Use of Niraparib for the Treatment of Brain Cancer

Abstract

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

Description

[Technical field]

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

[0002] Cancer is a serious public health problem. An estimated 308,102 people worldwide were diagnosed with primary brain or spinal cord tumors in 2020. The 5-year survival rate for people with cancerous brain or CNS tumors in the United States is approximately 36% (Cancer Facts & Figures 2022, ACS website), and 609,640 people died from cancer in the United States in 2018 alone. American Cancer Society, Cancer Facts & Figures 2018 (available on the American Cancer Society website). Thus, there remains a need for effective therapies to treat cancer patients, including those with primary and metastatic brain cancer. Summary of the Invention

[0003] The present disclosure relates to a method of treating primary or metastatic brain cancer in a human subject in need thereof, comprising administering to the human subject an effective dose of niraparib, or a pharmaceutically acceptable salt thereof.

[0004] The disclosure further provides niraparib, or a pharma- ceutically acceptable salt thereof, for use in treating primary or metastatic brain cancer in a human subject in need thereof.

[0005] The disclosure further provides niraparib, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of primary or metastatic brain cancer in a human subject in need thereof. [Brief description of the drawings]

[0006] [Figure 1] Figure 1 outlines the phase 0 clinical protocol of niraparib in newly diagnosed glioblastoma (HGG, high grade glioma) and recurrent IDH1 / 2+ATRX (WHO II-IV gliomas). [Diagram 2] FIG. 2 outlines the protocol for quantifying the effect of P-gp and BCRP in limiting CNS permeability of niraparib. [Diagram 3] FIG. 3 summarizes the results quantifying the effects of P-gp and BCRP in limiting the CNS penetration of niraparib. [Figure 4] Figure 4 outlines the clinical protocol for arm A of niraparib in newly diagnosed glioblastoma (HGG, high-grade glioma). [Diagram 5] Figure 5 provides an overview of patient demographics and patient safety profile of the phase 0 and expansion study of arm A of niraparib in newly diagnosed glioblastoma (HGG, high-grade glioma). [Figure 6] FIG. 6 shows an overview of unbound niraparib levels in non-enhancing tumor tissue in cohorts 1 and 2 of arm A. [Figure 7] FIG. 7 shows an overview of unbound niraparib levels in non-enhancing tumor tissue in cohorts 1 and 2 of arm A, with mean values ​​for the 300 mg and 200 mg doses for cohort 1 and the 300 mg dose for cohort 2. [Figure 8] FIG. 8 shows the total and unbound tumor / plasma ratios for cohorts 1 and 2 of niraparib arm A in non-enhancing and enhancing tumor tissues. [Figure 9] FIG. 9 shows functional pharmacodynamic data of niraparib including PAR levels following ex vivo radiation compared to untreated samples. [Figure 10] Figure 10 provides an overview of clinical outcomes in newly diagnosed glioblastoma, with median PFS shown in months. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] The present disclosure relates, inter alia, to a method of treating brain cancer in a human subject in need thereof, comprising administering to the human subject an effective dose of niraparib, or a pharma- ceutically acceptable salt thereof.

[0008] The present disclosure further relates, inter alia, to a method of treating primary or metastatic brain cancer in a human subject in need thereof, comprising administering to the human subject an effective dose of niraparib, or a pharma- ceutically acceptable salt thereof.

[0009] The present disclosure further relates to a method of treating central nervous system (CNS) cancer in a human subject in need thereof, comprising administering to the human subject an effective dose of niraparib, or a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, the method of treating brain cancer in a human subject in need thereof comprises: (i) administering to a human subject an effective dose of niraparib or a pharma- ceutical acceptable salt thereof; (ii) a step of resection of the brain cancer / tumor; (iii) determining the concentration of niraparib in the brain cancer / tumor; (iv) if sufficient niraparib is determined to be present in step (iii), administering niraparib or a pharma- ceutically acceptable salt thereof; (v) optionally further administering niraparib or a pharma- ceutically acceptable salt thereof as a maintenance treatment; Includes.

[0011] In some embodiments, the human subject is treated with niraparib, or a pharma- ceutically acceptable salt thereof, in step (i) for 4 days.

[0012] In some embodiments, sufficient niraparib is present in step (iii) at a concentration of unbound niraparib that is greater than 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.

[0013] In some embodiments, the human subject is also treated with radiation therapy, particularly stereotactic radiation therapy, in step (iv). In some embodiments, the administration of niraparib or a pharmaceutically acceptable salt thereof and radiation therapy are performed for about 6 to about 7 weeks. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an add-on therapy to radiation therapy in the treatment of brain cancer. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an add-on therapy to radiation therapy in the treatment of unmethylated MGMT glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an add-on therapy to radiation therapy in the treatment of unmethylated MGMT glioblastoma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an add-on therapy to radiation therapy in the treatment of unmethylated glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an add-on therapy to radiation therapy in the treatment of unmethylated glioblastoma.

[0014] In some embodiments, the human subject further receives, following treatment with niraparib or a pharma- ceutical acceptable salt thereof and radiation therapy in step (iv), a maintenance treatment of niraparib or a pharma- ceutical acceptable salt thereof without radiation therapy in step (v).

[0015] In some embodiments, the human subject is also treated with radiation therapy, in particular stereotactic radiotherapy. In some embodiments, radiation therapy may include, but is not limited to, one or more of the following: External beam radiation therapy delivers radiation from a machine into the body to reach metastatic tumors. · Whole brain radiation targets the entire brain to hit multiple tumors or any metastatic disease not seen on an MRI scan. Stereotactic radiosurgery (e.g., CyberKnife) directs high doses of radiation to target specific shapes of tumors, avoiding unnecessary radiation exposure to surrounding healthy tissue. Proton therapy uses protons (instead of x-rays) to treat metastatic brain tumors. Like stereotactic radiosurgery, proton therapy minimizes harm to healthy tissue surrounding the tumor. · Brachytherapy is the implantation of radioactive material into the tumor to prevent further growth.

[0016] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of brain cancer. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated MGMT glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated MGMT glioblastoma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated glioblastoma.

[0017] In some embodiments, the brain cancer is a primary brain cancer or a metastatic brain cancer. In some embodiments, the primary brain cancer or the 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.

[0018] In some embodiments, the human subject is treated with niraparib or a pharma- ceutically acceptable salt thereof pre-surgery. In some embodiments, the human subject is treated with niraparib or a pharma- ceutically acceptable salt thereof pre-surgery prior to surgical resection. In some embodiments, the human subject is treated with niraparib or a pharma- ceutically acceptable salt thereof pre-surgery prior to surgical resection, and the concentration of niraparib in the brain cancer tumor is measured after resection. In some embodiments, the human subject is treated with niraparib or a pharma- ceutically acceptable salt thereof pre-surgery for 4 days prior to surgical resection. In some embodiments, the final presurgical dose is administered 3-5 hours or 8-10 hours prior to tumor resection.

[0019] In some embodiments, the brain cancer is a primary brain cancer.

[0020] In some embodiments, the brain cancer is glioma.

[0021] In some embodiments, the brain cancer is high-grade glioma.

[0022] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0023] In some embodiments, the brain cancer is unmethylated glioma. In some embodiments, the brain cancer is unmethylated glioblastoma.

[0024] In some embodiments, administration of niraparib or a pharmaceutically acceptable salt thereof and administration of radiation therapy are initiated after resection of primary brain cancer tumor. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of brain cancer. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated MGMT glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated MGMT glioblastoma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated glioblastoma.

[0025] In some embodiments, the radiation therapy is about 60 Gy (Gy). In some embodiments, the radiation therapy is about 10 Gy (Gy).

[0026] In some embodiments, the administration of niraparib or a pharma- ceutically acceptable salt thereof and radiation therapy is carried out for about 6 to about 7 weeks.

[0027] In some embodiments, the human subject further receives a maintenance treatment of niraparib or a pharma- ceutically acceptable salt thereof without radiation therapy after treatment with niraparib, or a pharma- ceutically acceptable salt thereof, and radiation therapy.

[0028] In some embodiments, the human subject further receives treatment with niraparib, or a pharma- ceutically acceptable salt thereof, and radiation therapy, followed by maintenance treatment of niraparib, or a pharma- ceutically acceptable salt thereof, without radiation therapy.

[0029] In some embodiments, the human subject further receives treatment with niraparib, or a pharma- ceutically acceptable salt thereof, and radiation therapy, followed by maintenance treatment with niraparib, or a pharma- ceutically acceptable salt thereof, without radiation therapy until disease progression occurs.

[0030] In some embodiments, the human subject further receives a maintenance treatment of niraparib or a pharma- ceutically acceptable salt thereof without radiation therapy about 4 weeks after treatment with niraparib or a pharma- ceutically acceptable salt thereof and radiation therapy.

[0031] In some embodiments, administration of niraparib or a pharma- ceutically acceptable salt thereof follows a preceding therapy. In some embodiments, administration of niraparib or a pharma- ceutically acceptable salt thereof does not follow a preceding therapy. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered as an add-on therapy to radiation therapy.

[0032] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to 200mg or 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 300mg 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 per day. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to 200mg or 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 200mg of niraparib free base.

[0033] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered as niraparib tosylate monohydrate.

[0034] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered in the form of a tablet.

[0035] In some embodiments, a dose of niraparib or a pharma- ceutically acceptable salt thereof is administered daily.

[0036] 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 / rhabdomyosarcoma, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+)ATRX mutant glioma, malignant glioma, and primitive neuroectodermal tumor of the brain.

[0037] In some embodiments, the primary brain cancer is a WHO grade IV tumor.

[0038] 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.

[0039] In some embodiments, glioblastoma is recurrent glioblastoma.In some embodiments, glioblastoma is newly diagnosed glioblastoma.In some embodiments, newly diagnosed glioblastoma or recurrent glioblastoma is associated with IDH mutation and ATRX deficiency.In some embodiments, glioblastoma is primary glioblastoma.

[0040] In some embodiments, the human subject has a newly diagnosed 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.

[0041] 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.

[0042] 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 codeletion), or a glioblastoma (IDH wild type).

[0043] In some embodiments, the glioma is a pediatric diffuse low-grade glioma. In some embodiments, the pediatric diffuse low-grade glioma is selected from diffuse astrocytoma (MYB or MYBL1 altered), angiocentric glioma, young polymorphic low-grade neuroepithelial tumor, or diffuse low-grade glioma (MAPK pathway altered).

[0044] 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 modified), diffuse hemispheric glioma (H3 G34 mutant), diffuse high-grade glioma (H3 wild type and IDH wild type) or infantile hemispheric glioma.

[0045] In some embodiments, the glioma is a circumscribed astrocytic glioma. In some embodiments, the circumscribed astrocytic glioma is selected from pilocytic astrocytoma, high-grade astrocytoma with ciliary characteristics, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordomatoid glioma, or astroblastoma (MN1-altered).

[0046] In some embodiments, the glioma is an advanced 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.

[0047] In some embodiments, the human subject has recurrent high-grade glioma and a DNA damage repair deficiency.

[0048] 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.

[0049] 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.

[0050] In some embodiments, the human subject exhibits an unbound niraparib concentration in brain cancer tumor tissue that is greater than 5 times the biochemical IC50 value of niraparib. In some embodiments, the human subject exhibits an unbound niraparib concentration in brain cancer non-enhanced or enhanced tumor tissue that is greater than 5 times the biochemical IC50 value of niraparib. In some embodiments, the human subject exhibits an unbound niraparib concentration in brain cancer non-enhanced tumor tissue that is greater than 5 times the biochemical IC50 value of niraparib. In some embodiments, the human subject exhibits an unbound niraparib concentration in brain cancer enhanced tumor tissue that is greater than 5 times the biochemical IC50 value of niraparib. In some embodiments, the unbound niraparib concentration in brain cancer non-enhanced or enhanced tumor tissue is measured after pre-surgery niraparib treatment. In some embodiments, the unbound niraparib concentration in tumor tissue is measured after resection. In some embodiments, the unbound niraparib concentration is measured in brain tumor tissue samples taken during surgery. In some embodiments, the human subject exhibits an unbound niraparib concentration in the non-gadolinium enhancing regions of the brain cancer tumor that is greater than 5-fold the biochemical IC50 value of niraparib. In some embodiments, the unbound niraparib concentration in the non-gadolinium enhancing regions of the brain cancer tumor is measured after 4 days of pre-surgical niraparib (300 mg QD) treatment, 3-5 hours or 8-12 hours after the last dose, prior to scheduled resection. In some embodiments, the unbound niraparib concentration in the non-gadolinium enhancing regions of the brain cancer tumor is measured after 4 days of pre-surgical niraparib (200 mg QD) treatment, 3-5 hours or 8-12 hours after the last dose, prior to scheduled resection. In some embodiments, the unbound niraparib concentration is measured in brain tumor tissue samples taken during surgery.

[0051] In some embodiments, five times the biochemical IC50 value of Niraparib is 19 nM. In some embodiments, five times the biochemical IC50 value of Niraparib is about 19 nM.

[0052] 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-enhancing tumor tissue. In some embodiments, the tumor / plasma ratio is measured in enhancing tumor tissue. In some embodiments, the tumor / plasma ratio of Niraparib is about 4 in non-enhancing tumor tissue. In some embodiments, the tumor / plasma ratio of Niraparib is about 8 in enhancing tumor tissue.

[0053] In some embodiments, niraparib, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional active agents known to be useful in the treatment of cancer.

[0054] 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 pharma- ceutically acceptable salt thereof, or a combination thereof.

[0055] In some embodiments, the one or more additional active agents is temozolomide.

[0056] In some embodiments, the one or more additional active agents is atezolizumab. In some embodiments, the one or more additional active agents comprises atezolizumab or a pharma- ceutically acceptable salt thereof.

[0057] In some embodiments, the one or more additional active agents is pembrolizumab. In some embodiments, the one or more additional active agents comprises pembrolizumab or a pharma- ceutically acceptable salt thereof.

[0058] In some embodiments, the one or more additional active agents is toborafenib. In some embodiments, the one or more additional active agents comprises toborafenib or a pharma- ceutically acceptable salt thereof.

[0059] In some embodiments, the one or more additional active agents is dostarlimab. In some embodiments, the one or more additional active agents comprises dostarlimab or a pharma- ceutically acceptable salt thereof.

[0060] In some embodiments, the human subject or cancer has a complete or partial response to platinum-based chemotherapy.

[0061] In some embodiments, the cancer is platinum-insensitive.

[0062] In some embodiments, the cancer is platinum-sensitive.

[0063] In some embodiments, the cancer is homologous recombination deficient (HRD) negative.

[0064] In some embodiments, the patient is characterized as having a deleterious or suspected deleterious mutation in BRCA1 and / or BRCA2.

[0065] In some embodiments, the primary or metastatic brain cancer is recurrent.

[0066] In some embodiments, the cancer is brain cancer.

[0067] In some embodiments, the brain cancer is a primary brain cancer.

[0068] In some embodiments, the brain cancer is glioma.

[0069] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0070] In some embodiments, the brain cancer is unmethylated glioma. In some embodiments, the brain cancer is unmethylated glioblastoma.

[0071] In some embodiments, niraparib administration is initiated following resection of the metastatic brain cancer tumor.

[0072] In some embodiments, niraparib, or a pharma- ceutically acceptable salt thereof, is administered as a maintenance therapy.

[0073] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to 200mg or 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 300mg 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 per day. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to 200mg or 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 200mg of niraparib free base.

[0074] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered as niraparib tosylate monohydrate.

[0075] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered in the form of a tablet.

[0076] In some embodiments, a dose of niraparib or a pharma- ceutically acceptable salt thereof is administered daily.

[0077] In some embodiments, the primary recurrent 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 / rhabdomyosarcoma, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+)ATRX mutant glioma, malignant glioma, and primitive neuroectodermal tumor of the brain.

[0078] In some embodiments, the primary recurrent brain cancer is a WHO grade II-IV tumor.

[0079] In some embodiments, the primary recurrent brain cancer is an IDH1 / 2(+)ATRX mutant glioma.

[0080] In some embodiments, the cancer is brain cancer.

[0081] In some embodiments, the brain cancer is a primary brain cancer.

[0082] In some embodiments, the brain cancer is glioma.

[0083] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0084] In some embodiments, the brain cancer is unmethylated glioma. In some embodiments, the brain cancer is unmethylated glioblastoma.

[0085] In some embodiments, human subjects exhibit chromosomal fusions in a C-circle assay with a cutoff Ct value of 35. In some embodiments, chromosomal fusions in the C-circle assay are measured after 4 days of pre-surgery niraparib (300 mg QD) treatment, prior to planned resection, 3-5 hours or 8-12 hours after the last dose.

[0086] In some embodiments, the brain / plasma ratio of niraparib is about 0.5.

[0087] In some embodiments, niraparib, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional active agents known to be useful in the treatment of cancer.

[0088] 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 pharma- ceutically acceptable salt thereof, or a combination thereof.

