a study of niraparib combination therapies for the treatment of metastatic castration-resistant prostate cancer

Conditions: Prostatic Neoplasms, Castration-Resistant

Summary: the purpose of this study is to: a) establish the recommended phase 2 dose (rp2d) and to evaluate the antitumor activity and safety of niraparib combination therapies (combinations 1 and 2) and b) to determine the relative bioavailability of niraparib and abiraterone acetate (aa) in combination (combination 3) in participants with metastatic castration-resistant prostate cancer (mcrpc).

this multicenter study will evaluate safety and efficacy of niraparib in combination with other anti-cancer agents. combination 1 will combine niraparib with the anti-programmed cell death protein (pd)-1 monoclonal antibody cetrelimab, in participants with mcrpc. combination 1 has 2 parts: in part 1 (dose selection), participants will be enrolled to establish rp2d doses of niraparib and cetrelimab; and part 2 (dose expansion) will evaluate the combination therapy in an expanded number of participants into 2 cohorts (biomarker positive or biomarker negative). combination 2 will combine niraparib with abiraterone acetate plus prednisone (aa-p) in mcrpc participants with dna-repair gene defects (drd). combination 3 will evaluate the relative bioavailability (ba) of niraparib and aa in combination. in a pharmacokinetics (pk) assessment phase, niraparib and aa will be administered, and in an extension phase, niraparib and aa-p will be administered. combinations 1 and 2 will have 5 phases: a pre-screening phase, a screening phase, a treatment phase, a follow-up phase, and a long-term extension (lte) phase; combination 3 has 3 phases: a screening phase, a pk assessment phase, an extension phase (including lte phase). study evaluations will include efficacy, pk, pk/pharmacodynamics, biomarkers, safety and tolerability.

Eligibility criteria:
inclusion criteria for combination 3: * diagnosed with mcrpc, who in the opinion of the investigator may benefit from treatment in combination 3 of this study * able to continue gonadotropin releasing hormone analogue (gnrha) therapy during the study if not surgically castrate (that is, subjects who has not undergone bilateral orchiectomy). * eastern cooperative oncology group performance status (ecog ps) of less than or equal to (\<=) 1 * toxicity associated with prior chemotherapy or radiotherapy has resolved to grade \<= 1 (except alopecia or grade \<= 2 neuropathy) at screening * participant must agree not to donate sperm while on study treatment, and for 3 months following the last dose of study treatment exclusion criteria: * history or current diagnosis of myelodysplastic syndrome (mds)/acute myeloid leukemia (aml) * active malignancies (that is, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. the only allowed exceptions are: non-muscle invasive bladder cancer; skin cancer (non-melanoma or melanoma); breast cancer; malignancy that is considered cured with minimal risk of recurrence * active infection requiring systemic therapy * allergies, hypersensitivity, or intolerance to niraparib or the corresponding excipients combination 3: * symptomatic brain metastases * prior disease progression during combination treatment with aa and poly (adenosine diphosphate \[adp\]-ribose) polymerase inhibitor (parpi). prior discontinuation of treatment with aa or parpi due to aa- or parpi-related toxicity