inhibitors). In some embodiments, the patient suffers from primary or metastatic brain cancer before the administration of niraparib or a pharmaceutically acceptable salt thereof, and the brain cancer shows partial remission to platinum-based chemotherapy. In some embodiments, the patient suffers from primary or metastatic brain cancer before the administration of niraparib or a pharmaceutically acceptable salt thereof, and the brain cancer shows complete remission to platinum-based chemotherapy.

[0343] In some embodiments, the present invention provides a method of administering niraparib or a pharmaceutically acceptable salt thereof to a patient with platinum-resistant primary or metastatic brain cancer, the method comprising administering niraparib or a pharmaceutically acceptable salt thereof according to a determined regimen to achieve an extended progression-free survival. In some embodiments, for example, compared with patients who do not receive niraparib or a pharmaceutically acceptable salt thereof, the progression-free survival of patients receiving niraparib or a pharmaceutically acceptable salt thereof is longer. In some embodiments, the progression-free survival of patients receiving niraparib or a pharmaceutically acceptable salt thereof is longer than that of patients receiving alternative cancer therapies (e.g., therapies using different PARP inhibitors). In some embodiments, the patient suffers from primary or metastatic brain cancer, and prior to the administration of niraparib or a pharmaceutically acceptable salt thereof, the patient exhibits partial remission to platinum-based chemotherapy. In some embodiments, the patient suffers from primary or metastatic brain cancer, and prior to the administration of niraparib or a pharmaceutically acceptable salt thereof, it exhibits complete remission to platinum-based chemotherapy.

[0344] In some embodiments, progression for determination of progression-free survival is determined by: 1) tumor evaluation by CT / MRI showing clear progressive disease according to RECIST 1.1 criteria; and / or 2) additional diagnostic testing (e.g., histology / cytology, ultrasound, endoscopy, positron emission tomography) that identifies new lesions.

[0345] In some embodiments, the patient is characterized by having homologous recombination deficiency. In some embodiments, the patient has a positive homologous recombination deficiency state. The homologous recombination deficiency state can be determined according to methods known to those skilled in the art.

[0346] In some embodiments, the extended progression-free survival is at least about 6 months. In some embodiments, the extended progression-free survival is at least about 9 months. In some embodiments, the progression-free survival is at least about 12 months. In some embodiments, the progression-free survival is at least about 15 months. In some embodiments, the progression-free survival is at least about 18 months. In some embodiments, the progression-free survival is at least about 21 months. In some embodiments, the progression-free survival is at least about 24 months. In some embodiments, the progression-free survival is at least about 27 months. In some embodiments, the progression-free survival is at least about 30 months. In some embodiments, the progression-free survival is at least about 33 months. In some embodiments, the progression-free survival is at least about 36 months. In some embodiments, the progression-free survival is at least about 39 months. In some embodiments, the progression-free survival is at least about 42 months. In some embodiments, the progression-free survival is at least about 45 months. In some embodiments, the progression-free survival is at least about 48 months.

[0347] In some embodiments, the present invention provides a method of administering niraparib or a pharmaceutically acceptable salt thereof to a patient with brain cancer (primary brain cancer or metastatic brain cancer), the method comprising administering niraparib or a pharmaceutically acceptable salt thereof according to a determined regimen to achieve a risk ratio for disease progression or death. In some embodiments, for example, the risk ratio of a patient receiving niraparib or a pharmaceutically acceptable salt thereof is improved compared to a patient not receiving niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the risk ratio of a patient receiving niraparib or a pharmaceutically acceptable salt thereof is improved compared to a patient receiving an alternative cancer therapy (e.g., a therapy using a different PARP inhibitor). In some embodiments, the present invention relates to a method of converting a patient who is receiving cancer treatment with olaparib or a pharmaceutically acceptable salt thereof to a treatment comprising niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention relates to a method of converting a patient with brain cancer who is receiving olaparib or a pharmaceutically acceptable salt thereof to a treatment comprising niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention relates to a method for treating brain cancer (primary brain cancer or metastatic brain cancer), the method comprising administering niraparib or a pharmaceutically acceptable salt thereof to a patient who has previously been treated with at least one PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, at least one PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof includes but is not limited to olaparib, pamiparib, rucaparib and talazoparib and a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof is pamiparib or a pharmaceutically acceptable salt thereof. For example, compared to another PARP inhibitor (e.g., olaparib), niraparib exhibits superior brain penetration, as shown in Examples 3 and 4.

[0348] In some embodiments, the brain cancer is a primary brain cancer.

[0349] In some embodiments, the brain cancer is glioma.

[0350] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0351] In some embodiments, the brain cancer is an unmethylated glioma. In some embodiments, the brain cancer is an unmethylated glioblastoma.

[0352] Additional / Supporting Implementations

[0353] 1. A method for treating primary or metastatic brain cancer in a human subject in need thereof, the method comprising administering to the human subject an effective amount of niraparib or a pharmaceutically acceptable salt thereof.

[0354] 2. The method according to embodiment 1, wherein the human subject is also treated with radiotherapy, in particular stereotactic radiotherapy.

[0355] 3. The method according to embodiment 1 or 2, wherein the primary brain cancer or metastatic brain cancer is newly diagnosed.

[0356] 4. The method according to embodiment 2 or 3, wherein the niraparib and radiation therapy are initiated after resection of the primary brain cancer tumor.

[0357] 5. The method according to any one of embodiments 2-4, wherein the radiation therapy is about 60 Gy (unit gray).

[0358] 6. The method according to any one of embodiments 2-4, wherein the radiation therapy is about 10 Gy (unit gray).

[0359] 7. The method according to any one of embodiments 2-6, wherein the niraparib and radiation therapy are administered for about 6-7 weeks.

[0360] 8. The method according to any one of embodiments 2-7, wherein the human subject further receives maintenance treatment with niraparib without receiving radiation therapy after treatment with niraparib and radiation therapy.

[0361] 9. The method according to any one of embodiments 1-8, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to 200 mg or 300 mg of niraparib free base.

[0362] 10. The method according to any one of embodiments 1-9, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in the form of niraparib mesylate monohydrate.

[0363] 11. The method according to any one of embodiments 1-10, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

[0364] 12. The method according to any one of embodiments 1-11, wherein the dose of niraparib or a pharmaceutically acceptable salt thereof is administered daily.

[0365] 13. The method according to any one of embodiments 1-12, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 300 mg of niraparib free base.

[0366] 14. The method according to any one of embodiments 1-12, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 200 mg of niraparib free base.

[0367] 15. The method according to any one of embodiments 1-14, wherein the primary brain cancer is selected from: anaplastic astrocytoma, glioblastoma, glioblastoma multiforme, meningioma, pituitary carcinoma, schwannoma, oligodendroglioma, ependymoma, medulloblastoma, astrocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+) ATRX mutant glioma, malignant glioma and primitive neuroectodermal tumor of the brain.

[0368] 16. The method according to any one of embodiments 1-15, wherein the primary brain cancer is a WHO grade IV tumor.

[0369] 17. The method according to embodiment 16, wherein the primary brain cancer is glioblastoma.

[0370] 18. The method according to embodiment 17, wherein the human subject exhibits a free concentration of niraparib in gadolinium-non-enhancing areas of a brain cancer tumor that is >5 times the biochemical IC50 value of niraparib.