[0089] In some embodiments, the one or more additional active agents is temozolomide. In some embodiments, the one or more additional active agents comprises temozolomide or a pharma- ceutically acceptable salt thereof.

[0090] In some embodiments, the one or more additional active agents is atezolizumab. In some embodiments, the one or more additional active agents comprises atezolizumab or a pharma- ceutically acceptable salt thereof.

[0091] In some embodiments, the one or more additional active agents is pembrolizumab. In some embodiments, the one or more additional active agents comprises pembrolizumab or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, the one or more additional active agents is toborafenib. In some embodiments, the one or more additional active agents comprises toborafenib or a pharma- ceutically acceptable salt thereof.

[0093] In some embodiments, the one or more additional active agents is dostarlimab. In some embodiments, the one or more additional active agents comprises dostarlimab or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, the human subject or cancer has a complete or partial response to platinum-based chemotherapy.

[0095] In some embodiments, the cancer is platinum-insensitive.

[0096] In some embodiments, the cancer is platinum-sensitive.

[0097] In some embodiments, the cancer is homologous recombination deficient (HRD) negative.

[0098] In some embodiments, the human subject or cancer is not tested for homologous recombination deficiency (HRD) status prior to administration of niraparib or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the human subject or cancer is not tested for BRCA1 and / or BRCA2 mutations prior to administration of niraparib or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the cancer is brain cancer.

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

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

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

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

[0105] In some embodiments, the metastatic brain cancer has spread from its site of origin in the lung, breast, colon, kidney, and melanoma.

[0106] In some embodiments, the metastatic brain cancer is asymptomatic or is an active, progressive brain metastasis.

[0107] 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.

[0108] In some embodiments, the metastatic brain cancer is caused by a breast cancer selected from a solid tumor, ductal carcinoma in situ (DCIS, ductal carcinoma in situ), invasive breast cancer (ILC or IDC, invasive lobular carcinoma or invasive ductal carcinoma), triple-negative breast cancer (TNBC), and inflammatory breast cancer.

[0109] In some embodiments, the metastatic brain cancer is caused by a kidney cancer selected from a solid tumor, renal clear cell carcinoma, papillary renal carcinoma, chromophobe renal carcinoma, renal cell carcinoma, urothelial carcinoma, renal sarcoma, Wilms' tumor, and renal lymphoma.

[0110] 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.

[0111] In some embodiments, the metastatic brain cancer is caused by a melanoma selected from superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentigo melanoma, choroidal melanoma, conjunctival melanoma, iris melanoma, and mucosal melanoma.

[0112] In some embodiments, niraparib administration is initiated following resection of the metastatic brain cancer tumor.

[0113] In some embodiments, niraparib, or a pharma- ceutically acceptable salt thereof, is administered as a maintenance therapy.

[0114] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to 200mg or 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 300mg 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 per day. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to 200mg or 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 300mg of niraparib free base. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered in a daily dose equivalent to about 200mg of niraparib free base.

[0115] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered as niraparib tosylate monohydrate.

[0116] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered in the form of a tablet.

[0117] In some embodiments, a dose of niraparib or a pharma- ceutically acceptable salt thereof is administered daily.

[0118] In some embodiments, the brain / plasma ratio of niraparib is about 0.5.

[0119] In some embodiments, niraparib, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional active agents known to be useful in the treatment of cancer.

[0120] 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 pharma- ceutically acceptable salt thereof, or a combination thereof.

[0121] In some embodiments, the one or more additional active agents is temozolomide. In some embodiments, the one or more additional active agents comprises temozolomide or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments, the one or more additional active agents is atezolizumab. In some embodiments, the one or more additional active agents comprises atezolizumab or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the one or more additional active agents is pembrolizumab. In some embodiments, the one or more additional active agents comprises pembrolizumab or a pharma- ceutically acceptable salt thereof.

[0124] In some embodiments, the one or more additional active agents is toborafenib. In some embodiments, the one or more additional active agents comprises toborafenib or a pharma- ceutically acceptable salt thereof.

[0125] In some embodiments, the one or more additional active agents is dostarlimab. In some embodiments, the one or more additional active agents comprises dostarlimab or a pharma- ceutically acceptable salt thereof.

[0126] In some embodiments, the human subject or cancer has a complete or partial response to platinum-based chemotherapy.

[0127] In some embodiments, the cancer is platinum-insensitive.

[0128] In some embodiments, the cancer is platinum-sensitive.

[0129] In some embodiments, the cancer is homologous recombination deficient (HRD) negative.

[0130] In some embodiments, the cancer is brain cancer.

[0131] In some embodiments, the brain cancer is a primary brain cancer.

[0132] In some embodiments, the brain cancer is glioma.

[0133] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0134] In some embodiments, the brain cancer is unmethylated glioma. In some embodiments, the brain cancer is unmethylated glioblastoma.

[0135] I. Definition Throughout this specification, reference to "one embodiment" or "an embodiment" or "some embodiments" or "a particular embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "some embodiments" or "a particular embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0136] As used herein, the term "administration" typically refers to the administration of a composition to a subject or system.Those skilled in the art will recognize the various routes that can be used for administration to a subject, for example, a human subject, in the appropriate circumstances.In some embodiments, administration can include dosing that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., individual doses separated by a common period) dosing.

[0137] As used herein, the term "dosage form" or "unit dosage form" refers to a physically distinct unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount is a unit dosage (or a whole fraction thereof) appropriate for administration according to a regimen (i.e., a treatment regimen) that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population. Those skilled in the art will understand that the total amount of a therapeutic composition or therapeutic agent to be administered to a particular subject is determined by one or more attending physicians and may include administration of multiple dosage forms.

[0138] As used herein, the term "regimen" refers to a set of unit doses (typically more than one) that are typically administered to a subject individually one or more time periods apart. In some embodiments, a given therapeutic agent is administered according to a regimen that may include one or more doses. In some embodiments, a regimen includes multiple doses, each separated in time from the other doses. In some embodiments, the individual doses are separated from each other by the same length of time. In some embodiments, a regimen includes multiple doses, which are separated by different length of time. In some embodiments, a regimen includes multiple doses of the same amount. In some embodiments, a regimen includes multiple doses of different amounts. In some embodiments, a regimen includes at least one dose, where the dose includes one unit dose of a therapeutic agent. In some embodiments, a regimen includes at least one dose, where the dose includes two or more unit doses of a therapeutic agent. For example, a 300 mg dose may be administered as a single 300 mg unit dose or as two 150 mg unit doses. In some embodiments, the regimen correlates with or results in a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic regimen). In some embodiments, the regimen includes doses over the course of treatment to achieve a desired result or beneficial outcome, or until disease progression or unacceptable adverse reactions are reached.

[0139] As used herein, the terms "patient," "subject," or "test subject" refer to any organism to which a provided compound described herein is administered in accordance with the present invention, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Exemplary subjects include animals (e.g., mammals, e.g., 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 be suffering from and / or susceptible to a disease, disorder, and / or condition (e.g., cancer, e.g., brain cancer). In some embodiments, the patient is a human who has been diagnosed with primary or metastatic brain cancer. In some embodiments, the patient has glioblastoma. In some embodiments, the patient has WHO grade II-IV glioma. In some embodiments, the WHO grade II-IV glioma is recurrent. In some embodiments, the patient has IDH1 / 2(+)ATRX mutant glioma. In some embodiments, the IDH1 / 2(+)ATRX mutant glioma is recurrent. As used herein, a "patient population" or a "subject population" refers to a plurality of patients or subjects.

[0140] As used herein, a "therapeutically effective amount" or "effective dose" refers to an amount of a therapeutic agent that produces a desired effect when administered. In some embodiments, the term refers to an amount that is sufficient to treat a disease, disorder, and / or condition when administered to a population suffering from or susceptible to the disease, disorder, and / or condition according to a regimen. In some embodiments, a therapeutically effective amount is one that reduces the occurrence and / or severity of and / or delays the onset of one or more symptoms of a disease, disorder, and / or condition. Those skilled in the art will appreciate that the term "therapeutically effective amount" does not in fact require that successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be an amount that, when administered to a patient in need of such treatment, provides a particular desired pharmacological response in a significant number of subjects. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount measured in one or more specific tissues (e.g., tissues suffering from a disease, disorder, or condition) or bodily 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 particular agent or treatment may be formulated and / or administered in a single dose, in some embodiments, a therapeutically effective amount may be formulated and / or administered in multiple doses, for example, as part of a regimen.

[0141] As used herein, "chemotherapeutic agent" refers to a chemical agent that inhibits the proliferation, growth, life span, and / or metastatic activity of cancer cells. In some embodiments, the chemotherapeutic agent is platinum-based, e.g., a platinum agent. In some such embodiments, the platinum agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.

[0142] As used herein, "homologous recombination" refers to the process in which nucleotide sequences are exchanged between separate DNA strands. Homologous recombination is involved in several different biological processes, for example, it occurs as part of DNA repair processes (e.g., double-strand break repair pathway and synthesis-dependent strand annealing pathway) and during the process of meiosis / gametogenesis in eukaryotes. As used herein, "homologous recombination deficiency", "homologous recombination repair deficiency", "homologous repair deficiency", or "HRD" refers to the reduction or impairment of homologous recombination process. Such impairment may be due to chromosomal abnormality or due to mutation in one or more genes involved in DNA repair. Reduction or impairment of the homologous recombination process can also be measured by assessing epigenetic modifications (i.e., hypermethylation) on the promoters of HRR genes; for example, BRCA1 and RAD51C promoter methylation leads to repression of gene transcription and is associated with PARP inhibitor sensitivity.

[0143] The reduction or impairment of the homologous recombination process can also be measured by a RAD51 focus formation assay, where the absence of RAD51 focus formation indicates a deficiency in the homologous recombination pathway.

[0144] A reduction or impairment of the homologous recombination process can also be measured by HRR, BRCA1, BRCA2 protein expression; abnormally low protein levels of BRCA1, BRCA2, and other HRR genes can indicate a defect in the homologous recombination pathway.

[0145] As used herein, "BRCA mutation" or "BRCA mutation" refers to a change or difference in the sequence of at least one copy of either or both of the BRCA1 or BRCA2 genes compared to an appropriate reference sequence (e.g., a wild-type reference and / or a sequence present in non-cancerous cells in a subject). Mutations in the BRCA1 / 2 genes can result in BRCA1 / 2 defects, which can include, for example, the loss or reduction of expression or function of BRCA genes and / or encoded proteins. Such mutations can also be referred to as or suspected to be "detrimental mutations". A BRCA mutation can be a "germline BRCA mutation", which indicates that it is inherited from one or both parents. A germline mutation affects all cells in an organism and is passed on to offspring. BRCA mutations can also be acquired during life, i.e., arise spontaneously (i.e., non-inherited) in any cell of the body ("corpus") at any time during a patient's life, and are referred to herein interchangeably as "sporadic BRCA mutations" or "somatic BRCA mutations." Genetic tests are available and known to those of skill in the art.

[0146] As used herein, the term "gene involved in DNA repair" refers to any gene involved in the repair of DNA in a cell. Components of the DSB repair pathway include ATM (NM-000051), RAD51 (NM-002875), RAD51LI (NM-002877), RAD51C (NM-002876), RAD51L3 (NM-002878), DMCl (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA1 (NM-007295), BRCA2 (NM-000059), RAD5O (NM-005732), MRE11A (NM-005590), and NBSl (NM-00248 5), ADPRT(PARP-1), ADPRTL2, (PARP2)CTPS, RPA, RPAI, RPA2, RPA3, XPD, ERCCI, XPF, MMS19, RAD51p, RAD51D, DMC1, XRCCR, XRCC3, RAD54, NB51, WRN, 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 regulators such as EMSY (Cell (2003) 115:523-535).

[0147] 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 mutation in one or more of the genes involved in DNA repair.In some embodiments, the present invention comprises the use of Niraparib to treat cancer patients regardless of DNA repair status.

[0148] As used herein, the term "progression free survival" refers to the period during which a subject with a disease (e.g., cancer) survives without significant deterioration of the disease state. Progression free survival can be assessed as the period during which tumor growth does not progress and / or the patient's disease status is not determined to be progressive disease. In some embodiments, the progression free survival of a subject with cancer is assessed by evaluating tumor (lesion) size, tumor (lesion) number, and / or metastasis.

[0149] As used herein, "progression free survival 2" (PFS2) is defined as the time from randomization of treatment to assessment of progression on the next anticancer therapy after study treatment or death from any cause, whichever occurs first. In some embodiments, assessment of progression may be assessed by clinical and / or radiographic assessment.

[0150] The term "progression" or "progressive disease" (PD) of tumor growth, as used herein with reference to cancer status, refers to an increase in the sum of the diameters of target lesions (tumors). In some embodiments, tumor growth progression refers to an increase of at least 20% in the sum of the diameters of target lesions, with reference to the minimum sum during the study (including the minimum sum at baseline, if any), 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 may also be included in the assessment of tumor growth progression.

[0151] As used herein, the term "partial response" or "PR" refers to a reduction in tumor progression in a subject, as indicated by a reduction in the sum of diameters of target lesions, and takes the sum of diameters at baseline as reference. In some embodiments, PR refers to at least a 30% reduction in the sum of diameters of target lesions, taking the sum of diameters at baseline as reference. Exemplary methods for evaluating partial response are specified by the RECIST guidelines. See EAE Isenhauer, et al., "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.)," Eur. J. of Cancer, 45: 228-247 (2009).

[0152] As used herein, "stabilization" or "stable disease" (SD) of tumor growth refers to neither sufficient regression to meet the criteria for PR nor sufficient increase to meet the criteria for PD. In some embodiments, stabilization refers to a change (increase or decrease) of less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% in the sum of the diameters of the target lesions, with reference to the sum of the diameters at baseline. Exemplary methods for evaluating the stabilization or stability of tumor growth are specified by the RECIST guidelines. See EAE Isenhauer, et al., "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.)," Eur. J. of Cancer, 45: 228-247 (2009).

[0153] As used herein, the term "complete response" or "CR" is used to mean the disappearance of all or substantially all target lesions. In some embodiments, CR refers to a reduction of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the sum of the diameters of the target lesions, referring to the sum of the diameters at baseline (i.e., disappearance of the lesions). In some embodiments, CR indicates that less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less of the sum of the diameters of the lesions remain after treatment. Exemplary methods for assessing complete response are specified by the RECIST guidelines. See EAE Isenhauer, et al., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45:228-247 (2009).

[0154] As used herein, "hazard ratio" (or "HR" when used in the context of niraparib treatment effect calculations, e.g., HR 0.38) is the hazard or probability of an event occurring in the treatment arm expressed as a ratio to the event occurring in the control arm. Hazard ratios may be determined by the Cox model, which is a regression method for survival data and provides an estimate of the hazard ratio and its confidence interval. Hazard ratios are estimates of the ratio of hazard rates between the treatment group and the control group. Hazard ratios are 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 is constant over time.

[0155] As used herein, "HGG" refers to high-grade glioma.

[0156] As used herein, "MGMT" refers to O-6-methylguanine-DNA methyltransferase, which is a gene encoding a DNA repair enzyme. As used herein, "MGMT unmethylated" or "unmethylated MGMT" refers to the absence of DNA methylation in the promoter region of the MGMT gene associated with cancer, i.e., glioma or glioblastoma. As used herein, "hypermethylated MGMT promoter", "MGMT promoter hypermethylation", or "methylated MGMT promoter" refers to the presence of DNA methylation in the promoter region of the MGMT gene associated with cancer, i.e., glioma or glioblastoma. As used herein, "MGMT status" refers to MGMT methylation status, i.e., positive status is associated with MGMT gene promoter methylation, and negative status is associated with unmethylated MGMT gene promoter.

[0157] As used herein, the term "treatment" (similarly, "treat" or "treating") refers to any administration of a therapy that partially or completely alleviates, improves, relieves, inhibits, delays the onset of, reduces the severity of, and / or reduces the occurrence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be treatment of subjects who do not exhibit symptoms of the associated disease, disorder, and / or condition and / or subjects who exhibit only early symptoms of the disease, disorder, and / or condition. Alternatively, or in addition, such treatment may be treatment of subjects who exhibit one or more established symptoms of the associated disease, disorder, and / or condition. In some embodiments, treatment may be treatment of subjects who have been diagnosed as suffering from the associated disease, disorder, and / or condition. In some embodiments, treatment may be treatment of subjects who have been found to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the associated disease, disorder, and / or condition. In some embodiments, "niraparib treatment" includes administration of niraparib or a pharma- ceutically acceptable salt thereof to a human subject in need thereof.

[0158] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. 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 include the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfate, and the like. Examples of the salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, 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, and valerate.

[0159] As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated together with one or more pharma- ceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as those intended for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue. Pharmaceutical composition may also refer to medicine.

[0160] As used herein, the term “niraparib” means either the free base compound ((3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine), a salt form, including a pharma- ceutically 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 tosylate), or a solvate or hydrate form thereof (e.g., (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine tosylate monohydrate). In some embodiments, such forms may be individually referred to as "niraparib free base," "niraparib tosylate," and "niraparib tosylate 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.

