"This trial did not require a biomarker for entry in, so patients were treated with combination therapy or standard care, which would have been the abiraterone alone, to see if there was a benefit," says Michael S. Cookson, MD, MMHC.
In this video, Michael S. Cookson, MD, MMHC, Urology Times’® Co-Editor-in-Chief, discusses the PROpel trial (NCT03732820) results, which were presented at the 2023 ASCO Genitourinary Cancers Symposium in San Francisco, California. Cookson is a professor and chair of urology at the University of Oklahoma Health Sciences Center in Oklahoma City.
We're in a constant state of evolution with the [treatment] of men with advanced prostate cancer. The PROpel trial looks at metastatic castration-resistant prostate cancer (mCRPC) patients using combination therapy, a PARP inhibitor, combined with a novel hormonal androgen synthesis inhibitor, abiraterone. Historically, the PARP inhibitors came into play in men with castration resistance after failed 2 lines of therapy. Now we're moving those up into earlier first-line therapy, and now combining them with novel hormonal therapy, if you will. That's what they tried to address.
This study was interesting because, again, when PARP inhibitors were introduced, we knew that HRR mutations were key to the mechanism of action. So really, it was restricted to those patients who had for example, a BRCA mutation or one of the known genetic alterations associated with prostate cancer. Well, this trial did not require a biomarker for entry in, so patients were treated with combination therapy or standard care, which would have been the abiraterone alone, to see if there was a benefit.
The radiographic progression free endpoint was met and there was a statistically significant improvement in progression free survival using the combination of the PARP inhibitor and abiraterone plus prednisone as compared [with] abiraterone and prednisone alone. It met that, and that's significant because again, these patients weren't pre-selected for a biomarker, so, a little bit surprising. Backing up a little bit though, I gave a nice introduction where the proof of principle and why there could be a mechanistic improvement using novel hormonal therapy, which can interrupt some of the DNA stranding and perhaps prime the pump, if you will, to allow for the PARP inhibitor to be more effective. There is a scientific rationale for why this could work even in a patient without a true genetic alteration that's targeted by a PARP inhibitor.
However, there's a little bit of a tail to this story, and that's that, statistically speaking, it did not meet the overall survival benefit, at least as of presented today with intent to treat. Statistically, it met the radiographic progression free which is meaningful, but didn't meet the overall survival advantage. To further complicate matters, however, there was about a 7 1/2 month advantage to the combination over abiraterone alone. That's clinically meaningful to patients compared [with] before. Remember, some of these drugs received our initial approval for something as small as 3 months of survival benefit.
You have a little bit of a 'to be continued' story in that you can add a PARP inhibitor, you can add it to a novel hormonal agent, there's probably synergistic benefit, there could be benefit for all comers. They did provide some data on the subsets of patients, roughly I think 10%, that had, for example, a BRCA mutation where there was significant benefit and even survival benefit. Whenever we see patients who come in with first-line treatment options for metastatic CRPC, we'll have to decide if we're going to offer them this combination therapy in patients who don't necessarily have a genetic defect. However, there [are] some adverse events and toxicities to be considered in that tradeoff for the overall radiographic progression free survival benefit.
This transcription has been edited for clarity.