[0371] 19. The method according to embodiment 18, wherein following preoperative niraparib (300 mg QD) treatment 4 days before a planned resection, the free concentration of niraparib in gadolinium-non-enhancing areas of brain cancer tumors is measured 3-5 hours or 8-12 hours after the last dose.

[0372] 20. The method according to embodiment 18, wherein following preoperative niraparib (200 mg QD) treatment 4 days before a planned resection, the free concentration of niraparib in gadolinium-non-enhancing areas of a brain cancer tumor is measured 3-5 or 8-12 hours after the last dose.

[0373] 21. The method according to any one of embodiments 18-20, wherein 5 times the biochemical IC50 value of niraparib is 19 nM.

[0374] 22. The method according to any one of embodiments 1-21, wherein the brain / plasma ratio of niraparib is about 0.5.

[0375] 23. The method according to any one of embodiments 1-22, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents known to be useful for treating cancer.

[0376] 24. The method according to embodiment 23, wherein the one or more additional active agents are temozolomide, bevacizumab, or a combination thereof.

[0377] 25. The method according to any one of embodiments 1-24, wherein the human subject or cancer is in complete or partial response to platinum-based chemotherapy.

[0378] 26. The method according to any one of embodiments 1-25, wherein the cancer is not sensitive to platinum.

[0379] 27. The method according to any one of embodiments 1-25, wherein the cancer is platinum-sensitive.

[0380] 28. The method according to any one of embodiments 1-27, wherein the cancer is homologous recombination deficiency (HRD) negative.

[0381] 29. The method according to embodiment 1, wherein the primary or metastatic brain cancer is recurrent.

[0382] 30. The method according to embodiment 29, wherein the niraparib administration is initiated after brain cancer tumor resection.

[0383] 31. The method according to embodiment 29 or 30, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered as a maintenance therapy.

[0384] 32. The method according to any one of embodiments 29-31, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to 200 mg or 300 mg of niraparib free base.

[0385] 33. The method according to any one of embodiments 29-32, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in the form of niraparib mesylate monohydrate.

[0386] 34. The method according to any one of embodiments 29-33, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

[0387] 35. The method according to any one of embodiments 29-34, wherein the dose of niraparib or a pharmaceutically acceptable salt thereof is administered daily.

[0388] 36. A method according to any one of embodiments 29-35, wherein the primary recurrent brain cancer is selected from: anaplastic astrocytoma, glioblastoma, glioblastoma multiforme, meningioma, pituitary carcinoma, schwannoma, oligodendroglioma, ependymoma, medulloblastoma, astrocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+) ATRX mutant glioma, malignant glioma and primitive neuroectodermal tumor of the brain.

[0389] 37. The method according to any one of embodiments 29-36, wherein the primary recurrent brain cancer is a WHO grade II-IV tumor.

[0390] 38. The method according to any one of embodiments 29-37, wherein the primary recurrent brain cancer is an IDH1 / 2(+)ATRX mutant glioma.

[0391] 39. A method according to embodiment 38, wherein the human subject shows a chromosome fusion in a C-loop assay with a cutoff Ct value of 35.

[0392] 40. The method according to embodiment 38, wherein following preoperative niraparib (300 mg QD) treatment 4 days prior to planned resection, chromosome fusions in the C-circle assay are measured 3-5 hours or 8-12 hours after the last dose.

[0393] 41. The method according to any one of embodiments 29-40, wherein the brain / plasma ratio of niraparib is about 0.5.

[0394] 42. The method according to any one of embodiments 29-41, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents known to be useful for treating cancer.

[0395] 43. The method according to embodiment 42, wherein the one or more additional active agents are temozolomide, bevacizumab, or a combination thereof.

[0396] 44. The method according to any one of embodiments 29-43, wherein the human subject or cancer is in complete or partial response to platinum-based chemotherapy.

[0397] 45. The method according to any one of embodiments 29-44, wherein the cancer is not sensitive to platinum.

[0398] 46. ​​The method according to any one of embodiments 29-44, wherein the cancer is platinum-sensitive.

[0399] 47. The method according to any one of embodiments 29-46, wherein the cancer is homologous recombination deficiency (HRD) negative.

[0400] 48. The method according to any one of embodiments 1-47, wherein the metastatic brain cancer has spread from a primary site of lung cancer, breast cancer, colon cancer, kidney cancer and melanoma.

[0401] 49. The method according to embodiment 48, wherein the metastatic brain cancer is asymptomatic or actively progressive brain metastasis.

[0402] 50. The method according to embodiment 48 or 49, wherein the metastatic brain cancer is caused by a lung cancer selected from solid tumors, squamous cell carcinoma of the lung, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and lung adenocarcinoma.

[0403] 51. The method according to embodiment 48 or 49, wherein the metastatic brain cancer is caused by a breast cancer selected from solid tumors, ductal carcinoma in situ (DCIS; intraductal carcinoma), invasive breast cancer (ILC or IDC; invasive lobular carcinoma or invasive ductal carcinoma), triple-negative breast cancer (TNBC) and inflammatory breast cancer.

[0404] 52. The method according to embodiment 48 or 49, wherein the metastatic brain cancer is caused by a renal cancer selected from solid tumors, renal clear cell carcinoma, renal papillary carcinoma, renal chromophobe cell carcinoma, renal cell carcinoma, urothelial carcinoma, renal sarcoma, Wilms tumor and renal lymphoma.

[0405] 53. The method according to embodiment 48 or 49, wherein the metastatic brain cancer is caused by a colon cancer selected from colorectal cancer, squamous cell carcinoma, gastrointestinal neuroendocrine tumors, solid tumors and adenocarcinoma.

[0406] 54. The method according to embodiment 48 or 49, wherein the metastatic brain cancer is caused by a melanoma selected from the group consisting of superficial spreading melanoma, nodular melanoma, lentigo maligna, acral lentigo, choroidal melanoma, conjunctival melanoma, iris melanoma, and mucosal melanoma.

[0407] 55. The method according to any one of embodiments 48-54, wherein the niraparib administration is initiated after brain cancer tumor resection.

[0408] 56. The method according to embodiment 55, wherein the human subject is also treated with radiotherapy, in particular stereotactic radiotherapy.

[0409] 57. The method according to embodiment 56, wherein the niraparib and radiation therapy are initiated after resection of a metastatic brain cancer tumor.

[0410] 58. The method according to any one of embodiments 48-57, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered as a maintenance therapy.

[0411] 59. The method according to any one of embodiments 48-58, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to 200 mg or 300 mg of niraparib free base.

[0412] 60. The method according to any one of embodiments 48-59, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in the form of niraparib mesylate monohydrate.

[0413] 61. The method according to any one of embodiments 48-60, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

[0414] 62. The method according to any one of embodiments 48-61, wherein the dose of niraparib or a pharmaceutically acceptable salt thereof is administered daily.

[0415] 63. The method according to any one of embodiments 48-62, wherein the metastatic brain cancer comprises asymptomatic and actively progressive brain metastases.

[0416] 64. The method according to any one of embodiments 48-63, wherein the brain / plasma ratio of niraparib is about 0.5.

[0417] 65. The method according to any one of embodiments 48-64, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents known to be useful for treating cancer.