[0161] As used herein, "intra-operative" is defined as occurring during a surgical procedure. In some embodiments, the surgical procedure is the resection of brain tumor tissue.

[0162] As used herein, "post-resection" refers to events that occur after resection of the brain tumor tissue.

[0163] As used herein, "pre-surgical" or "presurgical" refers to events that occur before surgery. In some embodiments, the surgery is resection of brain tumor tissue. In some embodiments, "presurgical niraparib" or "pre-surgical niraparib" refers to administration of niraparib to a human subject before resection. For example, a patient identified as having brain cancer is administered niraparib for a period of time before resection, for example, up to 7 days before resection, or 4 days before resection.

[0164] As used herein, the term "maintenance therapy" or "maintenance treatment" refers to treatment that is performed to prevent disease recurrence. For example, maintenance therapy can prevent or minimize the growth of cancer after the cancer has been substantially reduced or eliminated after initial therapy (cancer treatment). Maintenance therapy can be continuous treatment in which multiple doses are administered at intervals, for example, daily, every other day, weekly, biweekly, 3 weeks, 4 weeks, or 6 weeks. In some embodiments, maintenance therapy can be continued for a predetermined length of time. In some embodiments, maintenance therapy can be continued until unacceptable toxicity occurs and / or disease progression occurs. In the course of maintenance treatment, treatment can be interrupted upon the occurrence of toxicity as indicated by adverse events. If toxicity is adequately resolved within 28 days to baseline or grade 1 or less, patients may resume treatment with niraparib, which may include a reduction in dose level if prevention is not considered feasible.

[0165] As used herein, overall survival ("OS") is defined as the time from the start of treatment to death from any cause. For use as an endpoint in clinical trials, OS is defined as the time from randomization to death from any cause and is measured in the intent to treat population.

[0166] As used herein, "objective response rate" ("ORR") is defined as the proportion of patients who have a reduction in tumor size of a predefined amount and minimum duration. The duration of response is usually measured from the time of first response until tumor progression is confirmed. In general, ORR can be defined as the sum of partial responses and complete responses.

[0167] As used herein, "time to first subsequent therapy" (TFST) is defined as the date from randomization in the current study to the start date of the first subsequent treatment regimen (e.g., anti-cancer therapy).

[0168] As used herein, "time to second subsequent therapy" (TSST) is defined as the date from randomization to the current study to the start date of the second subsequent treatment regimen (e.g., anti-cancer therapy).

[0169] As used herein, "chemotherapy-free interval" (CFI) is defined as the time from the last dose of the last anti-cancer therapy (e.g., platinum-based chemotherapy) to the start of the next dose of the anti-cancer therapy.

[0170] As used herein, "stereotactic radiotherapy" is a highly focused radiation treatment that provides a high dose of radiation concentrated to the tumor while limiting the dose to surrounding organs.

[0171] Niraparib is an orally available selective inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Niraparib has the following structure:

[0172] [ka]

[0173] The chemical name of niraparibut tosylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1) and has the following chemical structure:

[0174] [ka]

[0175] The empirical molecular formula of niraparib is C 26 H 30 Niraparib is N4O5S and has a molecular weight of 510.61 g / mol. Niraparib tosylate monohydrate drug substance is a white to off-white, non-hygroscopic, crystalline solid. The solubility of niraparib is pH independent below pKa 9.95, with an aqueous free base solubility of 0.7 mg / mL to 1.1 mg / mL over the physiological pH range. Certain solid forms of niraparib are described in WO 2018 / 183354, which is incorporated by reference in its entirety.

[0176] Methods for the preparation of niraparib include those described in WO 2014 / 088983, WO 2014 / 088984, WO 2018 / 200517, U.S. Patent Nos. 8,071,623, 8,436,185, U.S. Application No. 62 / 489,415, filed April 24, 2017, and Jones et al., J. Med. Chem., 52:7170-7185, 2009, each of which is incorporated by reference in its entirety.

[0177] Niraparib inhibits PARP 1 and 2 at IC 50 = 3.8 and 2.1 nM, and in whole cell assays, PARP activity was 50 = 4 nM and inhibited the proliferation of cancer cells harboring mutant BRCA-1 and BRCA-2 at CC = 10–100 nM range. 50 (See Jones et al., Journal of Medicinal Chemistry, 2009, 52, 7170-7185). Methods of administering niraparib to cancer patients are also described in International Publication No. WO 2018 / 005818, which is incorporated herein by reference in its entirety. Exemplary dosage forms that include niraparib are described, for example, in International Publication Nos. WO 2018 / 183349 and WO 2019 / 067634, each of which is incorporated herein by reference in its entirety.

[0178] II. Combination Treatments In some embodiments, the method of the present invention may be used in combination with one or more additional therapeutic active agents (i.e., in combination with one or more additional active agents) known to be useful in the treatment of cancer, including immunotherapy (e.g., immune checkpoint inhibitors), cell and gene therapy, chemotherapy, or radiation treatment. The term one or more additional therapeutic active agents, as used herein, includes any compound or therapeutic agent that is known to exhibit or exhibits advantageous properties when administered to a patient in need of cancer treatment. Furthermore, it is irrespective of whether the compounds are administered in the same dosage form, for example, one compound may be administered by injection and another compound may be administered orally. In some embodiments, the method of the present invention is used as an adjunct therapy to radiation therapy in the treatment of cancer. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of brain cancer. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated MGMT glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated MGMT glioblastoma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated glioma. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as an adjunct therapy to radiation therapy in the treatment of non-methylated glioblastoma.

[0179] The term "co-administration" as used herein means either simultaneous administration or separate sequential administration in any manner of niraparib or its pharma- ceutically acceptable salt as described herein and one or more additional active agents known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term one or more additional active agents as used herein includes any compound or therapeutic agent known to exhibit or exhibits advantageous properties when administered to a patient in need of cancer treatment. Preferably, when administration is not simultaneous, the compounds are administered in close temporal proximity to each other. Moreover, it does not matter whether the compounds are administered in the same dosage form, for example, one compound may be administered by injection and another compound may be administered orally.

[0180] Typically, any anti-neoplastic agent having activity against the susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Co-administration is defined as including administration with one or more additional agents. Such one or more additional active agents (or one or more additional active agents) may be selected from any known therapy for the treatment of cancer, including small molecule therapy, antibody therapy, antibody drug conjugate (ADC) therapy, and cell and gene therapy. Examples of anti-neoplastic agents include, but are not limited to, chemotherapeutic agents, immune modulators, and immune stimulatory adjuvants. Examples of such agents are described in Cancer Principles and Practice of Oncology by VTDevita, TSLawrence, and SARosenberg (editors), 11 thedition (November 29, 2018), Lippincott Williams & Wilkins Publishers. One of ordinary skill in the art would be able to determine which combinations of agents would be useful based on the specific characteristics of the drug and cancer involved. Exemplary antineoplastic agents useful 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, antimetabolic agents, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, heat shock protein inhibitors, inhibitors of cancer metabolism, and cancer gene therapy agents.

[0181] As used herein, "immunomodulator" refers to any substance, including monoclonal antibodies, that affect the immune system. The niraparib of the present invention or its pharmaceutical salts may be considered as an immunomodulator. The niraparib of the present invention or its pharmaceutical salts may be considered as an immunomodulator. The immunomodulator may be used as an anti-neoplastic agent for the treatment of cancer. For example, immunomodulators include, but are not limited to, antibodies or other antagonists against CTLA-4, such as ipilimumab (YERVOY®) and tremelimumab, antibodies or other antagonists against PD-1, such as dostallimab, nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), and cemiplimab (LIBTAYO®), and antibodies or other antagonists against TIM-3, such as covolimab. In some embodiments, the immune modulator comprises ipilimumab, tremelimumab, dostallimab, nivolumab, pembrolizumab, cemiplimab, covolimab, or a pharmaceutically acceptable salt thereof. Other immune modulators include, but are not limited to, antibodies or other antagonists against PD-L1, OX-40, LAG3, TIM-3, 41BB, and GITR.

[0182] In some embodiments, the further active agent (or additional active agent) may be selected from those described in, for example, WO 2018 / 208968, WO 2018 / 213732, and WO 2020 / 051142. For example, a PD-1 inhibitor, such as dostallimab or pembrolizumab. In some embodiments, the PD-1 inhibitor is dostallimab. In some embodiments, the PD-1 inhibitor comprises dostallimab, pembrolizumab, or a pharmaceutically acceptable salt thereof. In some embodiments, the PD-1 inhibitor comprises dostallimab or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the further 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, velbalafenib, TAK-580, JZP815, and toborafenib, have been studied in patients with, for example, 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 advanced solid tumors. In some embodiments, the type II pan-RAF kinase inhibitor comprises CCT3833 / BAL3833, LY3009120, lifirafenib, belbalafenib, TAK-580, JZP815, toborafenib, or a pharmaceutically acceptable salt thereof. In some embodiments, the type II pan-RAF kinase inhibitor is toborafenib. In some embodiments, the type II pan-RAF kinase inhibitor comprises toborafenib or a pharmaceutically acceptable salt thereof.

[0184] 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 comprises temozolomide or a pharma- ceutically acceptable salt thereof. In some embodiments, temozolomide is administered to the human subject in combination with radiation therapy. In some embodiments, the human subject has a positive MGMT status. In some embodiments, the human subject has a negative MGMT status. In some embodiments, temozolomide is administered to the human subject in combination with radiation therapy, wherein the human subject has a positive MGMT status. In some embodiments, temozolomide is administered to the human subject in combination with radiation therapy, wherein the human subject has a negative MGMT status. In some embodiments, the human subject has a newly diagnosed glioblastoma and MGMT promoter hypermethylation. 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, temozolomide is administered to a human subject in combination with radiation therapy, where the human subject has newly diagnosed glioblastoma and MGMT promoter hypermethylation. In some embodiments, treatment with alkylating chemotherapy drugs, such as temozolomide, is useful when brain cancer is identified as having cells with methylated MGMT promoter, particularly glioblastoma cells. Thus, in some embodiments, temozolomide is administered to a human subject in combination with radiation therapy, where the human subject has methylated MGMT promoter. In some embodiments, temozolomide is administered as a pharmaceutically acceptable salt.

[0185] In some embodiments, the cancer is brain cancer.

[0186] In some embodiments, the brain cancer is a primary brain cancer.

[0187] In some embodiments, the brain cancer is glioma.

[0188] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0189] In some embodiments, the brain cancer is unmethylated glioma. In some embodiments, the brain cancer is unmethylated glioblastoma.

[0190] In some embodiments, when the brain cancer is metastatic, the further active agent (or additional active agent) may be selected from the group consisting of chemotherapy and immunotherapy, where the chemotherapy is selected from the group consisting of trastuzumab and erlotinib, and the immunotherapy is selected from the group consisting of atezolizumab, ipilimumab, pembrolizumab, and nivolumab. In some embodiments, the chemotherapy is toborafenib. In some embodiments, the immunotherapy is pembrolizumab. In some embodiments, the immunotherapy is atezolizumab. In some embodiments, the immunotherapy is dostarlimab. In some embodiments, the chemotherapy is selected from the group consisting of trastuzumab, erlotinib, and pharmaceutically acceptable salts thereof, and the immunotherapy is selected from the group consisting of atezolizumab, ipilimumab, pembrolizumab, nivolumab, and pharmaceutically acceptable salts thereof. In some embodiments, the chemotherapy comprises toborafenib or a pharmaceutically acceptable salt thereof. In some embodiments, the immunotherapy comprises pembrolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the immunotherapy comprises atezolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the immunotherapy comprises dostarlimab or a pharmaceutically acceptable salt thereof.

[0191] In certain embodiments, the further active agent (or additional active agent) may be selected from the group consisting of temozolomide and bevacizumab. In certain embodiments, the further active agent (or additional active agent) comprises temozolomide, bevacizumab, or a pharma- ceutically acceptable salt thereof.

[0192] In certain embodiments, the further active agent (or additional active agent) may be temozolomide. In certain embodiments, the further active agent (or additional active agent) comprises temozolomide or a pharma- ceutically acceptable salt thereof.

[0193] In some embodiments, the further active agent (or additional active agent) may be atezolizumab. In some embodiments, the further active agent (or additional active agent) comprises atezolizumab or a pharma- ceutically acceptable salt thereof.

[0194] In some embodiments, the further active agent (or additional active agent) can be pembrolizumab. In some embodiments, the further active agent (or additional active agent) comprises pembrolizumab or a pharma- ceutically acceptable salt thereof.

[0195] In some embodiments, the further active agent (or additional active agent) can be toborafenib. In some embodiments, the further active agent (or additional active agent) comprises toborafenib or a pharma- ceutically acceptable salt thereof.

[0196] In some embodiments, the further active agent (or additional active agent) can be dostarlimab. In some embodiments, the further active agent (or additional active agent) comprises dostarlimab or a pharma- ceutically acceptable salt thereof.

[0197] Selective antineoplastic agents that may be used in combination with niraparib, or a pharma- ceutically acceptable salt thereof, include abarelix, abemaciclib, abiraterone, afatinib, aflibercept, aldoxorubicin, alectinib, alemtuzumab, arsenic trioxide, asparaginase, axitinib, AZD-9291, belinostat, bendamustine, bevacizumab, blinatumomab, bosutinib, brentuximab vedotin, cabazitaxel, and cabozantinib. , capecitabine, ceritinib, clofarabine, cobimetinib, crizotinib, daratumumab, dasatinib, degarelix, denosumab, dinutuximab, docetaxel, elotuzumab, entinostat, enzalutamide, epirubicin, eribulin, filgrastim, flumatinib, fulvestrant, fruquintinib, gemtuzumab ozogamicin, ibritumomab, ibrutinib, idelalisib, imatinib, irinotecan, ixabepilone, Ixazomib, lenalidomide, lenvatinib, leucovorin, mechlorethamine, necitumumab, nelarabine, netupitant, nilotinib, obinutuzumab, olaparib, omacetaxine, osimeritinib, oxaliplatin, paclitaxel, palbociclib, palonosetron, panitumumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, plerixafor, pomalidomide, ponatinib, pralatrexate, quiza These include, but are not limited to, ritinib, 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.

[0198] III. Brain Cancer and Research Principles The World Health Organization (WHO) classifies brain tumors into four categories based on increasing severity, as outlined in Table A below.

[0199] [Table A]

[0200] A non-limiting list of genes that may be altered or mutated in glioblastoma (GBM) is provided in Table B.

[0201] [Table B]

[0202] Primary brain tumors are among the top 10 causes of cancer-related deaths in the United States, accounting for approximately 1.4% of all cancers and 2.4% of all cancer-related deaths. Approximately 14 of 100,000 people in the United States are diagnosed with primary brain tumors each year, and 6-8 of 100,000 are diagnosed with WHO grade III or IV primary brain tumors. Nearly all grade II gliomas progress to high-grade gliomas (grade III / IV). Glioblastoma multiforme (GBM, WHO grade IV glioma) is the most frequently reported malignant brain tumor histology (29.6%) in the National Cancer Database. Patients who develop WHO grade III or IV gliomas have a grim prognosis, with median survival after diagnosis ranging from 12 to 16 months. Although conventional treatment with surgery, radiation, and temozolomide slows tumor progression and extends patient survival, these tumors uniformly recur and inexorably result in the patient's death. Regardless, the alkylating agent temozolomide remains the only effective adjuvant chemotherapy available for glioblastoma patients. Phase 0 trials identify promising new drugs by "humanizing" preclinical studies. There is a series of design modifications in Phase 0 to address a variety of possible research objectives. These include (1) studies to determine whether a mechanism of action (MOA) defined in a nonclinical model is achievable in humans, (2) studies to probe biomarker assays using human tumor tissue, (3) studies to develop novel imaging probes and evaluate their distribution, binding characteristics, and on-target effects in humans, (4) studies to evaluate the human pharmacodynamics (PD) and / or pharmacokinetics (PK) of two or more analogs to select the most promising candidates for further development, (5) studies to determine the dose range and sequence of administration of a biomodulator for use in combination with established chemotherapy, and (6) studies to obtain human PK-PD related data of a drug prior to Phase 1 trials. For CNS oncology studies, PK analysis refers to the measurement of investigational drug concentrations in brain tumor tissue, and PD analysis refers to the quantification of molecular / cellular targets affected by the investigational drug.

[0203] For brain tumor patients, phase 0 clinical trials are challenging not only due to study logistics but also because the non-therapeutic nature of such studies takes a toll on patient enrollment. Phase 0 trials with expansion phases employ a phase 0 strategy for brain tumor patients but incorporate PK and / or PD-dependent triggers that advance phase 0 patients to the exploratory expansion phase. In doing so, this approach is compelling by providing potential brain tumor patients with confidence that there is biological evidence suggesting that their tumors may respond if selected for treatment. For those patients who advance to the expansion phase, the biological evidence linking the experimental treatment to their individual case motivates the patient (and their provider). Although hard evidence is lacking, our institution's experience with both phase 0 and phase 0+ expansion studies speaks to the benefits, as patient enrollment has increased from 14% to 35% since moving to the latter model in 2016 (Tien, et al., 2019).

