Olaparib, a PARP inhibitor approved for treating BRCA1/2-mutated ovarian cancer, has been found effective in treating men with metastatic, castrate-resistant prostate cancer.
The most common cancer in men, prostate cancer although well classified clinically, lags in molecular stratification of treatment. In today's world of precision medicine, identifying predictive biomarkers to decide treatment strategies could result in much better outcomes for this disease that is held responsible for more than 24,000 annual deaths in the United States.
Metastatic, castration-resistant prostate cancer (mCRPC) can be defective in DNA repair pathways and research has shown that cells with these defects could be sensitive to teratment with PARP inhibitors. To test this hypothesis, researchers recruited men with mCRPC who had progressed on 1 or 2 chemotherapy treatments and had a Eastern Cooperative Oncology Group performance-status score of 0 to 2. The TOPARP-A trial was registered as an open-label, single-group, 2-stage, phase 2 study. These men were treated with olaparib—a PARP inhibitor approved for the treatment of ovarian cancer carrying BRCA1/2 mutations—at 400 mg twice a day.
According to the results, published in the New England Journal of Medicine, of the 50 patients enrolled, all had been treated with docetaxel, 49 had received either abiraterone or enzalutamide, and 29 had been previously treated with cabazitaxel. With the primary outcome beingresponse rate, 16 of 49 patients (33%) had a response, with 12 patients receiving the study treatment for more than 6 months, the authors write. Fourteen of the 16 patients who had mutations in DNA-repair genes (including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK), responded to olaparib; this included all 7 patients with BRCA2 loss, the authors report. While 35 of 50 (70%) of patients had died at data cutoff, 4 patients remained in the study after a minimum of 40 weeks of therapy. The authors reported a median overall survival of 10.1 months.
Their study, the authors conclude, provides hope for molecular stratification—based treatment of prostate cancer. They also recommend that next-generation sequencing (used to identify mutations in the biopsy samples) can be used to better understand patient response to treatment.