[0418] 66. The method according to embodiment 65, wherein the one or more additional active agents are temozolomide, bevacizumab, or a combination thereof.

[0419] 67. The method according to any one of embodiments 48-66, wherein the human subject or cancer is in complete or partial response to platinum-based chemotherapy.

[0420] 68. The method according to any one of embodiments 48-66, wherein the cancer is not sensitive to platinum.

[0421] 69. The method according to any one of embodiments 48-66, wherein the cancer is platinum-sensitive.

[0422] 70. The method according to any one of embodiments 48-69, wherein the cancer is homologous recombination deficiency (HRD) negative.

[0423] 71. The method according to any one of embodiments 1-70, comprising administering niraparib or a pharmaceutically acceptable salt thereof to a patient who has previously been treated with at least one PARP inhibitor other than niraparib, or a pharmaceutically acceptable salt thereof.

[0424] 72. The method according to embodiment 71, wherein at least one PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof is selected from olaparib, pamiparib, rucaparib and talazoparib and pharmaceutically acceptable salts thereof.

[0425] 73. The method according to embodiment 71, wherein at least one PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof is olaparib or a pharmaceutically acceptable salt thereof. Example

[0426] The following examples are provided to illustrate but not to limit the claimed invention.

[0427] Example 1. Phase 0 “Trigger” Trial of Niraparib in Newly Diagnosed Glioblastoma and Recurrent IDH1 / 2(+) ATRX Mutant Gliomas

[0428] This is an open-label, multicenter, Phase 0 study, including an extension phase, that will enroll up to 24 patients with newly diagnosed glioblastoma and up to 18 patients with recurrent glioma with IDH mutations and ATRX loss. As described below, the trial will consist of a Phase 0 portion (subdivided into Arms A and B) and a treatment extension phase. Patients whose tumors demonstrate a positive PK response (Arm A) or a positive PD response (Arm B) in the Phase 0 portion of the study will enter the treatment extension phase, which will combine niraparib treatment doses with standard fractionated radiotherapy (Arm A) or niraparib monotherapy (Arm B) until disease progression.

[0429] Group A will enroll patients only at the Ivy Brain Tumor Center, while Group B will be open to both the Ivy Brain Tumor Center and UCSF Medical Center.

[0430] 0th issue

[0431] Group A:

[0432] Participants undergoing resection for presumed newly diagnosed glioblastoma (WHO grade 4) will receive niraparib 4 days prior to surgical resection. A maximum of 24 participants will receive niraparib preoperatively, with an expected enrolment of 12 participants in the treatment extension phase (see below). The last preoperative dose will be administered 3-5 hours or 8-10 hours before tumor resection. Assignment to time cohorts will be randomized. Participants who do not have a histologically confirmed diagnosis of glioblastoma after craniotomy will be replaced. Tumor PK and PD analyses will be performed at the Ivy Brain Tumor Center in both time cohorts.

[0433] For PK analysis, blood, CSF, and brain tumor tissue samples (gadolinium-enhanced and non-enhanced) will be collected during surgery. Additional blood samples will be collected on day 1 pre-dose and pre-dose (trough concentrations), day 4 (day of surgery), and 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose.

[0434] For PD analysis, gadolinium-enhanced tumor tissue collected intraoperatively will be cut into 4 tissue sections of similar size. Two tissue samples will be exposed to 10 Gy of IR using the RAD2000 device, and two samples will receive sham radiation (not irradiated). One pair of sham-irradiated control and 10 Gy irradiated tissues will be fixed in formalin solution for FFPE slides. Another pair will be snap-frozen for PAR ELISA assay. Additional gadolinium-enhanced tumor tissue will be cryopreserved for genomic analysis.

[0435] Table 1: Time groups

[0436]

[0437] The optimal time interval (OTI) is the surgical time interval (STI) from the last preoperative dose to the time of tumor resection to detect the maximum free drug concentration in the non-enhancing tumor. The OTI will be determined after 3 participants are enrolled in each group. Once the OTI is determined, the remaining 18 participants in Group A will be dosed at the optimal time interval (i.e., 3-5 hours or 8-10 hours after the last dose). Group B will follow the OTI determined by Group A.

[0438] Pharmacokinetic (PK) methods

[0439] The primary endpoint of this Phase 0 trial is free niraparib concentration in gadolinium-nonenhancing glioblastoma tissue. Total and free niraparib concentrations will be assessed in each patient's plasma, CSF, and gadolinium-enhancing and gadolinium-nonenhancing areas of the tumor in the Ivy Center's CLIA-certified PK Core. Tumor-to-plasma ratios will be calculated. All assays and analyses will be developed, validated, and performed at the Ivy Brain Tumor Center.

[0440] To enter the treatment extension phase of the study, a positive PK response had to be demonstrated and was defined as free niraparib concentrations > 5 times the biochemical IC50 value in the gadolinium-free non-enhancing areas of the tumor.

[0441] Pharmacodynamic (PD) methods

[0442] A “functional” PD assay examining PAR activity in the setting of in vitro irradiation will serve as a secondary endpoint of this protocol. Changes in PAR, cleaved caspase 3, 𝛾H2AX, and Ki67 in in vitro irradiated and non-irradiated FFPE-embedded tumor tissues will be assessed using immunohistochemistry (IHC) assays in the CLIA-certified PD Core at the Ivy Center. Alternatively, an ELISA assay will be performed using frozen lysates of a second pair of control and irradiated samples to quantify PAR levels.

[0443] Group B:

[0444] Once six participants have been enrolled in Group A (3 in each time cohort) and the optimal time interval (OTI) has been determined, recruitment will begin in Group B. Participants undergoing resection for recurrent WHO grade II, III, or IV glioma (with IDH1 or IDH2 mutations and ATRX loss) will receive niraparib 4 days prior to planned surgical resection. Up to 18 participants will receive niraparib preoperatively, with an expected enrollment of 12 participants during the treatment extension phase. The last dose will be administered OTI prior to surgical specimen collection. After resection, participants with non-histologically confirmed tumor recurrence (e.g., pseudoprogression) will be replaced. Tumor PK and PD analyses will be performed for patients in both time cohorts.

[0445] For PK analysis, blood, CSF, and brain tumor tissue samples (gadolinium-enhanced and non-enhanced) will be collected during surgery. Additional blood samples will be collected on day 1 pre-dose and pre-dose (trough concentrations), day 4 (day of surgery), and 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose.

[0446] For PD analysis, tumor tissue collected intraoperatively will be snap-frozen to assess chromosomal fusions as the primary endpoint. Additional exploratory testing will be performed, including the c-loop assay and immunohistochemistry for MIB-1, Cleaved Caspase-3, and H2AX. If archival or preoperative biopsies are obtained, they will be used for baseline comparison. Additional tumor tissue collected intraoperatively will be cryopreserved for genomic analysis. Additional tumor tissue collected intraoperatively will be cryopreserved for genomic analysis.

[0447] Table 2: Time groups

[0448]

[0449] Pharmacokinetic (PK) methods

[0450] Free niraparib concentration in gadolinium-nonenhancing glioma tissue is a secondary endpoint in arm B of the protocol. Total and free niraparib concentrations will be assessed in each patient's plasma, CSF, and gadolinium-enhancing and gadolinium-nonenhancing areas of the tumor in the IvyCenter's CLIA-certified PK Core. Tumor-to-plasma ratios will be calculated. All assays and analyses will be developed, validated, and performed at the Ivy Brain Tumor Center.