[0204] Less than 1% of all published clinical trials for brain tumors include both PK and PD endpoints evaluating tissue effects after initial drug exposure. However, few studies have tested tissues obtained from these same patients after prolonged drug treatment, even though 19% of all high-grade glioma patients undergo, for example, three or more tumor resections. Using the proposed study paradigm, patients scheduled for re-resection for tumor recurrence after therapeutic dosing of experimental agents provide an important opportunity for longitudinal tissue analysis. Within this population, enhancing and non-enhancing tumor tissues derived from early and slowly recurring tumors may be compared to identify the role of on-target and off-target pathways in tumor evasion. To control for inter-individual variability in CNS drug permeability, putative resistance mechanisms may also be tested in matched tissue specimens obtained from first, second (phase 0), and third (progression from expansion phase) resections. Beyond characterizing resistance mechanisms, planned identification of tissue biomarker signatures associated with sensitivity to experimental agents may inform future clinical trial design. For patients who completed the Phase 0 component of the study with evidence of sufficient tumor penetration (i.e., "positive" PK endpoints), the variability in observed PD effects provides an opportunity to distinguish biological responders (i.e., patients with positive PK and PD endpoints) from non-responders (i.e., patients with positive PK and negative PD endpoints). Using a variety of molecular and genetic techniques, a list of tumor biomarker combinations predictive of pharmacodynamic sensitivity to the study drug can be devised for prospective investigation. Taken together, these longitudinal studies of human brain tumors exposed to experimental treatments may provide a viable basis for future strategies.

[0205] Thus, the Phase 0 clinical trial mechanism originally proposed by the FDA was conceived with a general drug development committee in mind. Brain tumor drug development, however, imposes inherent research limitations due to the absence of predictive animal models, high risk of tumor acquisition, inadequacy of microdosing, BBB issues, and the potential confounding effects of neurosurgical anesthesia. Adapting the Phase 0 trial paradigm to neuro-oncology patients is a valid route to gain direct evidence of drug delivery and target modulation. Specific modifications included in this proposal are (1) abandoning microdosing in favor of high-dose regimens, (2) incorporating CSF into PK and PD analysis, and (3) adding an expansion component to patients with demonstrable PK and / or PD response. 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.

[0206] 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 / rhabdomyoid tumor, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+)ATRX mutant glioma, malignant glioma, and primitive neuroectodermal tumors of the brain.

[0207] In some embodiments, the patient has glioblastoma (GBM). In some embodiments, the glioblastoma patient has one or more of the following genes mutated or altered: isocitrate dehydrogenase (IDH), O 6-methylguanine-DNA methyltransferase (MGMT), epidermal growth factor receptor (EGFR), telomerase reverse transcriptase (TERT), chromosome 7p gain, chromosome 10q loss, histone H3 family 3A (H3F3A), fibroblast growth factor receptor (FGFR), neurotrophin tyrosine receptor kinase (NTRK), or X-linked alpha thalassemia / mental retardation syndrome (ATRX). In some embodiments, the human subject has a non-methylated MGMT glioblastoma. In some embodiments, the human subject has a non-methylated glioblastoma.

[0208] Brain metastasis (also known as secondary brain cancer) occurs when cancer cells spread from the primary cancer site to the brain. Any cancer can spread to the brain, but the types that are most likely to cause brain metastasis are lung, breast, colon, kidney, and melanoma. Brain metastasis can form one tumor or multiple tumors in the brain. In some embodiments, brain metastasis is asymptomatic. In some embodiments, brain metastasis is active progressive brain metastasis.

[0209] In some embodiments, the type of cancer causing brain metastases is lung cancer (e.g., solid tumors). In some embodiments, the lung cancer is advanced lung cancer. In some embodiments, the lung cancer is metastatic lung cancer. In some embodiments, the lung cancer is squamous cell carcinoma of the lung. In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma. In some embodiments, the lung cancer is ALK translocated lung cancer (e.g., lung cancer with a known ALK translocation). In some embodiments, the lung cancer is EGFR mutant lung cancer (e.g., lung cancer with a known EGFR mutation). In some embodiments, the lung cancer is MSI-H lung cancer. In some embodiments, the lung cancer is MSS lung cancer. In some embodiments, the lung cancer is POLE mutant lung cancer. In some embodiments, the lung cancer is POLD mutant lung cancer. In some embodiments, the lung cancer is a TMB-high lung cancer. In some embodiments, the lung cancer is associated with homology-directed repair deficiency / homology-directed repair deficiency ("HRD") or is characterized by mutations or deletions in homology-directed repair (HRR) genes.

[0210] In some embodiments, the type of cancer causing brain metastasis is breast cancer (e.g., solid tumor). In some embodiments, the 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 breast cancer, or triple-negative breast cancer (TNBC). In some embodiments, the cancer is ductal carcinoma in situ (DCIS, ductal carcinoma in situ). In some embodiments, the cancer is invasive breast cancer (e.g., ILC or IDC, invasive lobular carcinoma or invasive ductal carcinoma). In some embodiments, the cancer is triple-negative breast cancer (TNBC). In some embodiments, the cancer is inflammatory breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the cancer is stage II, stage III, or stage IV breast cancer. In some embodiments, the cancer is stage IV breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In embodiments, the breast cancer is metastatic breast cancer. In embodiments, the breast cancer is MSI-H breast cancer. In embodiments, the breast cancer is MSS breast cancer. In embodiments, the breast cancer is POLE mutant breast cancer. In embodiments, the breast cancer is POLD mutant breast cancer. In embodiments, the breast cancer is TMB high breast cancer. In embodiments, the breast cancer is associated with homology directed repair deficiency / homology repair deficient ("HRD") or is characterized by mutations or deletions in homology directed repair (HRR) genes.

[0211] In embodiments, the type of cancer causing brain metastases is colon cancer (e.g., solid tumors). In embodiments, the colon cancer is adenocarcinoma. In embodiments, the type of cancer causing brain metastases is colorectal (CRC) cancer (e.g., solid tumors). In embodiments, the colorectal cancer is advanced colorectal cancer. In embodiments, the colorectal cancer is adenocarcinoma. In embodiments, the colorectal cancer is metastatic colorectal cancer. In embodiments, the colorectal cancer is MSI-H colorectal cancer. In embodiments, the colorectal cancer is MSS colorectal cancer. In embodiments, the colorectal cancer is POLE mutant colorectal cancer. In embodiments, the colorectal cancer is POLD mutant colorectal cancer. In embodiments, the colorectal cancer is TMB high colorectal cancer. In some embodiments, the colorectal cancer is associated with homologous recombination repair deficiency / homology repair deficiency ("HRD") or is characterized by a mutation or deletion in a homology-directed repair (HRR) gene. In some embodiments, the colon cancer is selected from colorectal cancer, squamous cell carcinoma, and gastrointestinal neuroendocrine tumors.

[0212] In embodiments, the type of cancer causing brain metastases is renal cancer (e.g., solid tumors). In embodiments, the renal cancer is renal clear cell carcinoma. In embodiments, the renal cancer is papillary renal cancer. In embodiments, the renal cancer is chromophobe renal cancer. 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.

[0213] In embodiments, the type of cancer causing brain metastases 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 TMB high melanoma.

[0214] Exemplary DNA repair pathways and defects therein are described in this disclosure, as well as in International Publication Nos. 2018 / 005818 and 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, and disruptions in these pathways can lead to the development and / or growth of cancer. See, for example, Kelley et al., "Targeting DNA repair pathways for cancer treatment: what's new?", Future Oncol., 10(7):1215-37 (2014).

[0215] In some embodiments, the patient is administered PARP therapy (i.e., Niraparib) independently of the homologous repair deficiency (HRD status) in the cancer. In some embodiments, the patient is administered Niraparib or a pharmaceutically acceptable salt thereof independently of the HRD status. In some embodiments, the patient is not tested for the presence or absence of BRCA mutation or the presence of homologous recombination deficiency, including the presence of deficiency in DNA repair, prior to administration of Niraparib or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, administration of niraparib, or a pharma- ceutically acceptable salt thereof, is initiated within 12 weeks of the first day of the last cycle of chemotherapy.

[0217] In some embodiments, the patient is administered niraparib or a pharma- ceutically acceptable salt thereof independent of the determination of HRD status (e.g., the patient is administered niraparib or a pharma- ceutically acceptable salt thereof independent of the determination of BRCA status).

[0218] In some embodiments, the patient's HRD status is known prior to treatment.

[0219] In some embodiments, the HRD status of the patient is determined.Various test strategies are utilized to measure homologous recombination deficiency (HRD) in ovarian cancer (including fallopian tube cancer and peritoneal cancer), and are known in the art.The genetic alterations of BRCA1 / 2 and other HRR-related genes can be sequenced to obtain information about germline or somatic gene mutation status.

[0220] In some embodiments, the cancer is characterized by defects in at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 genes involved in the HRR pathway that are not BRCA1 or BRCA2. In some embodiments, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 genes involved in the HRR pathway, and any combination thereof.

[0221] In some embodiments, at least one defect in the HRR pathway is a monoallelic mutation in a gene (e.g., a monoallelic mutation in a gene that is not BRCA1 or BRCA2). In some embodiments, the monoallelic mutation is independently a germline mutation. In some embodiments, the monoallelic mutation is independently a sporadic mutation.

[0222] 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 that is not BRCA1 or BRCA2). In some embodiments, the biallelic mutations are independently germline mutations. In some embodiments, the biallelic mutations are independently sporadic mutations.

[0223] The defect in the HRR pathway (e.g., the defect in at least one non-BRCA1 gene or non-BRCA2 gene involved in the HRR pathway, and / or the defect in BRCA1 and / or BRCA2) may be identified using methods known in the art.For example, the identification of the defect in the HRR pathway may include the determination by standard laboratory tests, such as and including the tests approved by relevant regulatory authorities.

[0224] In some embodiments, the defect in the gene involved in the HRR pathway is identified using a pre-specified HRR gene panel. In some embodiments, the pre-specified HRR gene panel comprises 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 the group consisting of ATM, ATR, BARD1, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, and RAD54L.

[0225] Surgical status and residual disease 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.

[0226] In some embodiments, the platinum-based chemotherapy regimen also includes a surgical procedure.

[0227] In some embodiments, the surgical procedure occurs prior to the initiation of a first-line platinum-based chemotherapy regimen (primary cytoreductive surgery).

[0228] In some embodiments, high-risk patients have residual disease following cytoreductive surgery, hi some embodiments, residual disease is observed following primary cytoreductive surgery.

[0229] In some embodiments, surgery may not completely remove cancer cells, and residual disease describes cancer cells that remain after surgery.

[0230] In some embodiments, the residual disease is visible residual disease. In some embodiments, the residual disease is less than about 2.0 cm. In some embodiments, the residual disease is greater than about 0.1 cm. In some embodiments, the residual disease is greater than about 0.1 cm and less than about 2.0 cm. In some embodiments, the residual disease is greater than about 1.0 cm.

[0231] In some embodiments, patients with stage III cancer have visible residual disease following surgery.

[0232] In some embodiments, patients with stage IV cancer have visible residual disease following surgery.

[0233] b. Neoadjuvant chemotherapy (NACT) In some embodiments, the patient is undergoing neoadjuvant chemotherapy (NACT), where the patient begins receiving platinum chemotherapy prior to surgery, and the surgery is an interim cytoreductive surgery that occurs prior to completion of platinum chemotherapy.

[0234] In an embodiment, the patient undergoes interim cytoreductive surgery followed by two or more cycles of post-operative platinum-based therapy.

[0235] In some embodiments, patients with stage III cancer are undergoing 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).

[0236] In some embodiments, patients with stage IV cancer are undergoing 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).

[0237] 1. First-line platinum-based chemotherapy In some embodiments, the platinum-based chemotherapy is a regimen of treatment cycles with a platinum agent (e.g., any platinum agent described herein). In some embodiments, administration of PARP therapy (e.g., niraparib) is initiated after completion of all treatment cycles in the regimen. In some embodiments, the platinum-based treatment regimen is about 3 to about 6 months in duration. In some embodiments, the patient must begin niraparib treatment within 12 weeks from the first day of the last cycle of chemotherapy, for example, within 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, or 1 week from the first day of the last cycle of chemotherapy.

[0238] As used herein, a first-line platinum-based chemotherapy regimen is the initial regimen administered to a patient after cancer diagnosis.

[0239] In some embodiments, the patient undergoes a platinum-based chemotherapy regimen, including multiple cycles of platinum chemotherapy. A cycle of platinum chemotherapy can refer to a period of treatment with a platinum chemotherapy agent followed by a rest period (no treatment), which is repeated on a regular schedule (thereby constituting a platinum-based chemotherapy regimen).

[0240] In some embodiments, the platinum-based chemotherapy regimen comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles of platinum chemotherapy. In some embodiments, the patient is receiving 6 or more cycles of platinum chemotherapy. In some embodiments, the patient is receiving 9 or fewer cycles of platinum chemotherapy. In some embodiments, the patient is receiving 4-9 cycles of platinum chemotherapy, i.e., the patient is receiving 4 or more and 9 or fewer cycles of platinum chemotherapy. In some embodiments, the patient is receiving 6-9 cycles of platinum chemotherapy, i.e., the patient is receiving 6 or more and 9 or fewer cycles of platinum chemotherapy. In some embodiments, the patient is receiving 4-8 cycles of platinum chemotherapy, i.e., the patient is receiving 4 or more and 8 or fewer cycles of platinum chemotherapy.

[0241] In some embodiments, the platinum-based chemotherapy regimen also includes surgery. In some embodiments, cytoreductive surgery occurs before administering platinum chemotherapy to the patient described herein (primary cytoreductive surgery). In some embodiments, the patient undergoes NACT, and the patient undergoes one or more cycles of platinum chemotherapy before cytoreductive surgery (intermediate cytoreductive surgery). In some embodiments, the patient undergoes NACT undergoes two or more (two or more) cycles of postoperative platinum chemotherapy after cytoreductive surgery.

[0242] Exemplary platinum chemotherapeutic agents suitable for the methods described herein include cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and / or satraplatin, or pharmaceutically acceptable salts thereof. In some embodiments, the first-line platinum-based chemotherapy comprises administration of cisplatin or carboplatin, or pharmaceutically acceptable salts thereof.

[0243] In some embodiments, the first-line platinum-based chemotherapy comprises administration of a second therapeutic agent in addition to the platinum chemotherapeutic agent.

[0244] In some embodiments, the first-line platinum-based chemotherapy includes administration of a second therapeutic agent that is a taxane chemotherapeutic agent (eg, paclitaxel or docetaxel, or a pharma- ceutically acceptable salt thereof).

[0245] In some embodiments, the first-line platinum-based chemotherapy comprises administration of a second therapeutic agent that is bevacizumab. In some embodiments, the first-line platinum-based chemotherapy comprises administration of a second therapeutic agent that is bevacizumab or a pharma- ceutically acceptable salt thereof.

[0246] In some embodiments, the first-line platinum-based chemotherapy is administered as intraperitoneal chemotherapy.

[0247] 2. Response to first-line platinum-based chemotherapy In some embodiments, administration of niraparib, or a pharma- ceutically acceptable salt thereof, is initiated within 12 weeks of the first day of the last cycle of chemotherapy (e.g., a platinum-based chemotherapy described herein).

[0248] In some embodiments, patients receiving PARP therapy (eg, niraparib) have cancer that has had a complete response to a first-line platinum-based chemotherapy regimen.

[0249] In some embodiments, patients receiving PARP therapy (eg, niraparib) have cancer that has had a partial response to a first-line platinum-based chemotherapy regimen.

[0250] In some embodiments, the response (e.g., complete or partial response) is assessed before the completion of the first-line platinum-based chemotherapy regimen. In some embodiments, the response (e.g., complete or partial response) is assessed at any time after the second or third cycle of platinum-based chemotherapy. In some embodiments, the response is assessed after three or more (three or more) cycles of platinum chemotherapy.

[0251] Tumor response to either platinum-based chemotherapy or PARP therapy (eg, niraparib administered following first-line platinum-based chemotherapy) can be assessed according to methods known in the art.

[0252] Tumor response can be measured, for example, by evaluating target and / or non-target lesions, for example, according to RECIST v 1.1 guidelines, for example, as described herein. This guideline is provided by EAEisenhauer, 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 by reference in its entirety. The guideline first requires an estimate of the overall tumor burden at baseline, which is used as a comparison for subsequent measurements. Tumors may be measured by using any imaging system known in the art, for example, by CT scan or X-ray. Measurable disease is defined by the presence of at least one measurable lesion. For studies in which the primary endpoint is tumor progression (either time to progression or rate of progression at a fixed date), the protocol should specify whether enrollment is restricted to those with measurable disease or whether patients with only nonmeasurable disease are also eligible.

