Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Can Be Preselected to Maximize Benefit of Olaparib - Maha Hussain

October 16, 2020

Reconsidering back-to-back AR-directed therapies: An interview with Maha Hussain, co-principal investigator of the PROfound study.

Precision medicine and targeted therapy are possible in prostate cancer. Unmet needs have included more focused treatment and novel modes of action to counter resistance to hormonal and cytotoxic therapies. The PROfound study of the PARP inhibitor olaparib in heavily pretreated patients with mCRPC and mutated homologous recombination repair (HRR) genes met its rPFS primary endpoint, and final OS data show significant and clinically meaningful improvement with olaparib versus enzalutamide or abiraterone.

The greatest benefit was seen in patients with mutated BRCA1, BRAC2, or ATM—genes with a role in HRR. Post-hoc analyses also revealed trends in patients with other mutated HRR genes, which may help physicians when counseling individuals.
We know that sequential use of androgen receptor (AR)–directed therapies may be limited by cross-resistance. Although there are no data on the optimal treatment sequence in mCRPC, when counseling appropriate patients in the clinic, the PROfound data may prompt consideration of olaparib instead of back-to-back AR-directed therapies.

Approximately 20% of all patients with mCRPC have DNA repair alterations, mostly commonly mutations in HRR genes such as BRCA1, BRAC2, or ATM. In the PROfound study, patients with mCRPC who progressed on previous treatment with a new hormonal agent and harbored BRCA1, BRCA2, or ATM aberrations (n = 245; cohort A) or other alterations in the HRR pathway (n = 142; cohort B) were randomized 2:1 to receive either olaparib or enzalutamide or abiraterone acetate.  Join Dr. Alicia Morgans, Associate Professor of Medicine and GU Medical Oncologist, as she interviews Dr. Maha Hussain, Professor of Medicine and GU Medical Oncologist; both are at Northwestern University, Chicago, Illinois, USA.

Official study title: A phase III, open-label, randomized study to assess the efficacy and safety of olaparib (Lynparza™) versus enzalutamide or abiraterone acetate in men with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations (PROfound) - NCT02987543


Maha Hussain, MD, FACP, FASCO, is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, and the Deputy Director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Read the Full Video Transcript

Alicia Morgans:  Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today a friend and colleague Dr. Maha Hussain, who is a Professor of Medicine and a GU Medical Oncologist also at Northwestern University. Thank you so much for being here with me today, Maha.

Maha Hussain:  Thank you very much for having me.

Alicia Morgans:  Wonderful. Well, I wanted to talk with you today about your latest New England Journal of Medicine paper. It sounds like you've had three this year, so it's been a wonderful year and this latest is an update on the PROfound trial, which you also presented at ESMO last year. Really an update on overall survival and some other updates in terms of exploratory analysis. Can you remind us what the PROfound trial was? And then we'll get to talking about what you found.

Maha Hussain:  Sure. So the PROfound trial actually was the first Phase 3 clinical trial that when we designed it, the intent was to apply precision medicine to prostate cancer based on accumulating data regarding the presence of homologous repair defects in prostate cancer. Data stemming from the Stand Up to Cancer. And of course, the TOPARP-A Trial demonstrated a benefit in the subgroup of patients who had again the HRR mutations.

And so when we designed the trial, we really aimed high. We wanted to pre-select for patients who have the appropriate mutations. The intent was obviously to have this trial address several questions. And at the time of the study design, we actually separated the HRR mutations between the BRCA1, BRCA2, and ATM because this is what I would call the canonical type cohort. And then there was a whole list of other mutations that at least had some suggestive data, but they were not necessarily proven yet with regard to the potential effect of a PARP inhibitor.

And so the trial was designed with a 2:1 randomization. The intent was to look at radiographic progression-free survival, which was done through a central reviewer for this study. And obviously, there were a series of secondary endpoints, and the overall survival was one of the secondary endpoints. The trial met its primary endpoint of radiographic progression-free survival, which we reported at ESMO last year. And the publication came out in the New England Journal this summer. And then it met several of the secondary endpoints. And of course, the most critical endpoint in the business we're in obviously is overall survival.

