Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to speak today with a friend and colleague, Dr. Oliver Sartor, who's a Professor of Medicine and GU medical oncologist, as well as the Medical Director of the Tulane Cancer Center.

Oliver's going to speak with us today about some updates on PARP inhibitors, particularly the PROfound trial that was recently published in the New England Journal of Medicine. Thank you so much for your time today, Oliver.

Oliver Sartor: Thank you, Alicia. Really a pleasure to be here and a delight to be able to discuss some new and I think game-changing results with regards to PARP inhibitors in prostate cancer. I have the opportunity to talk to you today about olaparib for metastatic castration-resistant prostate cancer, and I've just published in the New England Journal last week. I'm somewhere in the middle author, I think, somewhere around six or seven. I was part of the steering committee, participated in the trial. The good news is that it's a positive trial and one that I think has real implications for clinical care.

Just a little bit of background before we get into this trial. There was an earlier trial on DNA-repair defects and olaparib published way back in 2015 by Johann de Bono and many others. What they did was to look at olaparib and look at individuals that had various DNA repair alterations and looked at radiographic progression-free survival and overall survival. What was fairly amazing, a very, very small study, just 49 patients, is they actually seemed to have an overall survival benefit and clearly a radiographic progression-free survival benefit.

So with these data in hand, a Phase III was constructed and executed. And what I'll be talking about is the more recent publication from last week's New England Journal, which presents the data from the Phase III. Now, if you actually look, there's been a fair amount of work done in various genetics of prostate cancer. This happens to be a manuscript that I was involved with and it turns out that a lot of patients will have BRCA2, CHEK2, ATM. And of course, this is germline, not somatic.

In the olaparib study, what they did was to look at somatic alterations only and they did not allow germline only testing. By the way, there is another PARP inhibitor called rucaparib that has worked in some of the positive germline variants and by the way, reports activity in the BRCA1 and BRCA2 variants.

So here's this lovely article and there is a pretty simple inclusion criterion, metastatic castrate-resistance prostate cancer, and they had to have progression despite prior abiraterone or enzalutamide, and have ongoing ADT, taxane was allowed but it was a stratification variable, it was not required in order to get on the trial. And everybody who enrolled in the trial had a FoundationOne® assay on tissue, and tissue only, looking for one of 15 pre-specified genes involved in homologous recombination. BRCA1, BRCA2, the famous ones, ATM, BRIP1, BARD1, CDK12, and some others.

So this is the basics of the trial and it really involved a biomarker-driven stratification. There were two cohorts, the BRCA1, BRCA2, ATM patients were all combined into Cohort A and Cohort B was everything else. Why? Because we know a little bit about BRCA1, BRCA2, and ATM, but really not a lot about the other homologous recombination repair genes. There's a 2:1 randomization to olaparib, and these are compared to abiraterone or enzalutamide, depending on what you received previously. You could be randomized to receive the opposite. The stratification by prior taxane and measurable disease.

And the plan was to allow the treatment until disease progression or toxicity. And very, very importantly in this trial, following radiographic progression, the patients in the control arm could cross-over. So right off hand, you can see issues with the measurement of overall survival. Going to get a good rPFS readout that potentially had tainted overall survival readout.

The primary outcome was really based on Cohort A and looking at progression-free survival by soft tissue progression by RESIST, or the Prostate Cancer Working Group 3 criteria, or death. So this was an independent review of the scans and then a sensitivity analysis with the investigator reviews.

So this is kind of the nuts and bolts of the trial. Cohort A, Cohort B, 2:1 randomization, open-label, olaparib 300 mg bid versus physician's choice which in this case will be abiraterone or enzalutamide, stratification by prior taxane and measurable disease, the primary endpoint, rPFS, with key secondary endpoints including the rPFS of both Cohorts A and B, some responses, time to pain progression, and overall survival. And I'm not going to present everything here. It's just a short discussion.

When we looked at the statistical analysis, there was a hierarchical method in which everything had to be met before you could go on to the next analysis. And what you'll see is that the overall survival, using O'Brien-Fleming spending function, at the interim, which we'll be presenting here, is at a 0.01 for the P-value in order to achieve statistical significance with a subsequent allocation of the alpha at 0.047 in the final analysis. And I'll jump ahead and say the final analysis actually was released by press release last week. I'll wait on that for a bit more.

So they actually screened 4,400 patients to get into this trial, and that's very important because there's a lot of screening and not everybody had tumor that was available. At times, there was difficulty obtaining the tumor and these may have been from a prostate biopsy some years ago. Of the 4,400 patients screened, available tumor in a little over 4,000, about 2,900 were actually tested for the biomarker, and 778 had a qualifying alteration, and a total of 387 who met eligibility were randomized. So there's a long way to get from this 4,400 patients down to 387 and that's one of the limitations of the trial, is that tissue acquisition was somewhat problematic and these tumors that were obtained and available for testing, over a thousand of them that did not have a biomarker reported, were basically quality control failures. In other words, they went off to the lab, but the lab could not give a legitimate report based on the quality of the tissue that was received. They could not give a report.