[0253] If more than one measurable lesion is present at baseline, all lesions up to a total of five lesions (maximum two lesions per organ) representing all involved organs must be identified as target lesions, recorded and measured at baseline (this means that if a patient has only one or two involved organ sites, a maximum of two and four lesions will be recorded, respectively).

[0254] Target lesions are selected based on their size (lesions with the longest diameter) and should be representative of all involved organs, yet allow for reproducible and repeatable measurements.

[0255] Lymph nodes deserve special mention because they are normal anatomy and may be visible on imaging even when not associated with the tumor. To be defined as measurable and potentially identified as a target lesion, pathological lymph nodes must meet the criterion of a short axis of P15 mm by CT scan. Only the short axis of these lymph nodes contributes to the baseline total. The short axis of the lymph node is the diameter that is usually used by radiologists to determine whether the lymph node is associated with a solid tumor. Lymph node size is usually reported as 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 can be axial, sagittal, or coronal). The smaller of these measurements is the short axis.

[0256] For example, an abdominal lymph node reported as 20mm-30mm has a short axis of 20mm and qualifies as a malignant measurable lymph node. In this example, 20mm would be recorded as the lymph node measurement. All other pathological lymph nodes (those with a short axis of P10mm but less than 15mm) should be considered non-target lesions. Lymph nodes with a short axis less than 10mm should be considered non-pathological and not recorded or followed.

[0257] For all target lesions, the sum of the diameters (longer for non-lymph node lesions, short axis for lymph node lesions) is calculated and reported as the baseline sum diameter. If lymph nodes are included in the sum, only the short axis is added to the sum as described above. The baseline sum diameter is used as a reference to further characterize any objective tumor regression in measurable disease dimensions.

[0258] All other lesions (or sites of disease), including pathological lymph nodes, should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be tracked as "present," "absent," or in rare cases, "unequivocal progression." In addition, multiple non-target lesions associated with the same organ can be recorded as a single item on the case report (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases").

[0259] Target lesion responses may be assessed according to RECIST v 1.1 response criteria as follows: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (targeted or non-targeted) must have reduced in size to less than 10mm in their short axis. Partial Response (PR): At least a 30% reduction in the sum of the diameters of the target lesions, taken as the baseline sum diameter. Progression (PD): At least a 20% increase in the sum of the diameters of the target lesions, taken as reference to the smallest sum during the study (including the sum at baseline, if it was the smallest during the study). In addition to the 20% relative increase, 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 as progression). Stable (SD): There is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, based on the smallest summated diameter during the study.

[0260] Non-target lesion responses may be assessed according to response criteria per RECIST v 1.1 as follows: Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be of non-pathological size (short axis <10 mm). Non-CR / Non-PD: Persistence of 1 or 2 or more non-target lesions and / or maintenance of tumor marker levels above normal limits. Progressive disease (PD): Appearance of one or more new lesions and / or definite worsening of existing non-target lesions. Definite worsening should not normally be prioritized over target lesion status. This should represent a change in overall disease status, not an increase in a single lesion.

[0261] 3. Platinum-sensitive and platinum-resistant cancers Platinum-sensitive cancers are cancers that do not recur or progress after treatment with platinum chemotherapy for a period of at least about six months.

[0262] Platinum-resistant cancers are cancers that have an initial response to treatment with platinum chemotherapy, but in which recurrence or disease progression is observed within about six months following treatment.

[0263] In some embodiments, patients receiving niraparib are treated independent of the platinum-sensitive status of their cancer.

[0264] In some embodiments, patients receiving niraparib are treated independent of determining the platinum-sensitivity status of their cancer.

[0265] In some embodiments, the patient receiving niraparib has a cancer that is platinum-sensitive.

[0266] In some embodiments, the patient receiving niraparib has a cancer that is platinum-resistant.

[0267] IV. General Protocol As described herein, the methods provided include administering niraparib, or a pharma- ceutically acceptable salt thereof, to a patient, subject, or population of subjects according to a regimen that achieves any one or a combination of an increase in progression-free survival, a reduction in the hazard ratio for disease progression or death, and / or an increase in overall survival or a positive overall response rate.

[0268] In some embodiments, the methods described herein may be effective as first-line maintenance therapy for brain cancer in patients who have received and completed only one platinum-based chemotherapy regimen.

[0269] In some embodiments, the methods are suitable for prolonging the effect of first-line platinum-based chemotherapy in patients diagnosed with cancer (eg, brain cancer).

[0270] In some embodiments, the cancer is brain cancer.

[0271] In some embodiments, the brain cancer is a primary brain cancer.

[0272] In some embodiments, the brain cancer is glioma.

[0273] In some embodiments, the brain cancer is unmethylated MGMT glioma. In some embodiments, the brain cancer is unmethylated MGMT glioblastoma.

[0274] In some embodiments, the brain cancer is unmethylated glioma. In some embodiments, the brain cancer is unmethylated glioblastoma.

[0275] In some embodiments, the methods are suitable for treating primary or metastatic brain cancer.

[0276] In some embodiments, the suitable patient is a newly diagnosed primary or metastatic brain cancer. In some embodiments, the newly diagnosed primary or metastatic brain cancer patient has not yet received any treatment for the cancer (e.g., the newly diagnosed primary or metastatic brain cancer patient has not yet received any platinum chemotherapy, any radiation therapy, or any surgery). In some embodiments, the method comprises administering only one platinum-based chemotherapy regimen to the patient. In some embodiments, the patient's cancer responds to chemotherapy as evidenced by a complete or partial response. In some embodiments, the method comprises orally administering an effective dose of niraparib to the patient daily prior to determining the sensitivity of the cancer to the platinum-based chemotherapy regimen. In some embodiments, the cancer is platinum-sensitive. In some embodiments, the cancer is platinum-resistant.

[0277] In some embodiments, the suitable patient diagnosed with primary or metastatic brain cancer has previously undergone and completed one platinum-based chemotherapy regimen.For example, the suitable patient diagnosed with primary or metastatic brain cancer has previously undergone and completed only one platinum-based chemotherapy regimen.

[0278] In some embodiments, suitable patients are those with primary or metastatic brain cancer at high risk of disease progression.

[0279] In some embodiments, the primary or metastatic brain cancer is characterized as having BRCA deficiency and / or HRD (eg, positive HRD status).

[0280] In some embodiments, the primary or metastatic brain cancer is characterized by the absence of deleterious or suspected deleterious germline BRCA mutations.

[0281] In some embodiments, the primary or metastatic brain cancer is characterized by the absence of either germline or sporadic BRCA mutations.

[0282] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with an additional therapeutic agent, such as a chemotherapeutic agent. In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered before, during, or after administration of a chemotherapeutic agent. Administering niraparib or a pharmaceutically acceptable salt thereof simultaneously or sequentially with an additional therapeutic agent (e.g., a chemotherapeutic agent) is referred to as "combination therapy." In the combination therapy, niraparib, or a pharma- ceutically acceptable salt thereof, may 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 prior to), concomitantly with, or subsequent 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 after) administration of a chemotherapeutic agent to a subject in need thereof. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof and the chemotherapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 to 2 hours apart, 2 to 3 hours apart, 3 to 4 hours apart, 4 to 5 hours apart, 5 to 6 hours apart, 6 to 7 hours apart, 7 to 8 hours apart, 8 to 9 hours apart, 9 to 10 hours apart, 10 to 11 hours apart, 11 to 12 hours apart, 24 hours or less apart, or 48 hours or less apart.

[0283] In some embodiments, niraparib, or a pharma- ceutically acceptable salt thereof, is administered to a patient or subject population that has responded to a first-line platinum-based chemotherapy regimen.

[0284] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered to a patient as a first-line maintenance therapy after a complete or partial response to a first-line platinum-based chemotherapy regimen. The methods described herein are suitable for treating patients diagnosed with a cancer that is a primary or metastatic brain cancer, and for prolonging the effect of a first-line platinum-based chemotherapy regimen (e.g., as described herein).

[0285] In some embodiments, administration of niraparib, or a pharma- ceutically acceptable salt thereof, is initiated within 12 weeks of the first day of the last cycle of chemotherapy (e.g., a platinum-based chemotherapy described herein).

[0286] In some embodiments, the PARP therapy (e.g., administered after a first-line platinum-based chemotherapy regimen) comprises at least one oral dose of niraparib or a pharma- ceutically acceptable salt thereof. In some embodiments, the regimen comprises multiple oral doses. In some embodiments, the regimen comprises once-daily (QD) dosing.

[0287] In some embodiments, the PARP therapy 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 administration of an effective dose of niraparib or a pharma- ceutically acceptable salt thereof daily until disease progression or unacceptable toxicity occurs. In some embodiments, the regimen comprises a daily dose of at least 100, 200, or 300 mg of niraparib or a pharma- ceutically acceptable salt thereof, dosed daily until disease progression or unacceptable toxicity occurs.

[0288] In some embodiments, the oral dose is in the 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.

[0289] In some embodiments, the amount of niraparib is about 100 mg of niraparib. In some embodiments, the regimen comprises administration of 300 mg of niraparib once daily.

[0290] In some embodiments, the amount of niraparib is about 100 mg of niraparib. In some embodiments, the regimen comprises administration of 200 mg of niraparib once daily.

[0291] In some embodiments, the amount of niraparib is about 300 mg of niraparib. In some embodiments, the regimen comprises administration of 300 mg of niraparib once daily.

[0292] In some embodiments, the starting dose of niraparib treatment is based on the patient's baseline body weight or baseline platelet count. In some embodiments, patients with a baseline body weight of 77 kg or more and a baseline platelet count of 150,000 μL or more are administered niraparib in an amount equivalent to about 300 mg of niraparib free base per day. In some embodiments, patients with a baseline body weight of less than 77 kg or a baseline platelet count of less than 150,000 μL are administered niraparib in an amount equivalent to about 200 mg of niraparib free base per day. Additional dose modifications of study treatment will not be based on changes in the patient's body weight during study participation. For patients with a starting dose of about 200 mg of niraparib once daily, an increase to about 300 mg of niraparib once daily is permitted if no treatment interruption or discontinuation occurs during the first two treatment cycles. For any dose modification, the number of unit dosage forms (e.g., capsules or tablets) administered will be modified accordingly.

[0293] In some embodiments, the oral dose is administered in one or more unit dosage forms. In some embodiments, the one or more unit dosage forms are capsules. In some embodiments, the 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 is understood that any combination of unit dosage forms may be combined to form a once-daily (QD) dose. For example, three 100 mg unit dosage forms may be administered once daily such that about 300 mg of niraparib is administered once daily. In some embodiments, niraparib is administered as a single 300 mg unit dosage form. In some embodiments, niraparib is administered at 300 mg once daily. In some embodiments, niraparib is administered at 3 x 100 mg once daily (i.e., niraparib is administered as three 100 mg unit dosage forms). In some embodiments, niraparib is administered at 2×150 mg once daily (i.e., niraparib is administered as two 150 mg unit dosage forms).

[0294] In some embodiments, niraparib is administered as the free base form of niraparib. In some embodiments, niraparib is administered as a pharmaceutically acceptable salt of niraparib. In some embodiments, niraparib is administered as niraparib tosylate 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.

[0295] In some embodiments, the oral dose of niraparib is administered in a 7-day on, 7-day off regimen. In some embodiments, the 7-day on, 7-day off regimen includes three or more cycles. In some embodiments, the 7-day on, 7-day off regimen includes four 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 in the treatment of cancer. In some embodiments, the oral dose of niraparib is administered in combination with one additional active agent known to be useful in the treatment of cancer. In some embodiments, the oral dose of niraparib and one additional active agent are each administered in a 7-day on, 7-day off regimen. In some embodiments, the 7-day on, 7-day off regimen includes three or more cycles. In some embodiments, the 7-day on, 7-day off regimen includes four cycles. In some embodiments, niraparib is administered at weeks 1, 3, 5, and 7 of the regimen, and one additional active agent is administered at weeks 2, 4, 6, and 8 of the regimen. In some embodiments, the oral dose of niraparib is 45 mg / kg, and the oral dose of one additional active agent is 60 mg / kg. 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. In some embodiments, the one or more additional active agents are temozolomide. In some embodiments, the one or more additional active agents include temozolomide or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional active agents are atezolizumab. In some embodiments, the one or more additional active agents comprises atezolizumab or a pharma- ceutically acceptable salt thereof.In some embodiments, the one or more additional active agents are pembrolizumab. In some embodiments, the one or more additional active agents include pembrolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional active agents are toborafenib. In some embodiments, the one or more additional active agents include toborafenib or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional active agents are dostarlimab. In some embodiments, the one or more additional active agents include dostarlimab or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, dose interruptions (not to exceed 28 days) or dose reductions may be permitted based on treatment side effects. For patients with a starting dose of about 300 mg niraparib per day, a dose reduction to about 200 mg niraparib per day, followed by about 100 mg niraparib per day would be permitted.

[0297] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 6 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 9 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 12 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 15 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 18 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 21 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 24 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 27 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 30 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 33 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 36 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 39 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 42 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 45 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 48 months.

[0298] In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 9 to about 12 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 12 to about 15 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 15 to about 18 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 18 to about 21 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 21 to about 24 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 24 to about 27 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 27 to about 30 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 30 to about 33 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 33 to about 36 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 36 to about 39 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 39 to about 42 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 42 to about 45 months. In some embodiments, niraparib or a pharma- ceutically acceptable salt thereof is administered for at least about 45 to about 48 months.

[0299] In some embodiments, the method extends progression-free survival compared to a control. In some embodiments, the method reduces the hazard ratio for disease progression or death compared to a control. In some embodiments, the method extends overall survival compared to a control. In some embodiments, the method achieves an overall response rate of at least 30%. In some embodiments, the method achieves improved progression-free survival2 compared to a control. In some embodiments, the method achieves improved chemotherapy holiday compared to a control. In some embodiments, the method achieves improved time to first subsequent therapy compared to a control. In some embodiments, the method achieves improved time to second subsequent therapy compared to a control. In some embodiments, the method has been determined to have no adverse effect on quality of life as measured by FOSI and / or EQ-5D-5L. In some embodiments, it has been determined that the method does not affect the efficacy of subsequent treatment with a chemotherapeutic agent (e.g., a platinum agent, including but not limited to cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin).

[0300] Such an extension of progression-free survival may result in a reduction in the hazard ratio for disease progression or death. Maintenance therapy is administered during the period between discontinuation of first-line platinum-based chemotherapy regimens or radiation therapy aimed at delaying disease progression and subsequent intensive treatment, which may present tolerability problems for the patient. In another embodiment, the patient with primary or metastatic brain cancer is further characterized as having BRCA deficiency or HRD. In some embodiments, the patient has glioblastoma. In some embodiments, the patient has WHO grade II-IV glioma. In some embodiments, the patient has IDH1 / 2(+)ATRX mutant glioma.

[0301] In some embodiments, niraparib or a pharmaceutically acceptable salt thereof is administered as a maintenance therapy in patients with primary or metastatic brain cancer who have a complete or partial response after administration and completion of only one platinum-based chemotherapy treatment, where administration of niraparib or a pharmaceutically acceptable salt thereof results in an extension of progression-free survival. Such an extension of progression-free survival may result in a reduction in the hazard ratio for disease progression or death. Such first-line maintenance therapy is administered during the period between the interruption of chemotherapy aimed at delaying disease progression and subsequent intensive treatment, which may present tolerability problems for the patient. In some embodiments, the patient with primary or metastatic brain cancer is further characterized as having a BRCA deficiency or HRD. In some embodiments, the patient with primary or metastatic brain cancer is further characterized by the absence of a germline BRCA mutation that is or is suspected to be deleterious. In some embodiments, the patient has glioblastoma. In some embodiments, the patient has WHO grade II-IV glioma. In some embodiments, the patient has an IDH1 / 2(+)ATRX mutant glioma.

[0302] 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, independent of the sensitivity of the cancer to platinum. In some embodiments, the method comprises administering niraparib or a pharmaceutically acceptable salt thereof according to a regimen determined to achieve an increase in progression-free survival. In some embodiments, progression-free survival is longer in patients receiving niraparib or a pharmaceutically acceptable salt thereof, for example, compared to patients not receiving niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, progression-free survival is longer in patients receiving niraparib or a pharmaceutically acceptable salt thereof, than in patients receiving alternative cancer therapy, such as treatment with a different PARP inhibitor. In some embodiments, the patient has a primary or metastatic brain cancer that has shown a partial response to platinum-based chemotherapy prior to administration of niraparib or a pharmaceutically acceptable salt thereof (e.g., a platinum-sensitive or platinum-resistant primary or metastatic brain cancer that has shown a partial response to platinum chemotherapy). In some embodiments, the patient has a primary or metastatic brain cancer that has shown a complete response to platinum-based chemotherapy prior to administration of niraparib or a pharmaceutically acceptable salt thereof (e.g., a platinum-sensitive or platinum-resistant primary or metastatic brain cancer that has shown a complete response to platinum chemotherapy).