And amazingly again, overall survival was significantly improved, despite the fact that the trial included patients who really were heavily pre-treated. So at a minimum, they had to have at least one AR targeted drug being enza or abi as frontline. But the data clearly, as we published, these patients were heavily pre-treated. Several of them have seen multiple chemotherapies before, some of them have seen both abi and enza.

And one of the issues that was raised at the time is, is it appropriate to have people see abi, enza, and get into the study and get assigned to a physician choice, abi and enza again, something like that. And at the time of the study design, there were really not many options for these patients and the study was international. So this is essentially a touch better than placebo from that perspective.

Alicia Morgans:  Well, and that's important because I think one of the most important messages of PROfound has really been that it might not be the best use of our time and our resources to really do these back to back AR directed therapies. But when you were doing this trial, we were in a very different world.

Maha Hussain:  Exactly, exactly.

Alicia Morgans:  So can you tell us a little bit about the overall survival findings? So we got findings from cohort A, cohort B as well.

Maha Hussain:  Yes. So basically the overall survival data showed that the cohort A, which is the primary cohort had a significantly longer overall survival. The median was actually 19 months in the olaparib arm and 14.7 months in the control arm. And this is actually despite, again, crossover did occur in the cohorts. But basically, the overall survival, when you look at the risk of death reduction, when you look at the overall population before crossover like just for the primary analysis in the context of cohort A, there was a 31% reduction in the risk of death with the hazard ratio being 0.69.

If you actually adjust for the crossover, and two-thirds of the patients, in fact, crossed over to olaparib, that hazard ratio goes down to .42. And so clearly a benefit was pretty profound there. It's interesting that the cohort, patients with cohort B, which is the non-BRCA1, 2, and ATM, there was a survival trend, but it was not statistically significant, but the trend was there. And when you adjust for the crossover, the hazard ratio is 0.83. This is clearly highlighting the fact that not all HRR genes are equal. And certainly, there are selective benefits in some of the patients.

Alicia Morgans: Absolutely. And I think it was so interesting the way that you and the other investigators actually really kind of drill down on that. You had some beautiful exploratory endpoints that you looked at specifically, response by specific alterations. Can you tell us a little more about that?

Maha Hussain:
  Yeah and I'm more than happy to perhaps share some slides regarding this because obviously going through it one by one is going to be not easy. But definitely, there were some benefits that we are seeing in some cohorts of patients that to my surprise, I thought they were not likely to respond. So clearly the biggest benefit was in the BRCA1, BRCA2, and in the ATM. What's interesting, in the ATM and these are secondary sort of post hoc analyses, is that the patients within the context of the ATM cohort if they've seen Taxotere they have a better chance of responding compared to if they had not.

So I do think, again, these are what I would say are interesting findings that definitely would need validation, but it actually is okay to use it from a clinical practice. You have a patient in front of you and we have this data. In this case, I think clearly counseling the patient on their choices of treatment is important. But I think if they have an ATM mutation, this is where perhaps one consideration might be to say, maybe Taxotere first, then go to this drug.

The other cohorts that I think were interesting to see are the different other genes like the CHEK2, there was some suggestion of benefit. Rad, some suggestion of benefit there. And so I think that all in all, there is a trend and I would encourage the audience basically to look at the paper and at the data and then use that as a potential gauge for when they would like to offer their patients the potential for a PARP inhibitor.

Alicia Morgans:  I think that's a great message because the label is actually broader, certainly than BRCA1 and BRCA2. And also, it can be sort of not the right thing to do to necessarily rely 100% on exploratory analyses that are not powered. But if we have a patient in front of us and we go back to the data, we can at least get a sense of what we might try because there aren't any 100% answers in this.

