Olaparib in Treating Patients with High-Risk, Biochemically-Recurrent Prostate Cancer Who Have Undergone Surgery
- Willing and able to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information; provision of informed consent prior to any study procedures * NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
- Histological proof of adenocarcinoma of the prostate
- Prior local therapy with prostatectomy required, with available tissue from prostatectomy specimen to send for genomic and transcriptomic testing; specifically, either formalin-fixed paraffin-embedded (FFPE) blocks or 35-40 unstained slides from the primary prostatectomy specimen will need to be available for central pathologic review and processing
- Prior salvage or adjuvant radiation therapy is allowed but not mandated; radiation therapy must have been completed for at least 6 months
- Absolute PSA >=1 ng/ml; prior undetectable PSA post-prostatectomy is not required
- PSA doubling time (PSADT) =< 6 months, based upon >= 3 consecutive measurements collected in the past 12 months, at least 4 weeks apart, calculating using the Memorial Sloan-Kettering Cancer Center (MSKCC) calculator
- No radiographic evidence of metastatic disease by computed tomography (CT) scan and bone scan, performed within the prior 4 weeks
- Serum testosterone >= 150 ng/dl
- Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days, measured within 28 days prior to administration of study treatment
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L, measured within 28 days prior to administration of study treatment
- Platelet count >= 75 x 10^9/L, measured within 28 days prior to administration of study treatment
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), measured within 28 days prior to administration of study treatment
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) < 2.5 x institutional upper limit of normal, measured within 28 days prior to administration of study treatment * Note: patients with elevations in bilirubin, AST, or ALT should be thoroughly evaluated for the etiology of this abnormality prior to entry and patients with evidence of viral infection should be excluded
- Participants must have creatinine clearance estimated using the Cockcroft-Gault equation of >= 51 mL/min, measured within 28 days prior to administration of study treatment * Note: patients with creatinine clearance between 51- 80 mL/min either at trial enrollment or during the course of the trial should be monitored every 2 weeks for laboratory assessment and toxicity evaluation
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 1
- Participants must have a life expectancy >= 16 weeks
- Male participants and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 3 months after last dose of study drug to prevent pregnancy in a partner
- For enrichment stage of trial only (if necessary): Confirmation of a suspected/known deleterious mutation in a gene of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or other DNA repair genes) via Clinical Laboratory Improvement Act (CLIA) certified testing
- Metastatic disease or currently active second malignancy
- Prior androgen deprivation therapy (ADT) in the past 6 months; prior ADT in context of neoadjuvant/adjuvant primary; prior ADT for biochemical recurrence is allowed, as long as no ADT has been administered in past 6 months and testosterone has recovered (> 150 ng/dl); the total duration of prior ADT should not exceed 24 months
- Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g. abiraterone, orteronel) in the past 6 months; 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as long as subject has been stable on medication for past 6 months
- Prior treatment with intravenous chemotherapy
- Use of any prohibited concomitant medications within the prior 2 weeks
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- Previous enrolment in the present study
- Participation in another clinical study with an investigational product during the last 1 month
- Any previous treatment with PARP inhibitor, including olaparib
- Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
- 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; during the study, if co-administration of a strong or moderate inhibitor is required, exception to this criterion may be allowed with a suitable dose reduction of olaparib
- Concomitant use of known strong CYP3A inducers (e.g. phenobarbital, 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
- Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade 2) caused by previous cancer therapy, excluding alopecia
- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)
- Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
- Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection; examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
- Unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
- Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)
- Known hypersensitivity to olaparib or any of the excipients of the product
- Known active hepatitis (i.e. hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable)
I. To estimate the response rate (greater than 50% decline in PSA (PSA50) to olaparib for patients with high-risk biochemically-recurrent prostate cancer.
I. To determine the safety/tolerability of olaparib in the biochemically-recurrent prostate cancer patient population.
II. To estimate the median PSA progression-free survival.
III. To estimate the median time to PSA doubling from baseline.
IV. To estimate the rate of durable undetectable PSA in patients responding to olaparib.
I. To estimate PSA50 response in “biomarker positive” patients, based upon FoundationOne tissue-based mutations in the pre-specified gene list (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other deoxyribonucleic acid [DNA] repair genes). (If an enriched population is not accrued)
II. To estimate PSA50 response in “biomarker negative” patients, based upon tissue-based mutations in the pre-specified gene list. (If an enriched population is not accrued)
III. To estimate PSA50 response rate for patients with and without a mutation on the pre-specified list, based upon plasma cell-free DNA analysis using the pre-specified gene list.
IV. To develop a genetic mutation signature associated with response to olaparib.
V. To develop an ribonucleic acid (RNA) expression signature associated with response to olaparib.
VI. To investigate any association between PARP-1 and gammaH2AX protein levels in tumor with response to olaparib.
VII. To estimate median metastasis-free survival.
VIII. To estimate median time to next anti-cancer therapy.
Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 28 days.
Trial Phase Phase II
Trial Type Treatment
Johns Hopkins University / Sidney Kimmel Cancer Center
Emmanuel S. Antonarakis
- Primary ID J16163
- Secondary IDs NCI-2017-00733, CRMS-65586, 12079 ESCR, IRB00114635
- Clinicaltrials.gov ID NCT03047135