[0303] In some embodiments, the present invention provides a method of administering niraparib or a pharma- ceutically acceptable salt thereof to a patient with a platinum-sensitive primary or metastatic brain cancer, comprising administering niraparib or a pharma- ceutically acceptable salt thereof according to a regimen determined to achieve an increase in progression-free survival. In some embodiments, progression-free survival is longer in a patient receiving niraparib or a pharma- ceutically acceptable salt thereof, for example, compared to a patient not receiving niraparib or a pharma- ceutically acceptable salt thereof. In some embodiments, progression-free survival is longer in a patient receiving niraparib or a pharma- ceutically acceptable salt thereof than in a patient receiving an alternative cancer therapy, such as treatment with a different PARP inhibitor. In some embodiments, the patient has a primary or metastatic brain cancer that has shown a partial response to platinum-based chemotherapy prior to administration of niraparib or a pharma- ceutically acceptable salt thereof. In some embodiments, the patient has primary or metastatic brain cancer that has had a complete response to platinum-based chemotherapy prior to administration of niraparib or a pharmaceutically acceptable salt thereof.

[0304] 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, comprising administering niraparib or a pharmaceutically acceptable salt thereof according to a regimen determined to achieve an increase in progression-free survival. In some embodiments, progression-free survival is longer in patients receiving niraparib or a pharmaceutically acceptable salt thereof, for example, compared to patients not receiving niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, progression-free survival is longer in patients receiving niraparib or a pharmaceutically acceptable salt thereof than in patients receiving an alternative cancer therapy, such as treatment with a different PARP inhibitor. In some embodiments, the patient has a primary or metastatic brain cancer that has shown a partial response to platinum-based chemotherapy prior to administration of niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has primary or metastatic brain cancer that has had a complete response to platinum-based chemotherapy prior to administration of niraparib or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, for purposes of determining progression-free survival, progression is determined by 1) tumor assessment by CT / MRI showing overt progression according to RECIST 1.1 criteria, and / or 2) additional diagnostic tests identifying new lesions (e.g., histology / cytology, ultrasound techniques, endoscopy, positron emission tomography).

[0306] In some embodiments, the patient is characterized as having a homologous recombination deficiency. In some embodiments, the patient has a positive homologous recombination deficiency status. Homologous recombination deficiency status can be established according to methods known to those of skill in the art.

[0307] 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, progression free survival is at least about 48 months.

[0308] 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 or metastatic), comprising administering niraparib or a pharmaceutically acceptable salt thereof according to a regimen determined to achieve a hazard ratio for disease progression or death. In some embodiments, the hazard ratio is improved in patients receiving niraparib or a pharmaceutically acceptable salt thereof, for example, compared to patients not receiving niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the hazard ratio is improved in patients receiving niraparib or a pharmaceutically acceptable salt thereof, compared to patients receiving an alternative cancer therapy, such as treatment with a different PARP inhibitor. In some embodiments, the present invention relates to a method for switching a patient receiving cancer treatment with olaparib or a pharmaceutically acceptable salt thereof to treatment comprising niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention relates to a method for switching a patient undergoing treatment of brain cancer 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 for treating brain cancer (primary or metastatic), comprising administering niraparib or a pharmaceutically acceptable salt thereof to a patient previously undergoing treatment with at least one PARP inhibitor other than niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the 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 pharmaceutically acceptable salts 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, niraparib exhibits superior brain penetration when compared to other PARP inhibitors (eg, olaparib), as evidenced in Examples 3 and 4.

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

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

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

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

[0313] Additional / Supporting Embodiments 1. A method of treating primary or metastatic brain cancer in a human subject in need thereof, comprising administering to the human subject an effective dose of niraparib, or a pharma- ceutical acceptable salt thereof. 2. The method of embodiment 1, wherein the human subject is also treated with radiation therapy, in particular stereotactic radiation therapy. 3. The method of embodiment 1 or 2, wherein the primary or metastatic brain cancer is newly diagnosed. 4. The method of embodiment 2 or 3, wherein the niraparib and radiation therapy are initiated after resection of the primary brain cancer tumor. 5. The method according to any one of embodiments 2 to 4, wherein the radiation therapy is about 60 Gy (Gy). 6. The method according to any one of embodiments 2 to 4, wherein the radiation therapy is about 10 Gy (Gy). 7. The method of any one of embodiments 2-6, wherein administration of niraparib and radiation therapy is carried out for about 6 to about 7 weeks. 8. The method of any one of embodiments 2-7, wherein the human subject, after treatment with niraparib and radiation therapy, further receives a maintenance treatment of niraparib without radiation therapy. 9. The method of any one of embodiments 1-8, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered at a dose equivalent to 200 mg or 300 mg of niraparib free base. 10. The method of any one of embodiments 1-9, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered as niraparib tosylate monohydrate. 11. The method of any one of embodiments 1-10, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered in the form of a tablet. 12. The method of any one of embodiments 1-11, wherein the dose of niraparib or a pharma- ceutically acceptable salt thereof is administered daily. 13. The method of any one of embodiments 1-12, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered in a daily dose equivalent to about 300 mg of niraparib free base. 14. The method of any one of embodiments 1-12, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered in a daily dose equivalent to about 200 mg of niraparib free base. 15. The method of any one of embodiments 1-14, 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 / rhabdomyosarcoma, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+)ATRX mutant glioma, malignant glioma, and primitive neuroectodermal tumor of the brain. 16. The method of any one of embodiments 1 to 15, wherein the primary brain cancer is a WHO grade IV tumor. 17. The method of embodiment 16, wherein the primary brain cancer is glioblastoma. 18. The method of embodiment 17, wherein the human subject exhibits an unbound niraparib concentration greater than 5-fold the biochemical IC50 value of niraparib within non-gadolinium enhancing regions of the brain cancer tumor. 19. The method of embodiment 18, wherein the concentration of unbound niraparib in non-gadolinium enhancing areas of brain cancer tumors is measured after 4 days of pre-surgery niraparib (300 mg QD), 3-5 hours or 8-12 hours after the last dose, prior to planned resection. 20. The method of embodiment 18, wherein the concentration of unbound niraparib in non-gadolinium enhancing areas of brain cancer tumors is measured after 4 days of pre-surgery niraparib (200 mg QD), 3-5 hours or 8-12 hours after the last dose, prior to planned resection. 21. The method of any one of embodiments 18-20, wherein the 5-fold biochemical IC50 value of Niraparib is 19 nM. 22. The method of any one of embodiments 1-21, wherein the brain / plasma ratio of niraparib is about 0.5. 23. The method of any one of embodiments 1-22, wherein niraparib, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional active agents known to be useful in the treatment of cancer. 24. The method of embodiment 23, wherein the one or more additional active agents is temozolomide, bevacizumab, or a combination thereof. 25. The method of any one of embodiments 1-24, wherein the human subject or cancer has a complete or partial response to platinum-based chemotherapy. 26. The method of any one of embodiments 1-25, wherein the cancer is platinum-insensitive. 27. The method of any one of embodiments 1-25, wherein the cancer is platinum-sensitive. 28. The method of any one of embodiments 1 to 27, wherein the cancer is homologous recombination deficient (HRD) negative. 29. The method of embodiment 1, wherein the primary or metastatic brain cancer is recurrent. 30. The method of embodiment 29, wherein niraparib administration is initiated after resection of the brain cancer tumor. 31. The method of embodiment 29 or 30, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered as a maintenance therapy. 32. The method of any one of embodiments 29-31, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered at a dose equivalent to 200 mg or 300 mg of niraparib free base. 33. The method of any one of embodiments 29-32, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered as niraparib tosylate monohydrate. 34. The method of any one of embodiments 29-33, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered in the form of a tablet. 35. The method of any one of embodiments 29-34, wherein the dose of niraparib or a pharma- ceutically acceptable salt thereof is administered daily. 36. The method of any one of embodiments 29-35, wherein the primary recurrent 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 / rhabdomyosarcoma, pinealoma, diffuse intrinsic pontine glioma, IDH1 / 2(+)ATRX mutant glioma, malignant glioma, and primitive neuroectodermal tumor of the brain. 37. The method of any one of embodiments 29-36, wherein the primary recurrent brain cancer is a WHO grade II-IV tumor. 38. The method of any one of embodiments 29-37, wherein the primary recurrent brain cancer is IDH1 / 2(+)ATRX mutant glioma. 39. The method of embodiment 38, wherein the human subject exhibits a chromosomal fusion in a C-circle assay with a cutoff Ct value of 35. 40. The method of embodiment 38, wherein chromosomal fusions in a C-circle assay are measured after 4 days of pre-surgery niraparib (300 mg QD (300 mg administered once a day)) treatment, prior to planned resection, 3-5 hours or 8-12 hours after the last dose. 41. The method of any one of embodiments 29-40, wherein the brain / plasma ratio of niraparib is about 0.5. 42. The method of any one of embodiments 29-41, wherein niraparib, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional active agents known to be useful in the treatment of cancer. 43. The method of embodiment 42, wherein the one or more additional active agents is temozolomide, bevacizumab, or a combination thereof. 44. The method of any one of embodiments 29-43, wherein the human subject or cancer has a complete or partial response to platinum-based chemotherapy. 45. The method of any one of embodiments 29-44, wherein the cancer is platinum-insensitive. 46. ​​The method of any one of embodiments 29-44, wherein the cancer is platinum-sensitive. 47. The method of any one of embodiments 29 to 46, wherein the cancer is homologous recombination deficient (HRD) negative. 48. The method of any one of embodiments 1 to 47, wherein the metastatic brain cancer has spread from its site of origin in the lung, breast, colon, kidney, and melanoma. 49. The method of embodiment 48, wherein the metastatic brain cancer is asymptomatic or is an active progressive brain metastasis. 50. The method of 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. 51. The method of embodiment 48 or 49, wherein the metastatic brain cancer is caused by a breast cancer selected from solid tumors, ductal carcinoma in situ (DCIS, ductal carcinoma in situ), invasive breast cancer (ILC or IDC, invasive lobular carcinoma or invasive ductal carcinoma), triple-negative breast cancer (TNBC), and inflammatory breast cancer. 52. The method of embodiment 48 or 49, wherein the metastatic brain cancer is caused by a renal cancer selected from solid tumors, renal clear cell carcinoma, papillary renal carcinoma, chromophobe renal carcinoma, renal cell carcinoma, urothelial carcinoma, renal sarcoma, Wilms' tumor, and renal lymphoma. 53. The method of embodiment 48 or 49, wherein the metastatic brain cancer is caused by a colon cancer selected from colorectal cancer, squamous cell carcinoma, gastrointestinal neuroendocrine tumor, solid tumor, and adenocarcinoma. 54. The method of embodiment 48 or 49, wherein the metastatic brain cancer is caused by a melanoma selected from superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentigo melanoma, choroidal melanoma, conjunctival melanoma, iris melanoma, and mucosal melanoma. 55. The method of any one of embodiments 48-54, wherein niraparib administration is initiated after resection of the brain cancer tumor. 56. The method of embodiment 55, wherein the human subject is also treated with radiation therapy, in particular stereotactic radiation therapy. 57. The method of embodiment 56, wherein the niraparib and radiation therapy are initiated after resection of the metastatic brain cancer tumor. 58. The method of any one of embodiments 48-57, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered as a maintenance therapy. 59. The method according to any one of embodiments 48-58, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered at a dose equivalent to 200 mg or 300 mg of niraparib free base. 60. The method of any one of embodiments 48-59, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered as niraparib tosylate monohydrate. 61. The method according to any one of embodiments 48-60, wherein niraparib or a pharma- ceutically acceptable salt thereof is administered in the form of a tablet. 62. The method of any one of embodiments 48-61, wherein the dose of niraparib or a pharma- ceutically acceptable salt thereof is administered daily. 63. The method of any one of embodiments 48-62, wherein the metastatic brain cancer includes asymptomatic and active progressive brain metastases. 64. The method of any one of embodiments 48-63, wherein the brain / plasma ratio of niraparib is about 0.5. 65. The method of any one of embodiments 48-64, wherein niraparib, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional active agents known to be useful in the treatment of cancer. 66. The method of embodiment 65, wherein the one or more additional active agents is temozolomide, bevacizumab, or a combination thereof. 67. The method of any one of embodiments 48-66, wherein the human subject or cancer has a complete or partial response to platinum-based chemotherapy. 68. The method of any one of embodiments 48-66, wherein the cancer is platinum-insensitive. 69. The method of any one of embodiments 48-66, wherein the cancer is platinum-sensitive. 70. The method of any one of embodiments 48 to 69, wherein the cancer is homologous recombination deficient (HRD) negative. 71. The method of any one of embodiments 1-70, comprising administering niraparib, or a pharma- ceutically acceptable salt thereof, to a patient who has been previously treated with at least one PARP inhibitor other than niraparib, or a pharma- ceutically acceptable salt thereof. 72. The method of embodiment 71, wherein the at least one PARP inhibitor other than niraparib or a pharma- ceutically acceptable salt thereof is selected from the group consisting of olaparib, pamiparib, rucaparib, and talazoparib, and pharma- ceutically acceptable salts thereof. 73. The method of embodiment 71, wherein the at least one PARP inhibitor other than niraparib or a pharma- ceutically acceptable salt thereof is olaparib or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0314] The following examples are offered to illustrate, but not to limit, the claimed invention.

[0315] Example 1: Phase 0 "trigger" trial of niraparib in newly diagnosed glioblastoma and recurrent IDH1 / 2(+)ATRX mutant glioma This is an open-label, multicenter, Phase 0 study with an expansion phase, which will enroll up to 24 participants with newly diagnosed glioblastoma and up to 18 participants with recurrent glioma with IDH mutation and ATRX deficiency. As described below, the trial will consist of a Phase 0 component (subdivided into Arms A and B), as well as a treatment expansion phase. Patients with tumors that show a positive PK response (Arm A) and a positive PD response (Arm B) in the Phase 0 component of the study will proceed to a treatment expansion phase, which combines therapeutic dosing of niraparib with standard of care fractionated radiation therapy (Arm A) or niraparib monotherapy (Arm B) until disease progression.

[0316] Arm A will enroll patients exclusively at the Ivy Brain Tumor Center, while Arm B will take place at UCSF Medical Center in addition to the Ivy Brain Tumor Center.

[0317] Phase 0 Arm A: Participants undergoing resection of presumptive newly diagnosed glioblastoma (WHO grade 4) will be treated with niraparib for 4 days prior to surgical resection. Up to 24 participants will receive pre-surgical niraparib, with 12 participants expected to reach the treatment expansion phase (see below). The final pre-surgical dose will be administered 3-5 hours or 8-10 hours prior to tumor resection. Allocation to time cohorts will be random. Participants who do not demonstrate a histologically proven diagnosis of glioblastoma following craniotomy will be replaced. In each of the two time cohorts, tumor PK and PD analyses will be performed at the Ivy Brain Tumor Center.

[0318] 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 obtained pre-dose on day 1 and on day 4 (the day of surgery) pre-dose (trough levels), 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose.

[0319] For PD analysis, gadolinium-enhanced tumor tissues harvested during surgery are sectioned into four similarly sized tissue sections. Two tissue specimens are exposed to 10 Gy of IR using a RAD2000 device, and two specimens are sham-irradiated (non-irradiated). One sham control and 10 Gy irradiated tissue pair is fixed in formalin solution for FFPE slides. The other pair is snap frozen for PAR ELISA assay. Additional gadolinium-enhanced tumor tissues are cryopreserved for genomic analysis.

[0320] [Table 1]

[0321] Optimal Time-Interval (OTI) is the surgical time interval (STI) from the last pre-surgical dose to tumor resection to detect maximum unbound drug concentration in non-enhancing tumors. OTI will be determined after recruiting 3 participants in each cohort. After determining OTI, the remaining 18 participants in Arm A will be recruited to OTI either 3-5 hours or 8-10 hours after the last dose. Arm B will be recruited to the OTI determined in Arm A.

[0322] Pharmacokinetics (PK) methods Unbound niraparib concentrations in non-gadolinium-enhancing glioblastoma tissue are the primary endpoint of this Phase 0 study. Total and unbound niraparib concentrations in plasma, CSF, and gadolinium-enhancing and non-gadolinium-enhancing regions of tumor will be assessed for each patient 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.

[0323] Progression to the treatment expansion phase of the study must demonstrate a positive PK response, defined as an unbound niraparib concentration greater than five times the biochemical IC50 value within non-gadolinium-enhancing areas of the tumor.

[0324] Pharmacodynamics (PD) method A "functional" PD assay testing PAR activity in the context of ex vivo irradiation will serve as a secondary endpoint of this protocol. Tumor tissue from both ex vivo irradiated and non-irradiated will be FFPE embedded in the Ivy Center's CLIA-certified PD Core, and immunohistochemistry (IHC) assays will be used to assess changes in PAR, cleaved caspase 3, γH2AX, and Ki67. Alternatively, ELISA assays to quantify PAR levels will be performed using frozen lysates from a second control and irradiated sample pair.