Maha Hussain:  Exactly, exactly. And I think that the point here is some judgment has to be used with regard to how best to tackle the management of these patients. And at the end of the day, the vast majority of patients, once you put in the NGS testing for these patients, the bulk of these patients are going to be the BRCA1, BRCA2, and ATM. I think there's going to be a handful at best in our daily practice, patients who have alternative mutations. I would say the biggest one is the CHEK2. Certainly based again, on the CHEK2 and then the CDK12. This is based on obviously the PROfound data, but I have to say in my daily practice, this is something that we see.

The other thing I want to point out is that the FDA approval actually covered all genes, including cohort B genes, except for a gene that has a long name. I'm sorry. The mutations in the gene are the PPP2R2A. That one actually was allowed in terms of an eligibility criteria.  At the end of the day as more data accumulated and more pre-clinical data accumulated and so on. This is not an HRR gene, and so, a mutation gene. So this is out of the approval panel from the FDA perspective.

Alicia Morgans:  Thank you for pointing that out. Because I think anytime we have more information coming out particularly regarding whether patients are going to respond to a treatment or not, updates on the label and clarification, it's so important. One thing that folks have talked about as they are thinking about using these drugs, particularly from experience in ovarian cancer and other settings is the development of leukemias and things.

And I know that you were watching very closely at all of these patients. There was one patient who developed AML. I think this was after essentially, the study follow-up was planned to have ended, but you still included and reported that which I think is very helpful.

Maha Hussain:  Absolutely. Yeah. And I think safety trumps, in the business we are in. As physicians, safety trumps everything else. And I think you have to report it. There are obviously different reports; however, just by sheer accident, this could have happened. I mean, this is a population, 4,000 patients were screened for this particular trial, albeit, obviously the majority were not included. But I do think that it's important to be mindful of that.

The other thing I want to highlight is this, is the observation we made on tolerance. And what I think is fascinating is, the patient population and I would really encourage the audience to go look at the eligibility criteria and then look at the patient characteristics. A large number of these patients really had bad disease. They had visceral involvement, they had very high PSAs. The interesting thing is that the age group actually, some of these patients were in the late 80s and early 90s.

And again, it highlights the feasibility of actually treating those patients in our practice. And so age, again, age is to be respected, but it's not an exclusion factor in terms of offering this. Whereas, if you want to give chemo, you are to really worry a little bit when you have a 92-year-old, for example. So some of these subtleties are I think, important.

Alicia Morgans:  They are. And also recognizing that so many of these patients were actually exposed to chemo in the past are still being able to tolerate this. That's important as well. So if you had to sum up the data that you've newly presented and now published in the New England Journal, what would your summary be?

Maha Hussain:  I think the summary would be, as the first thing, the big picture is that precision medicine and targeted therapy are possible in prostate cancer. And that I would encourage all investigators, sponsors, pharma, whomever, to actually look at prostate cancer and look at PROfound and certainly the TRITON trial. It is feasible to do these trials and demonstrate benefits, in fact, if the drug is going to work, but that would be one.

The second part is, that obviously an exciting part now that we have another drug in the pipeline for managing patients and managing them in a much more personalized matter, similar to, again, the benefit is similar to what is seen in breast cancer, ovarian cancer, and pancreatic cancer. Is it a cure? Of course not. However, I would say that it is remarkable that some of our patients, you may have similar patients on olaparib that have been on treatment for over a year and these are patients that have been heavily pre-treated. So from that perspective, I think it's very exciting.

I do think that the sky is the limit as to what we can do. And I would love to see us begin to develop combination treatments, investigate additional agents to better personalize the care. And I think from the big picture perspective, understanding even when you're pre-selecting for the HRR mutations, even in the context of the BRACA situation, not everybody responds and the question is why? And so clearly investing in research in this area to better understand collaborative and sort of resistance mechanisms becomes very important.

Alicia Morgans:  Well, I always appreciate your overarching messages because they're not just summaries of what you found, but where you want to go in the future and certainly encouraging all of us to take those next steps. So thank you again for sharing your take on this fantastic work. Congratulations to you and everyone involved, including the patients for getting this personalized medicine treatment study Phase 3 in prostate cancer actually finished and showing a positive result. Thank you again.

Maha Hussain:  Thank you very much. And it takes a village as they say. So keep working.