Docetaxel, Carboplatin, and Rucaparib Camsylate in Treating Patients With Metastatic Castration Resistant Prostate Cancer With Homologous Recombination DNA Repair Deficiency

OUTLINE:

INDUCTION: Patients receive docetaxel intravenously (IV) and carboplatin IV on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive rucaparib camsylate orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion criteria

• Signed informed consent form (ICF) providing agreement to adhere to the dosing schedule, report for all trial visits and authorization, use and release of health and research trial information
• Histologically or cytologically confirmed adenocarcinoma of the prostate (excluding predominant small cell histology)
• 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
• Castration resistant prostate cancer as defined by serum testosterone < 50 ng/ml and PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions at least 1 week apart
• Presence of metastatic disease on bone or computed tomography (CT) scan

• Evaluable disease progression by modified RECIST 1.1 (Response Evaluation Criteria in Solid Tumors)
• Bone disease on bone scan
• Prior therapy with sipuleucel-T, abiraterone, enzalutamide, docetaxel, and/or cabazitaxel; there is no limit to the number of prior treatment regimens in the castration resistant setting, so long as prior therapy does not include platinum chemotherapy or a PARP inhibitor; prior platinum chemotherapy in the hormone sensitive setting is permitted, so long as it has been at least 6 months since last dose
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
• Life expectancy >= 12 weeks
• No prior malignancy is allowed except:

• Adequately treated basal cell or squamous cell skin cancer or
• In situ carcinoma of any site or
• Other adequately treated malignancy for which the patient has been disease-free for at least one year (any prior chemotherapy is allowed)
• Documented evidence of at least ONE or MORE of the following:

• Pathogenic mutation or inactivating alteration of a gene involved in homologous recombination repair in the tumor
• Note, that if this alteration is identified in a circulating tumor deoxyribonucleic acid (ctDNA) assay, the variant-allele fraction must be > 20% to indicate relevance to predominant tumor clone

• Mutation in one or more other genes involved in homologous DNA recombination repair in the tumor may be included at investigator's discretion
• Homologous recombination repair deficiency by genomic signature in the tumor by BROCA-HR, Foundation One or equivalent assay
• Presence of pathogenic or likely pathogenic germline mutation/variant in BRCA2, BRCA1, ATM or PALB2
• Note: Germline mutations in other HR genes will be considered at investigator's discretion)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 14 days of first dose of study drug)
• Platelets > 100 x 10^9/L (within 14 days of first dose of study drug)
• Hemoglobin >= 9 g/dL (within 14 days of first dose of study drug)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN; if liver metastases, then =< 5 x ULN (within 14 days of first dose of study drug)
• Bilirubin =< 1.5 x ULN (< 2 x ULN if hyperbilirubinemia is due to Gilbert's syndrome) (within 14 days of first dose of study drug)
• Serum creatinine =< 1.5 x ULN or estimated glomerular filtration rate (GFR) >= 45 mL/min using the Cockcroft Gault formula (within 14 days of first dose of study drug)

Exclusion criteria

• Currently receiving active therapy for other neoplastic disorders
• Symptomatic and/or untreated central nervous system (CNS) metastases; patients with asymptomatic previously treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, active or symptomatic viral hepatitis or chronic liver disease
• Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class II-IV heart disease or cardiac ejection fraction measurement of < 35 % at baseline
• Treatment with an investigational therapeutic drug within 30 days of cycle 1
• Prior therapy with a PARP inhibitor (e.g., olaparib, talazoparib, veliparib, niraparib, rucaparib)
• Prior therapy with a platinum chemotherapy (e.g. cisplatin, carboplatin, oxaliplatin) in the castration resistant setting; (prior platinum chemotherapy in the hormone sensitive setting is permitted, so long as time since last dose is 6 months or greater)
• Active, ongoing toxicity (Common Terminology Criteria for Adverse Events [CTCAE] grade 2 or higher) from prior therapy
• Presence of dementia, psychiatric illness, and/or social situations limiting compliance with study requirements or understanding and/or giving of informed consent
• Pre-existing duodenal stent and/ or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
• Any condition(s), medical or otherwise, which, in the opinion of the investigators, would jeopardize either the patient or the integrity of the data obtained