So looking at Table 1, just very briefly, things were very reasonably balanced between the arms. What you can see is that BRCA2 is by far the most important of the genes who were measured. And ATM is also there. We'll come back and look at some of these individual genes a little bit later. You can look down in the prior hormonal use, you can see enzalutamide, abiraterone, or both were used. You look at prior taxane and 39, 46% of the patients had docetaxel pre-treatment.

And here were the gene alterations that were present in the Cohort A, Cohort B. Again, you can see BRCA2 being dominant, ATM being quite common in Cohort A. And by the way, you see others in Cohort A, but that's because multiple genes were involved. If you get a somatic BRCA2, it's not uncommon that you'll have somatic alterations in other genes as well. In Cohort B, the one that was by far the most common was CDK12, and again, we'll have some individual data on these genes as well.

So here's the rPFS in Cohort A. Unequivocally positive, data maturity 71%, median 7.4 for olaparib, control 3.6. Hazard ratio very, very strong at 0.34, P-value less than 0.001. And really there was sensitivity analysis on investigator-assessed progression very similar to the bonded central review. So this is unequivocally positive. Remember, if you're on the control group you could cross-over.

Then moving on to the prespecified subgroups, there's some interesting data here and I think some of the most interesting data is actually on the right-hand side of the screen. If you look down towards the bottom, you begin to see that BRCA1, and there are very few BRCA1s, by the way, so the confidence intervals are big, seem to be favorable for the hazard ratio. And BRCA2 is what really drove this trial. Hazard ratio of the BRCA2 patients is 0.21, whereas ATM, which is fairly common, had a hazard ratio 1.04. Smack around one, really not better than the standard of care. CDK12 might've had a tiny bit of inflection toward the positive with olaparib, but certainly, the confidence intervals overlapped one and that was important to see.

And here's the overall survival as reported in the manuscript, remember the 81% cross-over and the hazard ratio was 0.64 but the alpha significance threshold was set at 0.01. So even though the P-value is 0.02, it's not actually positive. If you look at the data maturity, it's only 38%. Here's the punchline. Last week there was a press release saying they met the threshold on the final overall survival analysis. So now there is an overall survival benefit, but it's not in the New England Journal paper and it's particularly driven by these BRCA2 patients.

Now when you look at the Cohort A and B together, again, you have a hazard ratio that's positive at 0.67, P-value is good, but a lot of this is being inclusive of genes where there was no apparent genetic effect like ATM really did not appear to have benefited from the olaparib treatments.

Here is the sensitivity analysis for the cross-over within the New England Journal manuscript. And again, you can see the full analysis on Cohort A being 0.64 for the hazard ratio, 0.73 for Cohort B, but at the same time, it's the final analysis which is most interesting.

Side effects. Yes, there are side effects. Anemia was relatively common in the olaparib group, some degree of nausea was present, although the vast majority of this was grade 1, grade 2 and it was transient, not continuous. Some fatigue, very little in the way of grade 3, 4, most of the fatigue was well manageable. Some appetite issues, generally fairly well manageable. A little bit of diarrhea, a little bit of vomiting, but these are typical of the PARP inhibitors. I'll say that if you manage the toxicity and are willing to look at the dose reductions, you can see here, occurred in about 22% of the patients and 45% of the patients had an interruption followed by either restarting or a dose reduction. So the vast majority of patients can get a discontinuation due to an adverse event was 18%.

So in conclusion, the PROfound validated the earlier phase studies with olaparib. There was, of the patients who were tested, and this is different than the patients who were screened, about 26% of the patients had a qualifying gene mutation. The OS benefit, which was initially 0.02, was in fact probably impaired by the high rate of cross-over, which was 81%. And the higher AEs of course maybe be attributable, in part, to the longer duration of therapy, but they're definitely PARP-induced effects. And what we can see is that there is a clearly positive trial, this is going to be going to the FDA. And quite frankly, I think the FDA will rule favorably. The question is what subsets will they move favorably on? And I think that is debatable. It'll be interesting to see how the FDA handles this.

Alicia Morgans: I agree, Oliver, and it's really exciting to think that the FDA actually by the time everyone views this, may have already approved olaparib or it may be very, very shortly in our future. The study was really conducted in a patient population that was selected, of course, and one of the challenges that you highlighted really clearly was how we actually identify patients in our clinical practices who may be eligible for this treatment once it is approved for the metastatic castration-resistant population. How are you getting over that in your clinic? What do you think about using archival samples from a prostatectomy specimen, for example, if a patient has bone [inaudible] metastatic disease or a clinician tries to get a biopsy and really is unable to get tissue that is viable for sequencing.

Oliver Sartor: Great question, Alicia. There are three different ways that you can potentially obtain data inferred about somatic alterations. Number one, of course, is tissue. Number two is circulating tumor DNA. And number three is actually the germline. And the germline is an interesting way to view the data because, in a gene dependent fashion, there are the biallelic changes that are associated with this dramatic change. And it turns out that probably for BRCA2 germline, that about 75% of the patients will have a second hit.