[0451] Pharmacodynamic (PD) methods

[0452] PCR-based quantification of chromosome fusions will serve as the primary endpoint for Arm B of this protocol. gDNA will be extracted from frozen lysates of intraoperative tumor tissue in the CLIA-certified PD Core at the Ivy Center. 25 ng of gDNA will be used for qPCR-based chromosome fusion detection. C-circle assays will be performed as exploratory endpoints. MIB-1, 𝛾H2AX, and Cleaved Caspase-3 will be quantified by immunohistochemistry.

[0453] For recruitment into the extended component of the study, a positive PD response was defined as the presence of a chromosomal fusion with a cutoff Ct value of 35.

[0454] Treatment extension period:

[0455] Group A:

[0456] Patients whose tumors have an unmethylated MGMT promoter and who demonstrate a positive PK response in the Phase 0 component of Arm A (see above) will enter the treatment extension phase of this study. These participants will receive niraparib in combination with radiation therapy (60 Gy over 6-7 weeks, as per standard of care).

[0457] • For patients weighing <77 kg (<170 lb) or with a platelet count <150,000 / mcL, the recommended dose is 200 mg orally once daily.

[0458] • For patients weighing ≥77 kg (≥170 lb) and with a platelet count ≥150,000 / mcL, the recommended dose is 300 mg orally once daily.

[0459] After radiation therapy, study participants can receive maintenance niraparib therapy, which will begin after a 4-week rest period (+7 days) to allow for recovery from radiation therapy plus niraparib treatment. Participants will continue to receive maintenance therapy until disease progression, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or sponsor termination of the study.

[0460] Group B:

[0461] Patients whose tumors demonstrate a positive PD response in the Phase 0 component of Arm B (see above) will enter the expansion component of this study. Participants will receive niraparib until disease progression, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or sponsor termination of the study.

[0462] • For patients weighing <77 kg (<170 lb) or with a platelet count <150,000 / mcL, the recommended dose is 200 mg orally once daily.

[0463] • For patients weighing ≥77 kg (≥170 lb) and with a platelet count ≥150,000 / mcL, the recommended dose is 300 mg orally once daily.

[0464] All participants (Groups A and B) will return to the clinic for safety monitoring according to the event schedule until the end of treatment and then be contacted approximately every 3 months by letter or telephone to collect survival data for up to 24 months. Long-term survival follow-up will begin after completion of the Day 28 safety visit.

[0465] Additional biomarker analysis will be performed using surgical tissue. If a participant undergoes another craniotomy or biopsy due to brain tumor recurrence or progression, the Ivy Brain Tumor Center will request a sample from the resected tumor to allow for longitudinal sample collection and analysis to help identify possible mechanisms of resistance.

[0466] Main Objectives

[0467] 1. Phase 0:

[0468] Group A: To evaluate the relative pharmacokinetics (PK) of niraparib in tumor tissue from participants with glioblastoma who were treated with niraparib.

[0469] Group B: To evaluate the pharmacodynamic (PD) effect of niraparib on tumor tissues of patients with WHO grade 2-4.

[0470] 2. Extension: To examine progression-free survival (6 months) in participants with demonstrated PK (Arm A) and PD (Arm B) effects.

[0471] Primary End Point

[0472] 1. Phase 0:

[0473] Panel A: Total and free niraparib concentrations in Gd-enhanced and Gd-non-enhanced tumor tissues for PK analysis. The partition coefficients of total drug levels (Kp) and free drug levels (Kp,uu) of niraparib in intraoperative tumor (enhancing and non-enhancing tissues) and plasma (collected during surgery) will be evaluated.

[0474] Panel B: For PD analysis, chromosomal fusions were present in niraparib-treated glioma tissues with IDH and ATRX loss.

[0475] 2. Extension: Examining progression-free survival from the time of surgery to the date of recurrence.

[0476] Exploratory goals

[0477] Phase 1.0: Evaluation of other pharmacodynamic (PD) biomarkers of niraparib.

[0478] Phase 2.0: Evaluation of the relative pharmacokinetics (PK) of niraparib in CSF.

[0479] Exploratory End Points

[0480] 1. Phase 0: For Group A: Quantification of γH2AX, ClCas3, and Ki67 positive cells will be summarized in ex vivo irradiated samples.

[0481] For panel B, quantification of c-loop, γH2AX, ClCas3, and Ki67 positive cells will be summarized.

[0482] Phase 2.0: Niraparib levels in the intraoperative CSF (3-5 hours and 8-10 hours) will be determined.

[0483] Study population:

[0484] Group A: patients undergoing planned resection for suspected newly diagnosed glioblastoma.

[0485] Group B: patients with recurrent WHO grade 2-4 gliomas due to IDH mutation and ATRX loss undergoing planned resection.

[0486] Each participant had to meet all of the following inclusion criteria and not meet any of the exclusion criteria to be eligible for the study.

[0487] Inclusion criteria:

[0488] 1. Participants in Group A underwent resection for suspected newly diagnosed glioblastoma. For Group B, participants who underwent resection had previously had histologically diagnosed WHO grade II-IV gliomas (with IDH1 or IDH2 mutations and ATRX loss) resected.

[0489] 2. Participants in Group A must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion with 2 perpendicular measurements of at least 1 cm.

[0490] 3. Able to understand and willing to sign a written informed consent form (in person or by a legally authorized representative, if applicable).

[0491] 4. The participant has voluntarily agreed to participate and has signed a written informed consent form (either in person or by a legally authorized representative who signs and consents, as applicable). Written informed consent for this protocol must be obtained prior to any screening procedure. If consent cannot be expressed in writing, it must be formally documented and witnessed, preferably by an independent credible witness.

[0492] 5. Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other procedures.

[0493] 6. Age ≥ 18 years old at the time of consent

[0494] 7. Performance status (PS) ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al., 1982)

[0495] 8. Ability to swallow oral medications.

[0496] 9. Confirmed negative serum pregnancy test (β-hCG) prior to initiation of study treatment, or participant is no longer of childbearing potential due to surgical, chemical, or natural menopause. If serum pregnancy test is completed more than 7 days after Day 1, perform a urine pregnancy test prior to dosing on Day 1 to confirm the negative result.

[0497] 10. For females of childbearing potential: Use highly effective contraceptive measures for at least 1 month before treatment and agree to use such methods during the study and within 3 months after the end of treatment.

[0498] 11. For males of reproductive potential: Use condoms or other methods to ensure effective contraception with your partner and continue contraception within 3 months after the end of treatment. Avoid sperm donation during the study and within 3 months after the end of treatment.

[0499] 12. Agree to comply with lifestyle considerations throughout the study period.

[0500] 13. Participants receiving chemotherapy must have recovered from the acute effects of chemotherapy (Common Terminology Criteria for Adverse Events [CTCAE] ≤ Grade 1), with the exception of residual alopecia or Grade 2 peripheral neuropathy before Day 1. A washout period of at least 21 days (or longer at the discretion of the investigator) is required between the last chemotherapy and Day 1.