[0325] Arm B: Enrollment in Arm B will begin after six participants (three in each time cohort) have been enrolled in Arm A and the optimal time interval (OTI) has been determined. Participants undergoing resection of recurrent WHO grade II, III, or IV gliomas with IDH1 or IDH2 mutations and ATRX deficiency will be treated with niraparib for four days prior to planned surgical resection. Up to 18 participants will receive pre-surgical niraparib, with 12 participants expected to arrive within the treatment expansion phase. The final dose will be administered OTI before the surgical specimen is taken. Following resection, participants without histologically evident tumor recurrence (e.g., pseudoprogression) will be replaced. Tumor PK and PD analyses will be performed for patients in each of the two time cohorts.

[0326] 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 obtained pre-dose on day 1 and on day 4 (the day of surgery) pre-dose (trough levels), 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose.

[0327] For PD analysis, tumor tissue collected during surgery will be snap frozen to assess chromosomal fusions as the primary endpoint. Additional exploratory assays will be performed, including c-circle assays and immunohistochemistry for MIB-1, cleaved caspase-3, and H2AX. Archival or pre-surgical biopsies, if available, will be used for baseline comparison. Tumor tissue collected during additional surgeries will be frozen and stored for genomic analysis.

[0328] [Table 2]

[0329] Pharmacokinetic (PK) Methods Unbound niraparib concentrations in non-gadolinium enhancing glioma tissues are a secondary endpoint in Arm B of this protocol. Total and unbound niraparib concentrations in plasma, CSF, and gadolinium enhancing and non-gadolinium enhancing regions of the tumor will be assessed for each patient 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.

[0330] Pharmacodynamic (PD) methods PCR-based quantification of chromosome fusions will serve as the primary endpoint in Arm B of this protocol. gDNA will be extracted using frozen lysates derived from intraoperative tumor tissues at the Ivy Center's CLIA-certified PD Core. 25ng of gDNA will be used for qPCR-based detection of chromosome fusions. C-circle assays will be performed as exploratory endpoints. Quantification of MIB-1, γH2AX, and cleaved caspase-3 by immunohistochemistry assays will be performed.

[0331] For enrollment in the expansion portion of the study, a positive PD response was defined as the presence of a chromosome fusion at a cutoff Ct value of 35.

[0332] Treatment expansion phase: Arm A: Patients whose tumors have an unmethylated MGMT promoter and demonstrate a positive PK response (see above) in the phase 0 component of arm A will enter the treatment expansion phase of the study. These participants will receive niraparib in combination with radiation (60 Gy over 6-7 weeks, as per standard of care). For patients weighing less than 77 kg (less than 170 lbs) or with a platelet count less than 150,000 / mcL, the recommended dosage is 200 mg taken orally once daily. For patients weighing 77 kg or more (170 lbs or more) and with a platelet count of 150,000 / mcL or more, the recommended dosage is 300 mg taken orally once daily.

[0333] Following radiation therapy, study participants may receive niraparib maintenance treatment, which begins after a 4-week washout period (+7 days) to allow recovery from niraparib treatment in addition to RT. Participants will continue to receive maintenance treatment until disease progression, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or termination of the study by the sponsor.

[0334] Arm B: Patients whose tumors demonstrate a positive PD response (see above) in the Phase 0 component of Arm B will enter the expansion component of the study. Participants will receive niraparib until disease progression, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or termination of the study by the sponsor. For patients weighing less than 77 kg (less than 170 lbs) or with a platelet count less than 150,000 / mcL, the recommended dosage is 200 mg taken orally once daily. For patients weighing 77 kg or more (170 lbs or more) and with a platelet count of 150,000 / mcL or more, the recommended dosage is 300 mg taken orally once daily.

[0335] All participants (Arms A and B) will return to the clinic for safety monitoring according to the event schedule until treatment ends, and then will be contacted approximately every 3 months by letter or telephone for collection of survival data for up to 24 months. Follow-up for long-term survival will begin after completion of the Day 28 safety follow-up visit.

[0336] Additional biomarker analysis will be performed using surgical tissues. If a participant undergoes a repeat craniotomy or biopsy due to recurrence or progression of his / her brain tumor, the Ivy Brain Tumor Center will request samples from the resected tumor to allow for longitudinal sampling and analysis, which will help identify possible resistance mechanisms.

[0337] Main purpose 1. Phase 0: Arm A: To evaluate the relative pharmacokinetics (PK) of niraparib in tumor tissue obtained from glioblastoma participants treated with niraparib. Arm B: To evaluate the pharmacodynamic (PD) impact of niraparib in tumor tissue obtained from patients with WHO grades 2-4. 2. Expansion: Study progression-free survival (6 months) in participants who demonstrate PK (Arm A) and PD (Arm B) responses.

[0338] Primary endpoint 1. Phase 0: Arm A: PK analysis of total and unbound niraparib concentrations in Gd-enhanced and Gd-non-enhanced tumor tissues. Evaluate intraoperative tumor (enhanced and non-enhanced tissues) versus plasma (collected during surgery) partition coefficients of total (Kp) and unbound (Kp,uu) niraparib drug levels. Arm B: Presence of chromosomal fusions in niraparib-treated glioma tissues with IDH and ATRX deficiency for PD analysis. 2. Expansion: Examine progression-free survival measured from the time of surgery to the date of recurrence.

[0339] exploratory purpose 1. Phase 0: To evaluate additional pharmacodynamic (PD) biomarkers of niraparib. 2. Phase 0: To evaluate the relative pharmacokinetics (PK) of niraparib in CSF.

[0340] Exploratory endpoints 1. Phase 0: For Arm A: Quantification of γH2AX, ClCas3, and Ki67 positive cells will be summarized in ex vivo irradiated samples. For arm B, quantification of c-circle, γH2AX, ClCas3, and Ki67 positive cells is summarized. 2. Phase 0: Determine niraparib levels in CSF during surgery (3-5 hours and 8-10 hours).

[0341] Study population: Arm A: Patients undergoing planned resection for newly diagnosed suspected glioblastoma. Arm B: Patients undergoing planned resection for recurrent WHO grade 2-4 gliomas with IDH mutation and ATRX deficiency.

[0342] To be eligible to take part in the study, each participant must meet all of the following inclusion criteria and none of the exclusion criteria.

[0343] Inclusion Criteria: 1. Arm A, participants undergoing resection for newly diagnosed suspected glioblastoma. For Arm B, participants who have undergone upfront resection of histologically diagnosed WHO grade II-IV glioma with IDH1 or IDH2 mutation and ATRX deficiency and will undergo resection. 2. Participants in Arm A must have measurable disease preoperatively, defined as at least one contrast-enhancing lesion with two perpendicular measurements of at least 1 cm. 3. You are able to understand and willing to sign a written informed consent (either personally or, if applicable, by your legally authorized representative). 4. Participants have voluntarily agreed to participate by providing written informed consent (either personally or by a legally authorized representative, if applicable). Written informed consent for the protocol must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it must be formally documented and attested to, ideally by an independent and reliable witness. 5. Willing and able to comply with visit schedules, treatment schedules, laboratory tests, and other procedures. 6. You are 18 years of age or older at the time of consent. 7. Have a performance status (PS) of 2 or less on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al. 1982). 8. Ability to swallow oral medications. 9. A negative serum pregnancy test (β-hCG) confirmed prior to initiating study treatment or a participant who is no longer fertile due to surgical, chemical, or natural menopause. If a serum pregnancy test is completed >7 days after Day 1, a urine pregnancy test must be performed prior to dose administration on Day 1 to confirm a negative result. 10. For females of reproductive potential: Use highly effective contraception for at least 1 month prior to treatment, and agree to use such methods during study participation and for an additional 3 months after completion of treatment administration. 11. For males of reproductive potential: Use condoms or other methods to ensure effective contraception with your partner for an additional 3 months after the end of treatment. Avoid sperm donation during the study and for an additional 3 months after the end of treatment. 12. Agree to follow the Lifestyle Considerations for the duration of the study. 13. Participants who received chemotherapy must have recovered from the acute effects of chemotherapy (Common Terminology Criteria for Adverse Events [CTCAE] grade ≤1) except for residual alopecia or grade 2 peripheral neuropathy prior to Day 1. A washout period of at least 21 days (or longer at the investigator's discretion) is required between the last chemotherapy dose and Day 1. 14. Females of fertile potential must agree to abstain from breastfeeding beginning at screening, throughout the study, and for 6 months after the final study drug dose. 15. Participants must have normal blood pressure or adequately treated and controlled hypertension (defined as systolic BP ≤ 140mmHg and diastolic BP ≤ 90mmHg). 16. Participant will have adequate bone marrow and organ function as defined by the following laboratory values ​​(to be assessed by local laboratory for eligibility): Adequate bone marrow function: Absolute neutrophil count ≥ 1,500 / mcL Platelet count (at the time of surgery) ≥ 100,000 / mcL Hemoglobin level 9.0 g / dL or higher Participants may receive red blood cell transfusions to achieve this hemoglobin level at the discretion of the investigator. The first treatment should not begin earlier than the day after the red blood cell transfusion. Proper liver function: Total bilirubin ≤ 1.5 × ULN. Participants with Gilbert syndrome who have total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are accepted. AST (SGOT) is 2.5 x facility ULN or less ALT (SGPT) is 2.5 x facility ULN or less Adequate renal function: Estimated glomerular filtration rate (eGFR) of 30mL / min / 1.73m2 or more according to the Chronic Disease Epidemiology Collaboration (CKD-EPI) formula INR ≤ 1.5 × ULN

[0344] Exclusion criteria: 1. Current use of a coumarin-derived anticoagulant, prophylactic, or otherwise, that cannot be discontinued prior to surgery. Treatment with heparin, low molecular weight heparin (LMWH), or fondaparinux is acceptable. 2. Pregnancy or breastfeeding. 3. There have been known allergic reactions to components of niraparib tablets, including FD&C Yellow No. 5. 4. Active infection requiring systemic antibiotic, antifungal, or antiviral therapy or fever >38.5°C within 4 weeks from Day 1. 5. Known to have active (acute or chronic) or uncontrolled severe infection, liver disease, e.g., cirrhosis, decompensated liver disease, and active and chronic hepatitis as determined by the investigator. 6. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at the time of initiating study treatment), fungal infection, or detectable viral infection (e.g., known positive human immunodeficiency virus, or known active hepatitis B or C [e.g., positive hepatitis B surface antigen]). Screening is not required for recruitment. 7. Any of the following cardiovascular criteria: Current Evidence for Cardiac Ischemia Current symptomatic pulmonary embolism Acute myocardial infarction within 6 months prior to Day 1 -New York Heart Association Classification III or IV heart failure within 6 months prior to Day 1 Grade 2 or higher ventricular arrhythmia within 6 months prior to Day 1 - Stroke (CVA) or transient ischemic attack (TIA) within 6 months prior to Day 1 8. Participant has myelodysplastic syndrome / acute myeloid leukemia or has features suggestive of MDS / AML. 9. The participant has a severe and / or uncontrolled pre-existing medical condition that, in the opinion of the investigator, would preclude participation in this study (e.g., interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment, history of major surgical resection involving the stomach or small intestine, or pre-existing Crohn's disease or ulcerative colitis or a pre-existing chronic condition resulting in baseline grade 2 or higher diarrhea). 10. Prior treatment with a therapeutic dose of a PARP inhibitor. 11. Treatment with another investigational drug or other therapeutic intervention within 5 half-lives of the investigational product.

[0345] Phase: Phase 0 with treatment expansion phase

[0346] Description of the location / facility where participants will be recruited: Arm A: Participants will be recruited for this study at one site in the United States. Arm B: 2 locations in the United States.

[0347] Description of study intervention: Phase 0: For arm A, niraparib is administered orally once daily for 4 days prior to surgical resection. The last dose is an AM dose on day 4, 3-5 hours or 8-10 hours prior to planned resection. For arm B, niraparib is administered orally once daily for 4 days prior to surgical resection. The last dose is an AM dose on day 4, 3-5 hours or 8-10 hours prior to planned resection. expansion: Arm A: Participants with positive PK and unmethylated MGMT promoter (from Phase 0): Niraparib will be administered orally once daily continuously (7 days / week) in combination with RT 5 days / week for 6–7 weeks. Day 1 of each cycle will occur as the first day of radiation therapy. Arm B: Niraparib will be taken orally once daily by participants with positive PD (from Phase 0) as long as the drug is tolerated and the investigator believes the participant may be benefiting. Treatment will be taken by participants until progression is confirmed or end of treatment. Each arm will receive niraparib as follows: For patients weighing less than 77 kg (less than 170 lbs) or with a platelet count less than 150,000 / mcL, the recommended dosage is 200 mg taken orally once daily. For patients weighing 77 kg or more (170 lbs or more) and with a platelet count of 150,000 / mcL or more, the recommended dosage is 300 mg taken orally once daily. Maintenance Phase (Arm A): Niraparib (administered continuously on days 1–28). For patients weighing less than 77 kg (less than 170 lbs) or with a platelet count less than 150,000 / mcL, the recommended dosage is 200 mg taken orally once daily. For patients weighing 77 kg or more (170 lbs or more) and with a platelet count of 150,000 / mcL or more, the recommended dosage is 300 mg taken orally once daily.

[0348] Research period: The estimated total study length of approximately 38 months will include 2 months of protocol preparation (including IRB / IND approval), 12 months of study enrollment of 24 newly diagnosed nonmethylated glioblastoma patients (arm A) and 18 recurrent gliomas (arm B), and 24 months of follow-up of expansion phase participants.

[0349] The Ivy Brain Tumor Center performs approximately 600 surgeries for gliomas annually. Approximately 150 are newly diagnosed WHO grade IV gliomas. Of the 400 surgeries for recurrent gliomas per year, over 90% are for recurrent WHO grade II-IV gliomas.

[0350] UCSF Medical Center performs approximately 400 glioma surgeries annually. Approximately 100 are newly diagnosed WHO grade IV gliomas. Of the 300 recurrent glioma surgeries per year, over 90% are recurrent WHO grade II-IV gliomas.

[0351] Participation period: Phase 0: Up to approximately 2 months (from the 28-day screening window to the 28-day follow-up visit). Expansion (Arm A): Treatment for up to approximately 6 weeks. Expansion (Arm B): Niraparib will be taken by participants as long as the drug is tolerated and the investigator believes the participant may benefit. Treatment will be taken by participants until progression or end of treatment. Maintenance (Arm A): Niraparib will be taken by participants as long as the drug is tolerated and the investigator believes the participant may be benefiting. Treatment will be taken by participants until progression or end of treatment. All participants in Arm A will be followed for survival for up to 24 months. All participants in Arm B will be followed for survival for up to 48 months.

[0352] Statistical considerations: The primary objective is an exploratory study to evaluate the PK of niraparib in arm A and the PD of niraparib in arm B, and to test progression-free survival (PFS6) in both arms, without formal statistical hypothesis testing. The sample size was verified based on feasibility and previous studies by our group. In arm A, up to 12 participants will be assigned to each time cohort, and in arm B, up to 9 participants will be assigned to each time cohort. The planned sample size for phase 0 is up to 24 newly diagnosed glioblastoma patients for arm A and 18 recurrent glioma patients with IDH and ATRX mutations for arm B. The proportion of positive PK responses for each cohort will be reported in the phase 0 primary endpoint of PK analysis. To compare PD biomarkers, ex vivo treated tumor tissues will be tested with and without radiation treatment. After quantifying the percentage of individual biomarker-positive cells, log-transformed positive cell percentages are compared between treated and untreated tissues using paired t-tests at the two-sided 5% level. Chi-square test and normal approximation and corresponding 95% confidence intervals based on the difference in proportions at PFS6 are calculated for participants in the expansion phase. Log-rank tests are applied to compare overall survival between the two treatments using Kaplan-Meier curve analysis. Baseline characteristics including demographics and laboratory measurements are summarized using descriptive statistics. Means, medians, minimums, and maximums are reported for continuous values ​​such as age and laboratory values, and N and % are reported for categorical values ​​such as gender and performance status. The protocol for the Phase 0 Arm A and Arm B studies is summarized in Figure 1. The protocol for Arm A is further summarized in FIG.

[0353] Interim results, Arm A Methods: Newly diagnosed GBM patients received 4 days of pre-surgical niraparib (300 mg QD) prior to planned resection 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 unbound niraparib concentrations were measured using a validated LC-MS / MS method. Eligibility for the treatment expansion phase was determined by a PK "trigger," defined as unbound [niraparib] >5-fold the biochemical IC50 in non-enhancing tumors (i.e., 19 nM). Evidence of PARP inhibition was assessed by quantification of PARPylation in surgical tissues compared to 10 Gy ex vivo irradiation and non-irradiated control tissues. Patients with O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors above the PK threshold were eligible for expansion-phase dosing of niraparib plus fractionated radiotherapy, followed by a maintenance phase of niraparib monotherapy.

