An Open-label, Multicenter Phase II Study to Compare the Efficacy of Carboplatin as First-line Followed by Second-line Olaparib Versus Olaparib as First-line Followed by Second-line Carboplatin in the Treatment of Patients With Castration Resistant Prostate Cancer Containing Homologous Recombination Deficiency
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
• Male age \> 18 years
• 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
• mCRPC as defined by serum testosterone \< 50 ng/ml (for patients on GnRH analogues or antagonists) and at least one of the following:
‣ PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions at least 1 week apart
⁃ Evaluable disease progression by modified RECIST 1.1 (Response Evaluation Criteria in Solid Tumors)
⁃ Progression of metastatic bone disease on bone scan, CT or MRI with \> 2 new lesions
• Prior therapy with abiraterone acetate, enzalutamide, apalutamide, or darolutamide
• Eastern Cooperative Oncology Group (ECOG) Performance Status of \< 2 (see Appendix 3, ECOG Grading Scale)
• Results of previous standard DNA testing, or previous research testing, which confirms RAD51B, RAD51C, RAD51D, or RAD54L mutations (see Introduction, Section 2 for study design and previous research on targeted therapy) from primary, metastatic tumor or circulating tumor DNA, or pathogenic/likely pathogenic germline variant as assessed by a CLIA certified laboratory level assay for DNA sequencing.
• Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
‣ Hemoglobin \> 10.0 g/dL
⁃ Absolute neutrophil count (ANC) \> 1.5 x 109/L
⁃ Platelet count \> 100 x 109/L
⁃ Total bilirubin \< 1.5 x institutional upper limit of normal (ULN)
⁃ Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) \< 2.5 x institutional upper limit of normal unless liver metastases are present in which case, they must be \< 5x ULN
⁃ Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of \>51 mL/min: Estimated creatinine clearance =(140-age \[years\]) x weight (kg))/ (serum creatinine (mg/dL) x 72)