[0501] 14. Females of childbearing potential must agree not to breastfeed from screening, throughout the study, and for 6 months after the last dose of study medication.

[0502] 15. Participants had normotensive or adequately treated and controlled hypertension (defined as systolic blood pressure ≤140 mmHg and diastolic blood pressure ≤90 mmHg).

[0503] 16. Participants have adequate bone marrow and organ function, as defined by the following laboratory values ​​(eligibility will be assessed by local laboratories):

[0504] Adequate bone marrow function:

[0505] Absolute neutrophil count ≥1,500 / mcL

[0506] Platelet count (at the time of surgery) ≥100,000 / mcL

[0507] Hemoglobin ≥ 9.0 g / dL (9.0 g / dL)

[0508] Participants may receive red blood cell transfusions to achieve this hemoglobin level as recommended by the investigator. Initial treatment may not begin earlier than the day after the red blood cell transfusion.

[0509] Adequate liver function:

[0510] Total bilirubin ≤1.5 X ULN. Participants with Gilbert's syndrome and total bilirubin ≤2.0 times ULN and direct bilirubin within the normal range were eligible.

[0511] AST(SGOT) ≤2.5 X Agency ULN

[0512] ALT(SGPT) ≤2.5 X Agency ULN

[0513] Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 30 mL / min / 1.73 m according to the Chronic Disease Epidemiology Collaboration (CKD-EPI) formula 2

[0514] INR ≤1.5 x ULN

[0515] Exclusion criteria:

[0516] 1. Currently using coumarin-derived anticoagulants for treatment, prevention, or other purposes, and cannot be discontinued before surgery. Treatment with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.

[0517] 2. Pregnancy or breastfeeding.

[0518] 3. Known allergic reactions to the ingredients of niraparib tablets (including FD&C Yellow No. 5).

[0519] 4. Active infection or fever >38.5°C requiring systemic antibiotic, antifungal, or antiviral treatment within 4 weeks after day 1.

[0520] 5. Patients are known to have active (acute or chronic) or uncontrolled severe infection, liver disease (such as cirrhosis, decompensated liver disease), and active and chronic hepatitis as determined by the investigator.

[0521] 6. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at the start of study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or known active hepatitis B or hepatitis C [e.g., hepatitis B surface antigen positivity). No screening is required at enrollment.

[0522] 7. Meet any of the following cardiovascular criteria:

[0523] • Current evidence on cardiac ischemia

[0524] • Current symptomatic pulmonary embolism

[0525] • Acute myocardial infarction ≤ 6 months before Day 1

[0526] • New York Heart Association class III or IV heart failure ≤ 6 months before Day 1

[0527] • Grade ≥2 ventricular arrhythmia ≤ 6 months before Day 1

[0528] • Cerebrovascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months before Day 1

[0529] 8. Participants have myelodysplastic syndrome / acute myeloid leukemia or have features suggestive of MDS / AML.

[0530] 9. Participants have severe and / or uncontrolled pre-existing illnesses that, in the investigator's judgment, would preclude their participation in this study (e.g., interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal insufficiency, history of major surgical resection involving the stomach or small intestine, or pre-existing Crohn's disease or ulcerative colitis or pre-existing chronic illness causing baseline grade 2 or higher diarrhea).

[0531] 10. Previously treated with therapeutic doses of PARP inhibitors.

[0532] 11. Receiving treatment with another investigational drug or other intervention within 5 half-lives of the investigational product.

[0533] Phase: Phase 0, treatment extension phase

[0534] Description of the venue / facility where participants will be enrolled:

[0535] Group A: One U.S. site will recruit participants to this study.

[0536] Group B: Two US venues.

[0537] Description of Study Intervention:

[0538] Phase 0:

[0539] • For Group A, niraparib was administered orally once daily for 4 days before surgical resection. The last dose was given on the morning of Day 4 (i.e., 3-5 hours or 8-10 hours before planned resection). For Group B, niraparib was administered orally once daily for 4 days before surgical resection. The last dose was given on the morning of Day 4 (i.e., 3-5 hours or 8-10 hours before planned resection).

[0540] Extensions:

[0541] • Arm A: Participants with a PK-positive, unmethylated MGMT promoter (from period 0): Continuous oral niraparib once daily (7 days per week) plus radiation therapy 5 days per week for 6-7 weeks. The first day of each cycle will be the first day of radiation therapy.

[0542] • Arm B: Participants with positive PD (from Phase 0) will receive niraparib orally once daily, as long as the drug is well tolerated and the investigators believe the participant is likely to benefit. Participants will receive treatment until confirmed progression or end of treatment.

[0543] • Both groups will receive niraparib as follows:

[0544] For patients weighing <77 kg (<170 lbs) or with platelet counts <150,000 / mcL, the recommended dose is 200 mg orally once daily.

[0545] For patients weighing ≥77 kg (≥170 lbs) and with a platelet count ≥150,000 / mcL, the recommended dose is 300 mg orally once daily.

[0546] Maintenance period (Group A):

[0547] Niraparib (continuous administration from days 1 to 28).

[0548] For patients weighing <77 kg (<170 lbs) or with platelet counts <150,000 / mcL, the recommended dose is 200 mg orally once daily.

[0549] For patients weighing ≥77 kg (≥170 lbs) and with a platelet count ≥150,000 / mcL, the recommended dose is 300 mg orally once daily.

[0550] Study duration:

[0551] The total study duration is expected to be approximately 38 months, including 2 months of protocol preparation (including IRB / IND approval), 12 months of trial recruitment (recruiting 24 patients with newly diagnosed unmethylated glioblastoma (Group A) and 18 patients with recurrent glioma (Group B), and 24 months of follow-up of extension phase participants.

[0552] Ivy Brain Tumor Center performs approximately 600 glioma surgeries each year. Approximately 150 of these are newly diagnosed WHO grade IV gliomas. Of the 400 recurrent glioma surgeries performed each year, more than 90% are recurrent WHO grade II-IV gliomas.

[0553] UCSF Medical Center performs approximately 400 glioma surgeries each year. Approximately 100 of these are newly diagnosed WHO grade IV gliomas. Of the 300 recurrent glioma surgeries performed each year, more than 90% are recurrent WHO grade II-IV gliomas.

[0554] Participation duration:

[0555] Phase 0: Up to approximately 2 months (28-day screening window to follow-up on the 28th day).

[0556] Extension (Group A): The maximum duration of treatment is approximately 6 weeks.

[0557] Extension (Arm B): Participants will continue to take niraparib as long as the drug is well tolerated and the investigators believe that the participant may benefit from it. Participants will continue to receive treatment until confirmed disease progression or end of treatment.

[0558] Maintenance therapy (Group A): Participants will continue to take niraparib as long as the drug is well tolerated and the investigators believe that the participant may benefit from it. Participants will continue to receive treatment until confirmed disease progression or end of treatment.

[0559] All participants in Group A will be followed up for survival for up to 24 months.

[0560] All participants in Group B will be followed up for survival for up to 48 months.

