An expert explains PARP inhibitor use in the metastatic prostate cancer treatment landscape and typical adverse events seen during therapies.
Matthew Fowler: What’s the role of PARP inhibitors in prostate cancer?
Alicia Morgans, MD, MPH: PARP inhibitors have been approved for the treatment of patients with metastatic castration-resistant prostate cancer [mCRPC]. There are 2 that are approved: olaparib and rucaparib. Their FDA-approval labels are slightly different, so we should take a minute to understand the indications by label.
Olaparib was approved based on the PROfound trial, which included patients who had mCRPC and had progression of their cancer after treatment with an AR [androgen receptor]–targeted agent in combination with ADT [androgen deprivation therapy]. These patients could have received chemotherapy, but they didn’t have to have had chemotherapy, and some of them hadn’t had chemotherapy when they were included in the trial. They also could have had one of any number of mutations that included BRCA1, BRCA2, ATM, CHEK2, PALB2, and CDK12. There were a number of them, as well as PPP2R2A, which didn’t show that it was a helpful mutation to have when treated with olaparib.
The indication for approval for olaparib is that a patient must have mCRPC, must have had progression on an ADT- and AR-targeted agent combination, and can have any of the DNA-repair defect mutations that were included in the clinical trial. That’s a pretty broad indication. Patients don’t need to have had prior exposure to taxanes. That’s our olaparib approval.
Rucaparib was approved based on phase 2 data, the TRITON2 study. This patient population had mCRPC but had progression of disease after treatment with an AR-targeted agent, and after treatment with a taxane, at least docetaxel. The indication for approval for rucaparib is BRCA1 or BRCA2 alterations, because those patients very clearly had a significant response to treatment with rucaparib. This was a single-arm study, so that may have had a role in that targeted indication of BRCA1 and BRCA2. And the indication is for patients to have already been treated with an AR-targeted agent and a taxane prior to getting rucaparib. It’s a little different in terms of their labels.
Matthew Fowler: What testing is needed or typically used to identify a potential candidate for PARP inhibitors?
Alicia Morgans, MD, MPH: As we mentioned earlier, we typically do both germline genetic testing and somatic testing. If patients have DNA-repair defect alterations that are appropriate for the label, whichever drug you’re planning to use, on either of those testing modalities, you can move forward with treatment with a PARP inhibitor.
Matthew Fowler: What are the adverse events most commonly seen in prostate cancer when patients are treated with PARP inhibitors?
Alicia Morgans, MD, MPH: PARP inhibitors importantly are relatively well tolerated. For most patients, they’re able to take these pills and do pretty well and stay on treatment. Most patients in the trials didn’t have discontinuation prior to disease progression. But for those patients who did have adverse events, they were most commonly related to cytopenias—things like anemia or thrombocytopenia—or some GI [gastrointestinal] toxicities, like nausea and sometimes loose bowel movements or diarrhea. Those were the main ones. There was also some fatigue, but in general, those were the most compelling or important adverse effects that could cause patients to need a dose reduction to improve tolerance or could potentially be associated with discontinuation of treatment.
This transcript has been edited for clarity.