Carboplatin or Olaparib for BRcA Deficient Prostate Cancer

About This Trial

This study is for men with advanced prostate cancer that has spread, is no longer responding to standard hormone treatments, and has specific genetic changes that affect how cancer cells repair DNA.
Researchers are comparing two different medications—an intravenous chemotherapy drug and a daily targeted pill—to see which one works better as a first treatment option.
Participants are randomly assigned to start with one of the two medicines, but if the cancer begins to grow again, they will be switched to the other drug so they have the opportunity to try both.
Before joining, patients should know that they must continue their regular hormone therapy and cannot have previously received these specific types of cancer medications.

More Information

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.

Who Can Enroll

Age Range: 18 years and older
Gender: Male
Who This Trial is For: This study is for men with advanced prostate cancer that has spread, is no longer responding to standard hormone treatments, and has specific genetic changes that affect how cancer cells repair DNA.

Study Details

Start Date: October 1, 2019
Lead Sponsor: VA Office of Research and Development

Full Eligibility Criteria

Inclusion 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
mCRPC as defined by serum testosterone 2 new lesions
Prior therapy with abiraterone acetate, enzalutamide, apalutamide, or darolutamide
Eastern Cooperative Oncology Group (ECOG) Performance Status of 10.0 grams per deciliter (g/dL)
- Absolute neutrophil count (ANC) > 1.5 x 109/liter (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 51 mL/min: Estimated creatinine clearance =(140-age [years]) x weight (kg)/(serum creatinine (mg/dL) x 72)

Exclusion Criteria

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
Known parenchymal brain metastasis
Active or symptomatic viral hepatitis or chronic liver disease AST or ALT > 2.5 x ULN or total bilirubin > ULN (unless Gilbert's syndrome is the etiology of hyperbilirubinemia)
Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents
Subjects unable to swallow orally administered medication and subjects with gastrointestinal disorders likely to interfere with absorption of the study medication
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 within 30 days of Cycle-1
Presence of dementia, psychiatric illness, and/or social situations limiting compliance with study requirements or understanding HIPAA authorization and/or giving of informed consent
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