[0561] Statistical considerations:

[0562] The primary objective is to conduct an exploratory study to evaluate the PK of niraparib in arm A and the PD of niraparib in arm B and to examine progression-free survival (PFS6) in both arms without formal statistical hypothesis testing. The sample size was determined based on feasibility and previous studies by our group. A maximum of 12 participants will be assigned to each time cohort in arm A and a maximum of 9 participants will be assigned to each time cohort in arm B. The planned sample size for phase 0 is a maximum of 24 patients with newly diagnosed glioblastoma in arm A and 18 patients with recurrent glioma with IDH and ATRX mutations in arm B. The proportion of positive PK responses in each cohort will be reported as the primary endpoint of the phase 0 PK analysis. For comparison of PD biomarkers, ex vivo treated tumor tissues with and without radiation therapy will be examined. Once the percentage of cells positive for individual biomarkers is quantified, the log-transformed percentage of positive cells between treated and untreated tissues will be compared at the two-sided 5% level using paired t-tests. Chi-square tests and normal approximations and corresponding 95% confidence intervals based on the difference in PFS6 proportions will be calculated for extension phase participants. Overall survival between the two treatments will be compared by Kaplan-Meier curve analysis using the log-rank test. Baseline characteristics, including demographics and laboratory measurements, will be summarized using descriptive statistics. Means, medians, minimums, and maximums will be reported for continuous values ​​such as age and laboratory values, and N and % will be reported for categorical values ​​such as sex and performance status.

[0563] Figure 1 The protocols for the Phase 0, Arm A and Arm B studies are summarized.

[0564] Figure 4 The regimen of Group A is further summarized.

[0565] Interim results of Group A

[0566] Methods: Newly diagnosed GBM patients received 4 days of preoperative niraparib (300 mg QD) prior to planned resection (either 3-5 hours or 8-12 hours after last dose). Tumor tissue (enhancing and non-enhancing areas), cerebrospinal fluid (CSF), and plasma were collected. Tumor tissue (enhancing and non-enhancing areas), cerebrospinal fluid (CSF), and plasma were collected. Total and free niraparib concentrations were measured using a validated LC-MS / MS method. A PK "trigger" determined eligibility for a treatment extension period and was defined as free [niraparib] > 5x biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Evidence of PARP inhibition was assessed by quantifying PARylation by irradiating surgical tissue to 10 Gy in vitro compared with non-irradiated control tissue. Patients whose O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors exceed the PK threshold can receive an extended period of niraparib dosing combined with fractionated radiotherapy followed by a maintenance period of niraparib monotherapy.

[0567] Results: Twelve patients were enrolled in the phase 0 study, of which 2 continued into the extension phase. In the phase 0 study, 1 patient experienced a grade 3 treatment-related adverse event (elevated ALT and AST), and in the extension phase, 2 patients experienced treatment-related thrombocytopenia. The mean free concentrations of niraparib in Gd-nonenhanced tumor areas were 340.9 nM and 331.9 nM in the 3-5 hour cohort (n=8) and 8-12 hour cohort (n=3), respectively. All tumors met the PK criteria for the extension phase, with 2 tumors showing unmethylated MGMT. The fold increase in PAR levels after in vitro irradiation was 2.44-fold in nGBM controls (n=4) and 1.71-fold in study patients (n=10) compared with untreated samples, respectively.

[0568] Conclusions: This first-in-human study in patients with newly diagnosed GBM (nGBM) demonstrated that niraparib has brain tumor penetration exceeding that of any other studied PARP inhibitor and concurrent radiosensitization via PAR inhibition.

[0569] Additional interim results for Group A

[0570] Demographics and safety data: Thirty-three patients (45.4% female) participated in the Phase 0 cohort A, and 12 patients entered the extension phase. The demographics and safety data of the patients are summarized in Figure 5 In the Phase 0 portion of the trial, the median age (range) of patients in Group A was 60 years (21-85 years) and the median ECOG (range) at baseline was 1 (0-2).

[0571] Results: Figure 7As shown, the mean free concentrations of niraparib in the Gd non-enhancing tumor areas of cohort 1 patients at 3-5 hours were 250.8 nM and 366.2 nM in patients dosed with 200 mg (n = 6) and 300 mg (n = 20), respectively. Figure 7 As shown, the mean free concentration of niraparib in Gd non-enhancing tumor areas in cohort 2 patients at 8-12 hours was 331.9 nM in 300 mg dose patients (n = 3). These free niraparib concentrations are much higher than the IC 50 (i.e. 19 nM). Figure 8 As shown in Figure 2, the total tumor:plasma (Kp) ratios of niraparib in non-enhancing and enhancing tissues were 4.274 and 7.887, respectively. Figure 8 As shown in Figure 2, the free tumor:plasma ratios (Kp, uu) in non-enhancing and enhancing tissues were 0.8 and 1.8, respectively. Fig. 9 As shown, the fold increase in PAR levels after in vitro irradiation was more than 2.5 in nGBM controls and less than 1.5 in the study patients compared with untreated samples. Three or four days of niraparib exposure inhibited the induction of post-irradiation poly(ADP-ribose) (PAR) levels in in vitro newly diagnosed and recurrent GBM tissues. Fig.10 Clinical outcomes of patients with MGMT-unmethylated PK responders were summarized. MGMT-unmethylated PK responders received niraparib in addition to radiation therapy. Of the six patients followed up for ≥6 months, four were in remission and two experienced tumor recurrence.

[0572] Conclusions: Niraparib was generally well tolerated in patients with newly diagnosed and recurrent glioblastoma. Niraparib achieved pharmacologically relevant concentrations in newly diagnosed and recurrent glioblastoma tissues without enhancement at 200 mg and 300 mg doses. Three or four days of niraparib exposure inhibited the induction of PAR levels after radiation in newly diagnosed and recurrent glioblastoma tissues in vitro.

[0573] Further interim results of Group A

[0574] Materials / Methods: Patients with presumed newly diagnosed GBM were enrolled in a Phase 0 study and treated with niraparib (300 or 200 mg QD) for 4 days prior to planned resection (either 3-5 hours or 8-12 hours after the last dose). Tumor tissue (enhancing and non-enhancing areas), cerebrospinal fluid (CSF), and plasma were collected. Total and free niraparib concentrations were measured using a validated LC-MS / MS method. PARP inhibition was assessed by quantifying PAR induction after 10 Gy in vitro irradiation of surgical tissue compared with non-irradiated control tissue. A PK “trigger” determined eligibility for the therapeutic Phase 2 extension portion of the study. This was defined as free [niraparib] >5 times the biochemical IC50 (i.e., 19 nM) in non-enhancing tumors. Patients with MGMT-unmethylated tumors who exceeded this PK threshold were eligible for an extension phase of niraparib dosing with concurrent radiation therapy followed by a niraparib maintenance phase. Patients with MGMT-methylated tumors were not eligible for the extended phase and therefore continued with temozolomide (TMZ) combined with radiotherapy followed by TMZ maintenance therapy. Radiotherapy was delivered at a dose of 60 Gy in 30 fractions using volumetric modulated arc therapy (VMAT).

[0575] Results: All 29 patients who participated in the Phase 0 portion of the study reached the PK threshold. The free concentration of niraparib was much higher than the IC 50 . The mean free concentration of niraparib was 258.2 nM in non-enhancing areas. Suppression of PAR levels was observed in 79% of patients (17 / 22) after external beam radiation. Sixteen patients had unmethylated tumors, 11 of whom participated in the phase 2 study. Five of the six initial patients participating in the phase 2 study developed niraparib-related thrombocytopenia, of which three of five cases were considered severe and life-threatening. Therefore, the starting dose was reduced to 200 mg in both phases, and no serious adverse reactions were observed thereafter. The median follow-up was 8.1 months [range: 6.0-12.9 months], with a PFS6 of 64%, of which four patients are still receiving treatment and five patients are still in survival follow-up.

