Expert explains significance of PROpel study of olaparib/abiraterone in prostate cancer

Until recently, mono-therapeutic approaches to prostate cancer have been the standard of care. New trials, however, have demonstrated that a multimodal treatment method may be the best long-term option for this population of patients.

In a recent study, presented at the 2022 ASCO Genitourinary Cancers Symposium, Fred Saad, MD, FRCS, and a team of investigators evaluated the efficacy of olaparib (Lynparza) plus abiraterone (Zytiga) in patients with metastatic castration-resistant prostate cancer (mCRPC).1 In this interview, he comments on the promising outcomes of this trial and what they mean for future management of mCRPC. Saad is a professor and chief of urology, director of GU oncology, and Raymond Garneau Chair in prostate cancer at the University of Montreal Hospital Center (CHUM), as well as the director of prostate cancer research at the Montreal Cancer Institute/CRCHUM in Quebec.

Please discuss the background for this study.

The background for doing this study is that we are still using mono-therapeutic approaches for metastatic castration-resistant prostate cancer. We have some excellent drugs, but we definitely need to do better because patients will start to progress within 1 year [to] 18 months. And, unfortunately, many patients don't go on to subsequent therapy, and even when they do go on to subsequent therapy, everything we give after first line is less effective than in the first-line setting.

There is preclinical data that would suggest that combining a PARP inhibitor with a new-generation hormonal therapy [NHT], like abiraterone or enzalutamide [Xtandi], would make each one more effective. We know that PARP inhibition can help hormonal therapy through AR transcription, and then NHTs could make the environment more like a BRCA kind of environment and make PARP inhibitors even more effective. At least for olaparib, there was a phase 2 study that showed that, regardless of mutational status, patients had benefits in terms of radiographic progression-free survival. So, that was the rationale for going forward with a large phase 3 study that we call PROpel.

What were the notable findings of this study? Were any of them surprising to you or your co- authors?

If I summarize [PROpel briefly], the findings were really quite notable, and I think [they] caught a lot of people by surprise. I would admit, I was not surprised that it was more effective—the combination [more] than the single treatment—but the depth, or the intensity, of the difference was what [was] most notable.

The primary end point of this randomized, placebo-controlled trial of about 800 patients randomized to getting abiraterone plus placebo or abiraterone plus olaparib [was] radiographic progression-free survival. That turned out to be a 34% reduction in the risk of death or progression, which in months, turned out to be 8.2 months improvement in radiographic progression-free survival against abiraterone—a very effective first-line therapy, and probably the most widely used. What's amazing is that 8.2 months was exactly the same as we found with abiraterone against a pure placebo. So, it really [showed] that we went now beyond 2 years for radiographic progression-free survival, which is the longest we've ever seen in the first line setting. [Another] notable end point [was] overall survival, [which] was trending in the direction but we still have too few deaths. Time to subsequent therapy [and] time to second progression were improved significantly. Quality of life was maintained, even though we were combining abiraterone to a PARP inhibitor, such as olaparib. And in terms of adverse events, fortunately we didn't see worsening of adverse events by combining 2 drugs. Each drug had their adverse event profiles, and we didn't see anything more than what we would have expected with each one used individually.

How will these findings guide your management of mCRPC in the future?

Clearly, I think the [fields] of metastatic castration-resistant prostate cancer and lethal prostate cancer [are] really trying to improve on what we have. It's amazing for such a frequent disease that we're still using only mono-therapeutics in sequence. This, I think, is one of the first combinations that might actually make a difference. Why I say this is that when we looked at the subgroups of PROpel, whether or not you got chemotherapy in the hormone-sensitive setting, whether or not you have visceral disease in terms of metastases, and whether or not you harbored an HRR mutation or not, the benefit was there. They were all on the side of significance in terms of improving outcomes in radiographic progression-free survival. So, that makes this an attractive therapeutic option for all patients, not only patients that harbor HRR mutations. I think it does have a big impact in the future because it can help the majority of patients. But [more] importantly, it avoids the complexities of testing for HRR mutations. [It] is a big hurdle to access PARP inhibitors in mCRPC right now.

How does this study build on previous research of this topic?

This research was a logical step because we have preclinical evidence that combining new-generation hormonal therapy with a PARP inhibitor had the potential to have some synergy that would make each drug more effective, and the combination would lead to better outcomes. We showed this in a small phase 2 study of about 140 patients, where patients benefited with or without HRR mutations. And so, I think we always need to wait for a study like this—a phase 3 study—to confirm that this combination could be useful in patients with or without HRR mutations.

What is the take-home message for the practicing urologist?

For the practicing urologist, this is very important because it allows us to have a therapeutic option that does better than what we are presently using in the first-line setting and addresses the issue of the complexities of testing for mutations, which has been a hindrance to using PARP inhibitors in prostate cancer. So, I think it really addresses an unmet need for practicing urologists across the world.

Is there anything else you feel our audience should know about this topic?

I think the audience needs to be aware of this data. It goes a little bit against common preconceived notions that PARP inhibitors are only reserved for patients with HRR mutations. This questions our belief that only those patients benefit, so [we should] keep an open mind.

Reference

1. Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract #11