A Study Comparing Niraparib With Temozolomide in Adult Participants With Newly-diagnosed, MGMT Unmethylated Glioblastoma

Inclusion Criteria:

• 1. Histologic documentation of a newly-diagnosed intracranial GBM, per 2021 WHOclassification guidelines through local pathology review.
• 2. Age ≥18 years at the time of signing informed consent.
• 3. Sufficient tissue available for retrospective central pathology review,retrospective central confirmation of MGMT promoter methylation status and genomicanalysis. If insufficient tissue is available,pproval may be granted on acase-by-case basis after a review.
• 4. Unmethylated MGMT promoter region determined locally by a validated PSQ orqMS-PCR assay compliant to local regulations. Numerical cut-off for an MGMTunmethylated tumor will be defined in the protocol.
• 5. Suitability for SOC RT to 60 Gy in 30 fractions using ESTRO-EANO 'single phase'targeting approach [Niyazi, 2023], per investigator's judgment.
• 6. No prior treatment for GBM (including brachytherapy or BCNU wafers), other thansurgical resection or biopsy.
• 7. Female participants: Not pregnant, planning to get pregnant, or breastfeeding andone of the following conditions apply: is of nonchildbearing potential or is ofchildbearing potential AND using a contraceptive method that is highly effective (with a failure rate of <1% per year) from screening through at least 180 days afterthe last dose of study intervention. Breastfeeding is contraindicated during thestudy and for one month after the last dose of study intervention.
• 8. Male participants: Must agree to the following during the study interventionperiod and for at least 6 months after the last dose of study intervention: refrainfrom donation sperm PLUS be abstinent from heterosexual activity or agree to use amale condom and be advised of the benefit for a female partner to use acontraceptive method that is highly effective (with a failure rate of <1% per year).
• 9. The participant must be capable of providing signed informed consent, includingcompliance with the requirements and restrictions listed in the ICF and in thisprotocol.
• 10. Karnofsky performance status of ≥70.
• 11. Adequate organ function
• 12. Normal blood pressure (BP) or adequately treated and controlled hypertension (defined as systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg).
• 13. Stable or decreased dose of dexamethasone, requiring no more than 5 mg dailyequivalent dose, within 7 days before randomization.
• 14. Ability to swallow oral medications whole.

Exclusion Criteria:

• 1. Presence of metastatic or predominant leptomeningeal disease.
• 2. Current active pneumonitis or any history of pneumonitis requiring steroids (anydose) or immunomodulatory treatment within 90 days of planned start of the study.
• 3. Participant is at an increased bleeding risk due to concurrent conditions (e.g.,major injuries or major surgery within the past 28 days prior to start of studytreatment with the exception of tumor resection).
• 4. Any clinically significant gastrointestinal abnormalities that may alterabsorption such as malabsorption syndrome or major resection of the stomach and/orbowels.
• 5. Has cirrhosis or current unstable liver or biliary disease per investigatorassessment defined by the presence of ascites, encephalopathy, coagulopathy,hypoalbuminemia, esophageal/gastric varices, or persistent jaundice. NOTE: Stablenoncirrhotic chronic liver disease (including Gilbert's syndrome or asymptomaticgallstones), hepatobiliary involvement of malignancy, or chronic stable HBVinfection (in a participant for whom HDV infection has been excluded) or chronic HCVinfection is acceptable if the participant otherwise meets entry criteria.
• 6. Known human immunodeficiency virus (HIV) unless participants meet all of thefollowing criteria:

• Cluster of differentiation 4 ≥350/µL and viral load <400 copies/mL.

• No history of acquired immunodeficiency syndrome-defining opportunisticinfections within 12 months prior to enrollment.

• No history of HIV-associated malignancy for the past 5 years.

• Concurrent antiretroviral therapy as per the most current National Institutesof Health (NIH) Guidelines for the Use of Antiretroviral Agents in Adults andAdolescents Living with HIV [NIH, 2021] started >4 weeks prior to studyenrollment.

• 7. MDS/AML or with features suggestive of MDS/AML.
• 8. History of another malignancy within 2 years prior to registration. Participantswith a past history of adequately treated carcinoma-in-situ, basal cell carcinoma ofthe skin, squamous cell carcinoma of the skin, or superficial transitional cellcarcinoma of the bladder are eligible. Participants with a history of othermalignancies are eligible if they have been treated with curative intent orcontinuously disease free for at least 2 years after definitive primary treatment.
• 9. Prior history of posterior reversible encephalopathy syndrome (PRES).
• 10. Any psychological, familial, sociological, or geographical condition potentiallyhampering compliance with the study requirements and/or follow-up procedures.
• 11. Inability to undergo MRI brain with IV contrast.
• 12. Biopsy and/or resection (whichever is later) occurring >6 weeks prior to plannedRT start date.
• 13. Surgical wound complication recovery at the time of enrollment.
• 14. Known hypersensitivity to the components of niraparib, TMZ, or their formulationexcipients.
• 15. Known hypersensitivity to dacarbazine (DTIC).
• 16. Prior therapy with PARP inhibitors for systemic cancer.
• 17. Received a live vaccine within 30 days before the planned start of studyintervention. Coronavirus disease 2019 (COVID-19) vaccines that do not contain liveviruses are allowed. Note: mRNA and adenoviral-based COVID-19 vaccines areconsidered non-live.
• 18. Received a transfusion (platelets or red blood cells) or colony-stimulatingfactors (e.g., granulocyte macrophage colony-stimulating factor or recombinanterythropoietin) within 4 weeks of the planned start of study intervention.
• 19. Treatment with another investigational drug or other intervention within 5half-lives of the investigational product.
• 20. Treatment with tumor treating fields (e.g., Optune) for GBM.
• 21. Presence of known isocitrate dehydrogenase (IDH) mutation.
• 22. Presence of known H3 mutation.
• 23. Previous diagnosis of WHO Grade 2 or 3 glioma.