The Efficacy of Olaparib in the PROfound Study – Fred Saad

September 12, 2021

Fred Saad joins Alicia Morgans highlighting the efficacy of olaparib versus either abiraterone or enzalutamide, given a potential difference in the efficacy of NHA sequencing that he presented during a podium presentation at the American Urologic Association (AUA) Annual Meeting. The PROfound trial provided a rationale for United States Federal Drug Administration (FDA) approval of olaparib among men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on the next-generation hormonal agent (NHA) and who had alterations in homologous recombination repair (HRR) genes. Patients in the PROfound study had significantly prolonged radiographic progression-free survival (rPFS) with olaparib vs physician’s choice of abiraterone or enzalutamide.


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, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana Farber Cancer Institute in Boston, in the United States. I'm so excited to have here with me today, a good friend and colleague, Dr. Fred Saad, who is a Professor and Chief of Urology and the Director of GU Oncology at The University of Montreal. Thank you so much for being here with me today, Dr. Saad.

Fred Saad: Always a pleasure.

Alicia Morgans: Wonderful. Well, I wanted to talk with you a little bit about some updated data that you are presenting that really describes the control arm in the PROfound study, really the response of these patients to the second AR targeted therapy, to give us an understanding of what that looks like in a randomized clinical trial where these patients were followed very closely and meticulously. Can you tell us a little bit about your analysis?

Fred Saad: Right. So the most exciting part of PROfound was obviously the results from olaparib and seeing that we do much better than going from one hormonal to another. But I think for many of us, we thought that maybe we are getting responses when you go from one hormonal to another, especially the abi-enza sequence. So this analysis really digs deeper into what kind of responses we can expect going from hormonal to hormonal. Whether or not chemo was taken in between, the results don't change.

So the bottom line is with olaparib we had about 7 1/2 months of radiographic progression-free survival. With abi and enza, it was 3 1/2  months. And if we look at the details, it was 3.5 months for enza going to abi, and 3.6 for abi going to enza. So 0.1-month difference. And if we look at survival, which is what we are all aiming for, it was over 19 months with olaparib, however, it was 14.5 months for abi and 14.9 for enza. So really we are talking about days of difference when we go from hormonal to hormonal. And so really, I hope people will eventually stop doing this in all comers and maybe go to another mechanism of action and get better outcomes because these are patients' lives that we are dealing with.

Alicia Morgans: Yeah, In terms of that PFS, the radiographic progression-free survival, what's so striking to me is that the median is approximately the time when these patients would undergo their first scan. So really, if we're scanning at 12 weeks or three months, that's approximately what the median is for already having radiographic progression, which means we are failing those patients. We're not giving them something that is going to stop them from progressing radiographically, and they would have had to progress or have growth that is significant in order to be counted as progression. Can you speak to that a little bit?

Fred Saad: Yeah, absolutely. I mean, the definition of radiographic progression is not a soft definition. It's either significant growth in measurable lesions or at least two more additional bone metastatic lesions. And so clearly, most of these patients have progressed PSA-wise, even before radiographic progression, but we all agree we should not make decisions strictly on PSA. So like you say, RPFS is a very hard endpoint. And when we start progressing radiographically, clearly, our survivals are shrinking quickly.

Alicia Morgans: So one of the things that's important, and you alluded to this, is that there has been some thought that maybe going from abi to enza is more effective than going from enza to abi. And one of the ways that we can kind of think through this is to think about radiographic progression-free survival. You mentioned that. And another way is to think through perhaps differences in PSA response. What were the PSA responses to these patients as they switched from one to another? Were they having pronounced PSA responses in this control arm?

Fred Saad: Not even. If we're even looking for psychological benefit, it was under 8% PSA response going from hormonal to hormonal. Whereas with the patients who went onto olaparib, and these are many patients who were in the third line, we had a 43% PSA response, which we don't know what to make of with a PARP inhibitor. At least that's encouraging, that we can do much better than sticking to a hormonal approach in these patients.

Alicia Morgans: I could not agree with you more. And I guess as we sort of wrap up your thoughts on this, there may be some people who say that these were all patients who were treated who had these DNA repair defects, alterations. Do you feel or think that there is any reason to believe that these patients would have poorer responses to AR-targeted therapies in the control arm? Is there something about this population that leads them to a particularly poor response?

Fred Saad: If we didn't have the CARD trial, I might have said this might be a different patient population. But the CARD trial, that compared another hormonal to cabazitaxel in patients in the third line, had basically the same result. It's 3.5 months. So this is a recurring theme, that if we are expecting to do something of clinical benefit to our patients, it's obviously very attractive to go to another oral agent that has a very little side effect, but we have to think that we are dealing with a deadly disease here, and we have to make the choices that are most appropriate, even if our patients would prefer sticking to something that is soft.

Alicia Morgans: Yeah. Well, I agree with you. I think making decisions with our patients and really trying to avoid this sort of continuation of the same mechanism of action is going to be a theme, certainly in my practice, switching the mechanism of action, always important. What is your bottom line take on this and your message to the viewers?

Fred Saad: I think we have to individualize the care of our patients. So if they harbor these mutations, go with what has proven efficacy. And what is most impressive with a study like PROfound is that crossover was actually allowed. And regardless of the crossover, we had this really impressive, over 30% reduction in the risk of death, even though the patients that went from hormonal to hormonal have the opportunity to cross over. So try to understand what we are treating and treat appropriately.

Alicia Morgans: And I think from my view, the message is, do it as soon as possible because you can't always make up for lost time. And that's what we learned from these overall survival benefits, that maintain, even if the patient is on the control arm, cross to that effective therapy. So thank you so much for your time and your expertise today, Dr. Saad.

Fred Saad: Thank you very much, Alicia.