[0576] Conclusions: Niraparib achieved pharmacologically relevant concentrations in nonenhancing newly diagnosed glioblastoma tissue. When given concurrently with radiotherapy, niraparib was well tolerated with a low incidence of grade ≥ 3 toxicity. Preliminary clinical efficacy data are encouraging.

[0577] Example 2. Study of brain penetration of GSK3985771C (niraparib) in P-gp (P-glycoprotein / mdr1-a) and BCRP (breast cancer resistance protein / ABCG2) rat gene knockout models

[0578] method:

[0579] At least three days before the start of the study, six male rats per group (24 rats in total) received surgically implanted femoral vein and carotid artery catheters for infusion of the test molecule and blood collection. The doses were filtered before dosing, and the actual doses given to the animals were quantified. All PK parameters were calculated based on the actual doses given to each animal. Animals received an intravenous bolus loading dose followed by a constant intravenous infusion to maintain steady-state drug levels. At the end of the infusion, the animals were euthanized and brain tissue was collected. Tissue homogenates were prepared in PBS (1:4 w / v). Drug concentrations were quantified using an LC-MS / MS method. Tissue homogenate concentrations were corrected for the test compound contained in residual plasma in the tissue. The tissue to plasma ratio was calculated by dividing the corrected tissue concentration by the steady-state plasma concentration. In vitro protein binding of niraparib in rat plasma and brain tissue homogenates was evaluated by rapid equilibrium dialysis. Data are reported as free fraction (Fu). The protocol is summarized in Figure 2 middle.

[0580] in conclusion:

[0581] The plasma concentrations of niraparib were almost similar in all four groups tested. The penetration of niraparib in brain tissue of control rats was almost half that of niraparib in plasma. The brain tissue concentrations increased by 9-fold and 14-fold in Mdr1-a (P-gp) knockout rats and Pgp / BCRP double knockout rats, respectively, while the brain tissue concentrations increased by less than 2-fold in BCRP knockout rats. The brain: plasma (Kp) ratios in the control, P-gp knockout, BCRP knockout, and P-gp / BCRP double knockout rat models were 0.47, 3.7, 0.64, and 6.3, respectively. The free fractions of niraparib in rat plasma and brain were 0.17 and 0.04, respectively. The free brain: plasma ratios (Kp, uu) in the control, P-gp knockout, BCRP knockout, and P-gp / BCRP double knockout rat models were 0.1, 0.87, 0.15, and 1.5, respectively. Although P-gp plays a role in limiting niraparib penetration into the brain, the brain exposure of niraparib in control rats with fully functional P-gp and BCRP appears to indicate that niraparib has favorable properties as a potential therapeutic agent for the treatment of brain tumors. These results are summarized in Figure 3 middle.

[0582] Example 3. Comparison of brain permeability of niraparib and olaparib in a mouse brain metastasis model

[0583] There remains an unmet need to provide effective treatment options for patients with primary and metastatic brain tumors; this is primarily due to the inability of drugs to penetrate the blood-brain barrier (BBB). Synthetic lethality remains an attractive mechanism for treating brain tumors after radiotherapy. This study evaluated the brain penetration and distribution of niraparib and olaparib in a mouse brain tumor model.

[0584] Female mice (CrTac:NCr-Foxn1nu; 6 w / o) received 2.5E5 luciferase-transfected human breast cancer cell line (MDA 231-BRM2-831) by intracardiac injection. Mice were imaged twice weekly to monitor tumor growth using bioluminescence imaging (BLI). On day 35, mice with brain metastases (BM) were treated once daily with niraparib (35 mg / kg, n=4 BM, n=3 control), olaparib (50 mg / kg, n=3 BM, n=3 control), or vehicle (n=3 control) by oral gavage for 5 days. Terminal blood and brain samples were collected 2 hours after the last dose. Serial tissue sections were collected from 5 different levels of the brain for MALDI-IMS, H&E, and IHC staining. Tissues collected between each imaging plane were homogenized for LC-MS bioanalysis.

[0585] In vivo BLI imaging was used to identify mice with brain metastases (BM), and IHC was used ex vivo to confirm the presence of tumors throughout the brain. Quantitative ex vivo imaging analysis of coronal brain sections collected from mice treated with niraparib by MALDI IMS showed consistent niraparib concentration distribution throughout the brain parenchyma, with localized higher concentrations detected in tumor regions. Table 3 summarizes LC-MS bioanalytical concentrations in plasma and bulk brain homogenates and brain section concentrations detected by MALDI IMS. The estimated mean free brain-to-plasma partition coefficient (Kp, uu, brain) of niraparib was 3.0-fold and 5.6-fold higher than that of olaparib in control and BM mice, respectively.

[0586] These results suggest that niraparib has higher brain penetration than olaparib in both control and BM mice.

[0587] Table 3 Summary of LC-MS bioanalysis and MALDI IMS quantification results

[0588]

[0589] - Values ​​are total concentrations, values ​​in brackets are adjusted free concentrations

[0590] -K p, uu 大脑 Calculated using bulk brain homogenate and terminal plasma free concentrations

[0591] Example 4. Differences in brain penetration of niraparib and olaparib in healthy rhesus monkeys

[0592] There remains an unmet need to provide effective treatment options for patients with primary and metastatic brain tumors; this is primarily due to the inability of drugs to penetrate the blood-brain barrier (BBB). Synthetic lethality remains an attractive mechanism for treating brain tumors after radiotherapy. This study investigated the brain penetration of niraparib and olaparib in healthy monkeys to provide evidence that niraparib is able to penetrate the blood-brain barrier (BBB).

[0593] Four healthy male rhesus monkeys were dosed with niraparib (n=2; 6 mg / kg) or olaparib (n=2; 10 mg / kg) daily by oral gavage for 5 days. Predose blood was collected daily, and terminal blood, cerebrospinal fluid (CSF), and brain tissue were collected at necropsy. Coronal brain sections were analyzed by matrix-assisted laser desorption / ionization (MALDI) imaging mass spectrometry (IMS) to quantitatively assess tissue distribution of the administered compounds. Blood, CSF, and bulk brain homogenates were analyzed by LC-MS bioassay.

[0594] As shown in Table 4, niraparib had greater brain penetration than olaparib after five days of oral administration in healthy rhesus monkeys. The free brain to plasma partition coefficient (Kp, uu, brain) of niraparib was 15 times higher than that of olaparib. Quantitative ex vivo imaging analysis of coronal brain sections collected from monkeys administered niraparib by MALDI IMS showed consistent niraparib concentration distribution throughout the brain parenchyma. Olaparib was not detected in any coronal brain sections collected from monkeys administered olaparib by MALDI IMS. Similar plasma and CSF concentrations were observed between monkeys administered niraparib and monkeys administered olaparib, highlighting the unique ability of niraparib to cross the intact blood-brain barrier in monkeys and distribute throughout the brain.

