rPFS Improvement Regardless of Mutations in Biomarker Subgroups in the Phase III PROpel Trial in First-Line Therapy for Patients with mCRPC - Fred Saad

November 16, 2022

Fred Saad joins Alicia Morgans in a discussion focusing on the biomarker analysis and updated results from the Phase III PROpel trial of abiraterone and olaparib vs abiraterone and placebo as first-line therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). This updated analysis provides more detail on patients with HRR mutations in the PROpel trial. In this biomarker analysis investigators found that whether or not the patient has a HRR mutation, patients had improved rPFS. Patients with mutations had a hazard ratio of .5 and patients without, had a hazard ratio of .76. In the biomarker analysis and updated results Dr. Saad presented at ESMO 2022, he also presented BRCA mutated patients. BRCA mutated patients had a hazard ratio of .23 with the combination compared to abiraterone alone. Even patients without BRCA mutations showed more than a 5-month improvement in rPFS.

The updated results were consistent with the initially reported results and showed a continued trend towards an overall survival benefit in the intent to treat population. The safety and tolerability results were generally consistent with the primary analysis and the known profiles for abiraterone and olaparib. Results from PROpel continue to support a superior clinical benefit with abiraterone + olaparib versus abiraterone + placebo as first-line therapy for patients with mCRPC.


Fred Saad, MD, FRCS, Professor and Chief of Urology, Director of GU Oncology, Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Centre (CHUM), Director, Prostate Cancer Research, Institut du cancer de Montréal/CRCHUM

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here at ESMO 2022, where I have the opportunity to speak with Professor and Chairman, Fred Saad. Thank you so much for being here.

Fred Saad: It's always a pleasure, Alicia.

Alicia Morgans: Always a pleasure to talk to you too. And what an exciting presentation you gave at ESMO this year on the updated data from the PROpel trial. Can you tell us a little bit, just a brief overview of the PROpel trial, and then we'll talk about the new data?

Fred Saad: So, briefly, PROpel, we presented the first data at GU ASCO of this year in February, where we were at the first interim analysis, and we really met the final analysis basically of the rPFS, which is the primary endpoint of the study of looking at olaparib in combination with abiraterone, both at full dose versus abiraterone, which is considered a standard of care for mCRPC first line setting. And we had seen a very significant improvement in radiographic progression free survival with the combination over abiraterone alone. So, a 34% reduction in the risk of progression with patients getting combination therapy in an all-comer setting, irregardless of whether or not they harbored HRR mutations.

Alicia Morgans: Very, very important. Really, I think thought provoking and raised a lot of questions while, of course, answering some as well. So, what were you able to present at ESMO most recently?

Fred Saad: So, we're updating the data. Obviously, people are all very interested in knowing what's happening in terms of overall survival, in terms of subsequent therapy and other endpoints that are important. But, also, people are interested in knowing a little more about the biomarker status and how it influences outcome and more specifically, obviously BRCA mutated patients, where we know that's where most of the activity comes from with using a PARP inhibitor. And so, what I presented here was the updated analysis. So, clearly we're staying on track with rPFS, actually slightly improving, 8.6 month improvement in rPFS with the combination compared to abiraterone, which is actually a little bit better than what we saw with abiraterone against a placebo in first line mCRPC looking at the biomarker status of patients.

So, patients without detectable mutations of HRR showed an improvement in radiographic progression-free survival, that 24% reduction in the risk of progression, which is over five months. And based on blinded independent review, it's about 11 months difference. Now, looking at the BRCA mutated patients, those patients had outstanding improvements in our rPFS. Patients with BRCA mutations actually progressed in about eight months on abiraterone alone. And we haven't yet reached the rPFS in patients who got the combination of abi plus olaparib, and that's a .23 hazard ratio. So, a 76% reduction in the risk of progression.

Alicia Morgans: Well, and that's not unexpected perhaps, because we do know that BRCA2 alterations are associated with poorer prognosis, and we've seen some of that really interesting data from Elena Castro and from others looking at the way that those patients respond to standard therapies. But, that is really impressive, and I think striking that these patients had progression on abiraterone, which is an extremely effective agent in this setting at only eight months.

Fred Saad: Absolutely. And this is really some of the very first prospective studies looking at patients all-comer and not enriching for BRCA mutation. So, we took all-comer and BRCA mutation was as expected, around 10% of patients harbor BRCA mutation in an all-comer mCRPC population, and about 30% had a detectable mutation. So, it really gives us an opportunity to know the prevalence of these mutations, and also whether or not a PARP inhibitor can actually be useful in patients that don't harbor detectable mutations. And this study is really suggesting that there are opportunities to make a major difference in patients even without mutations by using full dose olaparib plus abiraterone based on the pre-clinical evidence that the combination can actually improve the outcome of individual drugs used alone. And in the phase two study, we saw that signal that led to the phase three PROpel study.

Alicia Morgans: Absolutely. And I think what's really interesting, you alluded to this, is that we think about olaparib as a single agent really having no effect in patients who are not harboring these HRR mutations. But, of course, we see this perhaps synergy with abiraterone. Something is driving that hazard ratio of 0.76. What are your thoughts on the biology there? Why is this happening?

Fred Saad: Well, pre-clinically we had the impression and was shown in the pre-clinical models that when you give a PARP inhibitor, you can actually have some effect on transcriptional activity of the androgen receptor. And on the other hand, when you give a novel hormonal therapy like abiraterone, or enzalutamide or any of them, you create an environment that appears to mimic a BRCA type environment, which makes the PARP inhibitor even more effective since it's more receptive to cells that might not have any mutation at all. And so, we're still understanding, but the biology need to be proven in a phase three study, and I think that's what we've been able to do with PROpel.

Alicia Morgans: Absolutely. So, if you had to sum this up and give your perspective on how this might be meaningful or useful information in clinic, are there patients where you might consider this strategy? What would your perspective be?

Fred Saad: Well, looking at the study as a whole, what we're seeing here is that we're doing much better for patients in the first line setting of mCRPC. And first line includes patients who got docetaxel in the hormone sensitive setting. And clearly we need to be doing better in the first line setting, because you and I know that many patients don't go beyond first line. And so, doing the very best we can in the first line setting as we've seen with other strategies, really leads to much better outcome. And what are the next lines of therapy when patients fail? Chemotherapy, we don't even know how effective chemotherapy is after abi, or enza or all the rest. So, really doing the very best we can in the first line setting is what we need to be doing to make a big difference in patients' lives.

Alicia Morgans: Absolutely. And I think that you make that point in this state and in other states, and I think it's a really important one for all of us to take home. We have to do our very best as soon as we can. That first line setting, whether it's mCRPC, whether it's mHSPC we always have to try to get that first shot on goal being our best shot on goal. And I think that this is a really exciting strategy for those patients who have not had an AR targeted agent in their earlier disease state. And so, really compelling and information and thank you for the talk today, as well as for presenting at ESMO 2022.

Fred Saad: Thanks a lot. Always a pleasure.