[0354] Results: Twelve patients were enrolled in the phase 0 study, and two patients progressed to the expansion phase. One patient experienced a grade 3 treatment-related adverse event (elevated ALT and AST) during phase 0, and two patients showed treatment-related thrombocytopenia during the expansion phase. Mean unbound niraparib concentrations in Gd-nonenhancing tumor regions were 340.9 nM and 331.9 nM in the 3-5 h (n=8) and 8-12 h (n=3) cohorts, respectively. All tumors met PK criteria for the expansion phase, and two showed unmethylated MGMT. The fold increase in PAR levels after ex vivo radiation compared to untreated samples was 2.44 in nGBM controls (n=4) vs. 1.71 in study patients (n=10), respectively.

[0355] Conclusions: This first-in-human study of niraparib in newly diagnosed GBM patients (nGBM) demonstrates brain tumor penetration superior to any other investigated PARP inhibitor, and concomitant radiosensitization with PAR inhibition.

[0356] Additional interim results, Arm A Demographic and safety data: Thirty-three patients (45.4% female) enrolled in arm A of phase 0, with 12 patients progressing to the expansion phase, and patient demographic and safety data are summarized in Figure 5. In the phase 0 component of the study, the median age (range) of patients in arm A was 60 (21-85) years, and baseline median ECOG (range) was 1 (0-2).

[0357] Results: The mean unbound niraparib concentrations in the Gd-nonenhancing tumor region of 3-5 hour cohort 1 patients were 250.8 nM and 366.2 nM in patients dosed at 200 mg (n=6) and 300 mg (n=20), respectively, as shown in Figure 7. The mean unbound niraparib concentrations in the Gd-nonenhancing tumor region of 8-12 hour cohort 2 patients were 331.9 nM in patients dosed at 300 mg (n=3), as shown in Figure 7. These unbound niraparib concentrations were consistent with the IC 50 (i.e., 19 nM). The total tumor:plasma (Kp) ratios of Niraparib were 4.274 and 7.887 in non-enhanced and enhanced tissues, respectively, as shown in FIG. 8. The unbound tumor:plasma ratios (Kp,uu) were 0.8 and 1.8 in non-enhanced and enhanced tissues, respectively, as shown in FIG. 8. The fold increase in PAR levels after ex vivo radiation compared to untreated samples was greater than 2.5 in nGBM controls versus less than 1.5 in study patients, respectively, as shown in FIG. 9. Niraparib exposure for 3 or 4 days suppressed the induction of poly(ADP-ribose) (PAR) levels after irradiation in ex vivo newly diagnosed and recurrent GBM tissues. Clinical outcomes of MGMT unmethylated PK responder expansion patients are summarized in FIG. 10. MGMT-unmethylated PK responders were treated with niraparib in addition to radiation therapy.Of six patients with at least six months of follow-up, four achieved remission and two had tumor recurrence.

[0358] Conclusions: Niraparib was generally well tolerated in patients with newly diagnosed and recurrent glioblastoma. Niraparib reached pharmacologically relevant concentrations in non-enhancing newly diagnosed and recurrent glioblastoma tissue at doses of 200 and 300 mg. Niraparib exposure for 3 or 4 days suppressed the induction of PAR levels after irradiation in ex vivo newly diagnosed and recurrent glioblastoma tissue.

[0359] Further interim results, Arm A Materials / Methods: Patients with presumed newly diagnosed GBM were enrolled in a phase 0 study and received 4 days of niraparib (300 or 200 mg QD (1x daily)) 3-5 hours after the last dose or 8-12 hours prior to planned resection. Tumor tissue (enhancing and non-enhancing areas), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using a validated LC-MS / MS method. PARP inhibition was assessed by quantifying PAR induction following 10 Gy ex vivo irradiation in surgical tissues compared to non-irradiated control tissues. A PK "trigger" determined eligibility for the therapeutic phase 2 expansion portion of the study. This was defined as unbound [niraparib] above 5x the biochemical IC50 (i.e., 19 nM) in non-enhancing tumors. Patients with MGMT-unmethylated tumors above this PK threshold were eligible for expansion phase dosing of niraparib with concurrent RT followed by a maintenance phase of niraparib. Patients with MGMT-methylated tumors were not eligible for the expansion phase and proceeded to temozolomide (TMZ) plus RT followed by maintenance TMZ. RT dose was 60 Gy in 30 fractions using intensity-modulated radiation therapy (VMAT).

[0360] Results: All 29 patients enrolled in the phase 0 portion of this study met the PK threshold. Unbound niraparib concentrations were consistent with the IC 50significantly exceeded the NIRA score. In non-enhancing regions, the mean unbound niraparib concentration was 258.2 nM. After ex vivo radiation, suppression of PAR levels was observed in 79% (17 of 22) of patients. Sixteen patients had unmethylated tumors, of which 11 patients were enrolled in phase 2. Five of the original six patients enrolled in phase 2 experienced niraparib-associated thrombocytopenia, three of five of which were considered severe and life-threatening. As a result, the starting dose in both phases was reduced to 200 mg, and no serious AEs were observed since. At a median follow-up of 8.1 months [range: 6.0-12.9 months], PFS6 was 64%, with four patients remaining on treatment and five patients alive and in follow-up.

[0361] Conclusions: Niraparib achieves pharmacologically relevant concentrations in non-enhancing newly diagnosed GBM tissue. When delivered with concurrent RT, niraparib was well tolerated with low rates of grade 3+ toxicity. Initial clinical efficacy data are promising.

[0362] Example 2: Investigation of brain penetration of GSK3985771C (Niraparib) in P-gp (P-glycoprotein / mdr1-a) and BCRP (Breast Cancer Resistance Protein / ABCG2) rat knockout models method: At least 3 days before the start of the study, 6 male rats per group (total of 24 rats) underwent surgical placement of femoral vein and carotid artery catheters for infusion of test molecules and blood sample collection, respectively. Doses were filtered prior to administration and the actual dose administered to the animals was quantified. All PK parameters were calculated based on the actual dose administered 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, animals were euthanized and brain tissue was harvested. Tissue homogenates were prepared in PBS (1:4 wt / vol). Drug concentrations were quantified using an LC-MS / MS method. Tissue homogenate concentrations were corrected for test compound contained in the remaining plasma in the tissue. Tissue-to-plasma ratios were calculated by dividing the corrected tissue concentration by the steady-state plasma concentration. In vitro protein binding of Niraparib in rat plasma and brain homogenates was assessed by a fast equilibrium dialysis method. Data are reported as unbound fraction (Fu). The protocol is summarized in Figure 2.

[0363] Conclusion: Niraparib plasma concentrations in all four groups tested were nearly similar. Niraparib brain penetration in control rats was nearly half that in plasma. Brain tissue concentrations were further increased 9-fold and 14-fold in Mdr1-a (P-gp) knockout and Pgp / BCRP double knockout, respectively, while BCRP knockout rats had less than a 2-fold increase. Brain:plasma (Kp) ratios were 0.47, 3.7, 0.64, and 6.3 in control, P-gp knockout, BCRP knockout, and P-gp / BCRP double knockout rat models, respectively. Unbound niraparib fractions were 0.17 and 0.04 in rat plasma and brain, respectively. The unbound brain:plasma ratios (Kp,uu) were 0.1, 0.87, 0.15, and 1.5 in control, P-gp knockout, BCRP knockout, and P-gp / BCRP double knockout rat models, respectively. Despite the role of P-gp in limiting niraparib's brain penetration, the brain exposure of niraparib in control rats, where P-gp and BCRP are fully functional, appears to indicate a favorable profile of niraparib as a promising therapeutic agent for treating brain tumors. These results are summarized in Figure 3.

[0364] Example 3: Differential brain penetration of Niraparib and Olaparib in a mouse brain metastatic tumor model There remains an unmet need to provide effective treatment therapy for patients with primary and metastatic brain tumors, mainly due to the lack of drug permeability across the blood-brain barrier (BBB).Synthetic lethality remains a promising mechanism in treating brain tumors after radiation therapy.In this study, the brain permeability and distribution of niraparib and olaparib in mouse brain tumor models were evaluated.

[0365] Female mice (CrTac:NCr-Foxn1nu, 6 w / o) received 2.5E5 luciferase-transfected human breast cancer lines (MDA 231-BRM2-831) by intracardiac injection. Mice were imaged twice weekly using bioluminescence imaging (BLI) to monitor tumor growth. On day 35, mice bearing brain metastases (BM) were treated with either niraparib (35 mg / kg, BM n=4, control n=3), olaparib (50 mg / kg, BM n=3, control n=3), or vehicle (control n=3) by oral gavage once daily for 5 days. Terminal blood samples and brains were collected 2 hours after the last dose. Serial tissue sections were taken from 5 different horizontal planes in the brain for MALDI-IMS, H&E, and IHC staining. The harvested tissue between each imaging plane was homogenized for LC-MS bioanalysis.

[0366] In vivo BLI imaging was used to identify mice with brain metastases (BM), and the presence of tumor throughout the brain was confirmed ex vivo using IHC. Quantitative ex vivo imaging analysis by MALDI IMS of coronal brain sections taken from mice treated with niraparib showed consistent concentrations distributed throughout the brain parenchyma, with locally higher concentrations detected in tumor regions. Table 3 summarizes the LC-MS bioanalytical concentrations in plasma and bulk brain homogenates, as well as brain section concentrations detected by MALDI IMS. The estimated mean unbound brain-to-plasma partition coefficients (Kp,uu,brain) were 3.0- and 5.6-fold higher for niraparib compared to olaparib in control and BM mice, respectively.

[0367] These results showed that niraparib had higher brain penetration compared with olaparib in both control mice and mice with BM.

[0368] [Table 3]

[0369] Example 4: Differentiation of Niraparib and Olaparib Brain Penetration in Healthy Rhesus Monkeys There remains an unmet need to provide effective treatment therapies to patients with primary and metastatic brain tumors, mainly due to lack of drug permeability across the blood-brain barrier (BBB). Synthetic lethality remains a promising mechanism in treating brain tumors after radiation therapy. This study investigates the brain permeability of niraparib and olaparib in healthy monkeys to obtain evidence of niraparib's ability to cross the blood-brain barrier (BBB).

[0370] Four healthy male rhesus monkeys were dosed daily for 5 days by oral gavage with either niraparib (n=2, 6 mg / kg) or olaparib (n=2, 10 mg / kg). Pre-dose 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 dosed compounds. Bulk homogenates of blood, CSF, and brain tissue were analyzed by LC-MS bioanalysis.

[0371] With reference to Table 4, greater brain penetration was observed for Niraparib compared to Olaparib after 5 days of oral dosing in healthy rhesus monkeys. The unbound brain-to-plasma partition coefficient (Kp,uu,brain) was 15-fold higher for Niraparib compared to Olaparib. Quantitative ex vivo imaging analysis by MALDI IMS of coronal brain sections taken from Niraparib-treated monkeys showed consistent concentrations distributed throughout the brain parenchyma. Olaparib was not detected by MALDI IMS in any of the coronal brain sections taken from Olaparib-treated monkeys. Similar plasma and CSF concentrations were observed between Niraparib-treated and Olaparib-treated monkeys, highlighting the unique ability of Niraparib to cross the intact blood-brain barrier in monkeys and distribute throughout the brain.

[0372] Niraparib demonstrated significantly greater brain penetration than olaparib in healthy rhesus monkeys, demonstrating enhanced ability to cross the intact BBB.

[0373] [Table 4]

[0374] Equivalent The articles "a" and "an" as used herein should be understood to include plural references in the specification and claims unless clearly indicated otherwise. Claims and descriptions including "or" between one or more members of a group are considered to be satisfied if one, more than one, or all of the group members are present in, utilized in, or otherwise relevant to a given product or process, unless otherwise indicated or otherwise clear from the context. The invention includes embodiments in which exactly one member of a group is present in, utilized in, or otherwise relevant to a given product or process. The invention also includes embodiments in which more than one or all of the group members are present in, utilized in, or otherwise relevant to a given product or process. Furthermore, it is to be understood that the present invention encompasses all variations, combinations, and permutations of one or more limitations, elements, phrases, descriptive terms, etc., from one or more of the enumerated claims that are introduced into another claim that is dependent on the same underlying claim (or any other claim, if relevant), unless otherwise indicated or unless it would be apparent to one of ordinary skill in the art that a contradiction or inconsistency would result. It is to be understood that when elements are presented as lists (e.g., in a Markush group or similar format), each subgroup of those elements is also disclosed, and that any element may be removed from the group. In general, when the invention or aspects of the invention are referred to as including certain elements, features, etc., it is to be understood that a certain embodiment of the invention or aspect of the invention consists of or consists essentially of such elements, features, etc. For the sake of simplicity, these embodiments have not necessarily been explicitly and specifically described herein in all instances. It is also to be understood that any embodiment or aspect of the invention may be expressly excluded from the claims, regardless of whether a specific exclusion is mentioned herein.Publications, websites, and other reference material referenced herein to describe the background of the invention and to provide further details regarding its practice are hereby incorporated by reference.

Claims

1. 1. A pharmaceutical composition comprising niraparib or a pharmaceutically acceptable salt thereof for treating primary or metastatic brain cancer in a human subject in need thereof, wherein the primary or metastatic brain cancer is newly diagnosed.

2. The human subject is also treated with radiation therapy, particularly stereotactic radiation therapy, 2. The pharmaceutical composition of claim 1, wherein the administration of niraparib or a pharmaceutically acceptable salt thereof and radiation therapy is initiated after resection of the primary brain cancer tumor.

3. The pharmaceutical composition of claim 2, wherein the radiation therapy is about 60 Gy (Gray).

4. The pharmaceutical composition of claim 2, wherein the radiation therapy is about 10 Gy (Gray).

5. The pharmaceutical composition of claim 2, wherein the administration of niraparib or a pharmaceutically acceptable salt thereof and radiation therapy are carried out for about 6 to about 7 weeks.

6. 3. The pharmaceutical composition of claim 2, wherein the human subject, after treatment with niraparib and radiation therapy, further receives maintenance treatment of niraparib or a pharmaceutically acceptable salt thereof without radiation therapy.

7. 2. The pharmaceutical composition of claim 1, wherein niraparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to 200 mg or 300 mg of niraparib free base.

8. 10. The pharmaceutical composition of claim 1, wherein niraparib or a pharmaceutically acceptable salt thereof is administered as niraparib tosylate monohydrate.

9. 10. The pharmaceutical composition of claim 1, wherein niraparib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

10. 10. The pharmaceutical composition of claim 1, wherein the dose of niraparib or a pharmaceutically acceptable salt thereof is administered daily.

11. The pharmaceutical composition of claim 1 , wherein the primary brain cancer is glioblastoma.

12. 2. The pharmaceutical composition of claim 1, wherein the human subject exhibits an unbound niraparib concentration in brain cancer tumor tissue that is greater than 5 times the biochemical IC50 value of niraparib.

13. 2. The pharmaceutical composition of claim 1, wherein the human subject exhibits an unbound niraparib concentration greater than 5-fold the biochemical IC50 value of niraparib in non-enhancing or enhancing brain cancer tumor tissue.

14. 14. The pharmaceutical composition of claim 13, wherein the concentration of unbound niraparib in non-enhancing or enhancing tumor tissue of the brain cancer is measured after pre-surgical niraparib treatment.

15. 2. The pharmaceutical composition of claim 1, wherein the human subject exhibits an unbound niraparib concentration greater than 5 times the biochemical IC50 value of niraparib within non-gadolinium-enhancing regions of brain cancer tumors.

16. The pharmaceutical composition of any one of claims 12 to 15, wherein the concentration of unbound niraparib in tumor tissue is measured after resection.

17. 16. The pharmaceutical composition of claim 15, wherein the concentration of unbound niraparib in non-gadolinium enhancing regions of brain cancer tumors is measured after 4 days of pre-surgical niraparib (300 mg QD) treatment and before planned resection 3-5 hours or 8-12 hours after the last dose.

18. 16. The pharmaceutical composition of claim 15, wherein the concentration of unbound niraparib in non-gadolinium enhancing regions of brain cancer tumors is measured after 4 days of pre-surgical niraparib (200 mg QD) treatment and before planned resection 3-5 hours or 8-12 hours after the last dose.

19. 19. The pharmaceutical composition of any one of claims 12, 15, 17 and 18, wherein the concentration of unbound niraparib is measured in a brain tumor tissue sample taken during surgery.

20. 19. The pharmaceutical composition of any one of claims 12, 15, 17 and 18, wherein five times the biochemical IC50 value of niraparib is 19 nM.

21. 19. The pharmaceutical composition of any one of claims 12, 15, 17 and 18, wherein the brain / plasma ratio of niraparib is about 0.

5.

22. 19. The pharmaceutical composition of any one of claims 12, 15, 17 and 18, wherein niraparib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents known to be useful in the treatment of cancer.

23. 23. The pharmaceutical composition of claim 22, wherein the one or more additional active agents is temozolomide, bevacizumab, or a combination thereof.

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