Phase II Study of Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis

Brief Summary

Detailed Description

The proposed study is an open-label single-arm phase II trial. Eligible patients are those with non-metastatic biochemically-recurrent prostate cancer and a PSADT of ≤6 months and a minimum PSA of 1.0. After enrollment, patients will be treated with olaparib at the established dose of 300mg tablets by mouth twice daily. Patients will be followed monthly with clinic visits, safety labs (including CBC w/diff, Comp), PSA, and toxicity assessments. Treatment \[with a minimum drug exposure of 12 weeks\] will be continued until PSA doubling from study entry (confirmed with another measurement at least 4 weeks later), development of radiographic metastatic disease, or toxicity requiring drug cessation. CT scans and NM bone scans will be performed every 6 months for patients remaining on olaparib treatment. This study will enroll up to 50 subjects. The study design will employ a stepwise adaptive statistical plan, derived in part from Biankin et al, Nature 2015 Oct 15;526(7573):361-70. The design is adapted from a multi-stage design, with interim stopping rules to determine futility or need for enrichment of the study population. The study will initiate with a two-stage design in an unselected population. The assumptions for the trial of the unselected population are: null hypothesis of 0.1 PSA response rate and alternative hypothesis of 0.3 for the unselected population. The first stage is 20 subjects. If ≤2 subjects responds in the first stage, then unselected population study is halted for futility and an assessment of DNA mutations present in the initial cohort will be undertaken. If less than 3 subjects with a known/suspected deleterious mutation in the following genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other DNA repair genes) have been accrued in the first stage, then the trial will proceed with enrichment. If 3 or more subjects with known/suspected deleterious mutation in the genes of interest have been accrued, then the trial will proceed with enrichment, as long as the response rate in that subset of subjects is ≥20%. In the case that 3 or more subjects have been accrued, yet the response rate in that subset is \<20%, then the trial is halted for futility. However, if ≥3 subjects among the first 20 respond, then additional 10 unselected subjects are accrued. If ≥6 subjects respond out of 30 in the unselected population after the second stage, then the null hypothesis is rejected in the unselected population and broad efficacy will be concluded. The trial proceeds to complete accrual of 50 subjects in order to better estimate PSA response rate and strengthen data for correlative studies. If \<6 respond, then the null hypothesis is not rejected. Again, if less than 3 subjects with a known/suspected deleterious mutation in the following genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other DNA repair genes) have been accrued in the first and second stage combined, then the trial will proceed with enrichment. If 3 or more subjects with those mutations have been accrued, then enrichment will again proceed as long as the response rate in that subject of subjects is ≥20%.

Primary Outcomes

Secondary Outcomes

• Treatment-related Adverse Events as Assessed by CTCAE v4.0(Baseline to End of Treatment)
• PSA Progression-free Survival(7 years)
• PSA Doubling From Baseline(7 years)
• Duration of Undetectable PSA(7 years)