[0595] In healthy rhesus monkeys, brain penetration of niraparib was significantly higher than that of olaparib, indicating an enhanced ability of niraparib to cross an intact blood-brain barrier.

[0596] Table 4 Summary of LC-MS bioanalysis and MALDI IMS quantification results

[0597]

[0598] - Values ​​are total concentrations, values ​​in brackets are adjusted free concentrations

[0599] -K p, uu 大脑 Calculated using bulk brain homogenate and terminal plasma free concentrations

[0600] Equivalent

[0601] Unless expressly indicated to the contrary, the articles "a" and "an" as used herein in the specification and claims should be understood to include plural referents. If one, more than one, or all of the group members are present in a given product or process, used in a given product or process, or otherwise related to a given product or process, a statement or description including "or" between one or more members of the group is deemed to be satisfied, unless otherwise indicated to the contrary or obvious from the context. The present invention includes embodiments in which an exact member of the group is present in, applied to, or otherwise related to a given product or method. The present invention also includes embodiments in which more than one group member or all group members are present in, applied to, or otherwise related to a given product or method. In addition, it should be understood that the present invention includes all variations, combinations, and substitutions in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim (or any other claim related thereto) that is subordinate to the same base claim, unless otherwise indicated or unless it is obvious to a person of ordinary skill in the art that a contradiction or inconsistency would result. When elements are presented as a list (e.g., in Markush groups or similar formats), it should be understood that each subgroup of the elements is also disclosed, and any element can be removed from the group. It should be understood that, in general, when the present invention or aspects of the present invention are referred to as comprising specific elements, features, etc., certain embodiments of the present invention or aspects of the present invention are composed of such elements, features, etc. or are essentially composed of them. For the purpose of simplification, these embodiments are not specifically described in each case with so many words stated herein. It should be understood that any embodiment or aspect of the present invention can be explicitly excluded from the claims, regardless of whether such specific exclusions are described in the specification. Publications, websites and other reference materials cited herein that describe the background of the present invention and provide additional details about its practice are incorporated herein by reference.

Claims

1. A method for treating primary or metastatic brain cancer in a human subject in need thereof, the method comprising administering to the human subject an effective amount of niraparib or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the human subject is also treated with radiotherapy, in particular stereotactic radiotherapy.

3. The method according to claim 1 or 2, wherein the primary brain cancer or metastatic brain cancer is newly diagnosed.

4. The method according to claim 2 or 3, wherein administration of niraparib or a pharmaceutically acceptable salt thereof and radiation therapy is initiated after resection of the primary brain cancer tumor.

5. The method according to any one of claims 2 to 4, wherein the radiation therapy is about 60 Gy (unit gray).

6. The method according to any one of claims 2 to 4, wherein the radiation therapy is about 10 Gy (unit gray).

7. The method according to any one of claims 2-6, wherein the niraparib or a pharmaceutically acceptable salt thereof and radiation therapy are administered for about 6-7 weeks.

8. The method according to any one of claims 2 to 7, wherein the human subject further receives maintenance treatment with niraparib or a pharmaceutically acceptable salt thereof without receiving radiation therapy after treatment with niraparib and radiation therapy.

9. The method according to any one of claims 1 to 8, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to 200 mg or 300 mg of niraparib free base.

10. The method according to any one of claims 1 to 9, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in the form of niraparib mesylate monohydrate.

11. The method according to any one of claims 1 to 10, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

12. The method according to any one of claims 1-11, wherein the dose of niraparib or a pharmaceutically acceptable salt thereof is administered daily.

13. The method according to any one of claims 1-12, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 300 mg of niraparib free base.

14. The method according to any one of claims 1-12, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 200 mg of niraparib free base.

15. The method according to any one of claims 1 to 14, wherein the primary brain cancer is selected from the group consisting of anaplastic astrocytoma, glioblastoma, glioblastoma multiforme, meningioma, pituitary carcinoma, schwannoma, oligodendroglioma, ependymoma, medulloblastoma, astrocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+) ATRX mutant glioma, malignant glioma and primitive neuroectodermal tumor of the brain.

16. The method according to any one of claims 1 to 15, wherein the primary brain cancer is a WHO grade IV tumor.

17. The method according to claim 16, wherein the primary brain cancer is glioblastoma.

18. The method according to any one of claims 1-17, wherein the human subject exhibits a free concentration of niraparib in brain cancer tumor tissue that is > 5 times the biochemical IC50 value of niraparib.

19. The method according to any one of claims 1-18, wherein the human subject exhibits a free concentration of niraparib in non-enhancing or enhancing tumor tissue of brain cancer that is > 5 times the biochemical IC50 value of niraparib.

20. The method according to claim 19, wherein the free concentration of niraparib in non-enhancing or enhancing tumor tissue of brain cancer is measured after preoperative niraparib treatment.

21. The method according to any one of claims 1-20, wherein the human subject exhibits a free concentration of niraparib in gadolinium-non-enhancing areas of a brain cancer tumor that is >5 times the biochemical IC50 value of niraparib.

22. The method according to any one of claims 18 to 21, wherein the free concentration of niraparib in the tumor tissue is measured after resection.

23. The method according to claim 21, wherein following preoperative niraparib (300 mg QD) treatment 4 days prior to a planned resection, the free concentration of niraparib in gadolinium-non-enhancing areas of a brain cancer tumor is measured 3-5 hours or 8-12 hours after the last dose.

24. The method according to claim 21, wherein following preoperative niraparib (200 mg QD) treatment 4 days prior to a planned resection, the free concentration of niraparib in gadolinium-non-enhancing areas of a brain cancer tumor is measured 3-5 hours or 8-12 hours after the last dose.

25. The method according to any one of claims 18 to 24, wherein the free concentration of niraparib is measured in a brain tumor tissue sample collected during surgery.

26. The method according to any one of claims 18-25, wherein the 5-fold biochemical IC50 value of niraparib is 19 nM.

27. The method according to any one of claims 1-26, wherein the brain / plasma ratio of niraparib is about 0.

5.

28. The method according to any one of claims 1-27, wherein the niraparib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents known to be useful for treating cancer.

29. The method according to claim 28, wherein the one or more additional active agents is temozolomide, bevacizumab, or a combination thereof.

30. The method according to any one of claims 1-29, wherein the human subject or cancer is in complete or partial response to platinum-based chemotherapy.

31. The method according to any one of claims 1-30, wherein the cancer is not sensitive to platinum.

32. The method according to any one of claims 1-30, wherein the cancer is platinum sensitive.

33. The method according to any one of claims 1-32, wherein the cancer is homologous recombination deficiency (HRD) negative.

34. The method according to any one of claims 1-33, wherein the metastatic brain cancer has spread from a primary site of lung cancer, breast cancer, colon cancer, kidney cancer or melanoma.

35. The method according to any one of claims 1 to 34, comprising administering niraparib or a pharmaceutically acceptable salt thereof to a patient who has previously been treated with at least one PARP inhibitor other than niraparib, or a pharmaceutically acceptable salt thereof.

36. The method according to claim 35, wherein the at least one PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof is selected from olaparib, pamiparib, rucaparib and talazoparib and pharmaceutically acceptable salts thereof.

37. The method according to claim 36, wherein the at least one PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof is olaparib or a pharmaceutically acceptable salt thereof.

Images