This is an unblinded, randomized clinical study comparing the efficacy of DNA damaging chemotherapy using carboplatin, to standard of care therapy for patients who have metastatic castrate resistant prostate cancer. This trial will use olaparib or carboplatin as initial therapy with crossover to the alternate or second-line drug after first progression for patients with tumors containing BARD1, BRCA1, BRCA2, BRIP1, CHEK1, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L inactivating mutations.
Participants are randomized (1:1) and receive either carboplatin (AUC 5, IV) every 21 days, first or olaparib taken orally (300 mg), twice daily in 28 day cycles, until intolerance, complete response, or progression by Prostate Cancer Working Group 3 (PCWG3) criteria.
Participants then crossover from the first-line therapy to the second-line therapy with the opposite study medication and receive treatment to intolerance or progression (whichever is first). Enrolled participants will be allowed to crossover to second line therapy if they continue to meet initial eligibility criteria, and at least three weeks have elapsed since last administration of either carboplatin or olaparib. Throughout the study, safety and tolerability will be assessed. Progression will be evaluated with bone scan, CT of the abdomen/pelvis, or MRI and PSA as per PCWG3 criteria.
Signed study informed consent form (ICF) and HIPAA authorization form
Diagnosis of prostate cancer (pure small-cell histology or pure high-grade neuroendocrine histology are excluded; neuroendocrine differentiation is allowed)
Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) analogues, antagonists or orchiectomy. Patients who have not had an orchiectomy must be maintained on effective GnRH analogue/antagonist therapy
Prostate-specific antigen (PSA) level of at least 2 nanograms per milliliter (ng/ml) that has risen on at least 2 successive occasions at least 1 week apart
Currently receiving active therapy for other neoplastic disorder(s)
Concurrent enrollment in another clinical investigational drug or device study
Histologic evidence of small cell carcinoma (morphology alone - immunohistochemical evidence of neuroendocrine differentiation without morphologic evidence is not exclusionary)
Prior treatment with platinum, mitoxantrone or PARP inhibitor for castration resistant prostate cancer
Crossover
Carboplatin
DrugChemotherapy FDA approved drug used to treat: ovarian, lung, head and neck cancers. It is sometimes used in combination with other medications or off-label use to treat other metastatic cancers.
Olaparib
DrugOlaparib is a targeted therapy drug that is used for mCRPC and is approved by the FDA for this use.
Progression-free survival (PFS-1L) defined as the time interval between randomization and first documented disease progression or death due to any cause reported during, or after, first-line treatment
Progression free survival (PFS) by bone scan or measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST 1.1) to initial therapy (PFS-1L) with either study drug
Time interval between randomization and second documented disease progression during or after second-line or death (due to any cause)
Progression-free survival combined, a composite endpoint defined as the time interval between randomization and second documented disease progression reported during or after second-line or death due to any cause
PSA measurements/response
To assess PSA response to initial therapy with carboplatin vs. olaparib
PSA measurements/response
To assess PSA response duration to second line therapy with olaparib vs carboplatin
Grade 3 and 4 toxicities in first and second-line setting
To assess Grade 3 and 4 toxicities for each regimen in the first- and second-line setting
Exploratory Objective - PFS
To assess the PFS of patients who receive olaparib versus patients who receive carboplatin during the second-line of treatment (PFS-2L)
Exploratory Objective - objective response rate
To assess the objective response rate in patients who receive olaparib versus patients who receive carboplatin during second-line of treatment.
Exploratory Objective- objective duration of response
To assess the objective duration of response in patients who receive olaparib versus patients who receive carboplatin during second-line of treatment.
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