Other PARP inhibitors, now I mentioned rucaparib, have actually used germline testing, and the germline testing is the biomarker that they use in their trial. And by the way, that's also in front of the FDA, potentially they have a PDUFA this month. The rucaparib could actually be first to market, which is an important thing to note. So the PARP inhibitors are actually plentiful. Olaparib is the first one with the Phase III to support, but it may or may not [inaudible] with FDA approval.

So think about germline because it's easy to get and you can get every patient. Number two, the somatics, fresh tissue is always superior to old tissue, and that old biopsy from 14 years ago that you dredged up from the community urology office may in fact not be so good. That's going to be a limitation. Now, the circulating tumor DNA is being explored and this is not yet mature enough to be able to really comment upon, however, there are substantial trials that are being evaluated using the ctDNA. Those trials are still in progress. But as we go forth, the way I'm envisioning this is with olaparib it'll be a tissue-based biomarker and you'll use your best available tissue or obtain new tissue if, in fact, you don't have anything from the archive.

On the other hand, the germline may suffice but it may be a limited number of genes and in addition, the circulating tumor DNA work is going to progress. And quite frankly, I see a year or two from now, with the circulating tumor DNA, which is readily available may, in fact, be the way these assays go.

So you asked me about a simple question and I gave you a complex response because I don't view it simply, unfortunately, there's a lot of complexity in the way we assay the frequency of assays, and the ability to get the assays, as well as the coverage, insurance coverage, for the assays, which is also important.

Alicia Morgans: I totally agree and I think it's important to acknowledge that the NCCN currently recommends that germline testing be performed for all patients with actually high-risk localized disease or more advanced disease, which includes metastatic disease, of course. And so these patients should undergo germline genetic testing both for themselves, for potential implications in terms of a PARP inhibitor therapy, but also to counsel family members who may also have these genes. And then when it comes to somatic testing, I agree with you, I think that the circulating DNA is probably the direction we're going.

For now, we try to get a fresh biopsy. If we can't get one certainly if there's a prostatectomy specimen from a year ago, that's probably where I would go next. But it is important for us to try to make sure we get the best samples possible and the NCCN now recommends somatic testing as well as germline testing for these metastatic patients because you can actually have a mutation in either germline or somatic that could be driving this tumor. Is that correct?

Oliver Sartor: Absolutely. And I don't want to neglect the possibility of MSI-high or mismatch repair and their pembrolizumab, and I've mentioned the drug very specifically by name because pembrolizumab actually has an FDA approval for MSI-high or mismatch repair deficient regardless of the assay. It's only about 3 or 4%, but it's a really important 3 or 4% and if you're lucky enough to be able to have one of those patients, then the probability of response to a PD-1 inhibitor is really quite substantial. We have some in our practice and it literally has been lifesaving for some of those patients.

So the PARP inhibitors are actionable, particularly in the BRCA genes. By the way, the CDK12 and ATM, a little bit disappointing, there was some preliminary hope that those subsets might be positive but did not mention PALB2, but PALB2 definitely did look positive on not only in this trial but in others. So we're going to learn a great deal more in the months ahead, not necessarily years ahead, months ahead, about subsets and where to go.

The last issue, I did want to raise in particular, is platinum. So there are studies that are not to this level and not to this detail, not to this size, but studies with platinum that do indicate activity for those with DNA repair defects. We're still sorting out all the details, but clearly, if the BRCA mutations are present, then the utilization of a platinum-based therapy might be considered, particularly if the olaparib or other PARP inhibitor is not available, for cost or whatever other reason.

Alicia Morgans: I completely agree and have absolutely used those agents in the setting of not being able to get a PARP inhibitor. I think, hopefully, we'll be able to have access to PARP inhibitors soon with approval. But if you can't get that agent for some reason, whether it's a copay or some other reason, platinum can be very, very helpful. And when you're identifying patients to treat in your clinic, what are those key HRR mutations that you're looking for where you think, "This is a patient where I should try a PARP inhibitor?"

Oliver Sartor: Yeah, so the BRCA2 is incredibly convincing. The BRCA1 is likely convincing, but here's what's a little bit tricky. In the assays in PROfound study, you didn't have to have biallelic alteration. If you just had a monoallelic alteration, you'd be eligible for the trial. I think some of the non-responding patients, particularly the BRCA1, may, in fact, be due to the fact that a biallelic change is clearly optimal for a PARP inhibitor to get that synthetic lethality. And we're going to become a little more sophisticated about dealing with monoallelic and biallelic changes, I think, as we progress in our knowledge and our assessments.

So I'm looking at the BRCA genes, but BRCA2 is kind of the go-to money right now, PALB2 is definitely active. Again, I'm going to call out the mismatch repair deficient MSI-high, but there we're talking predominantly about MSH2 and MSH6. If you're looking at genetic alterations, the PMS2, we don't actually have a lot of data on yet. And in addition, the MLH1 is very, very rare when it comes to prostate cancer. So MSH2 and MSH6 are the two MMR genes as part of the Lynch syndrome, if you will, we need to watch out for.

There also, and I should mention this, there are some provocative data with ATM mutations with an ATR inhibitor, you may have not heard of that. We're just about to get the ATR inhibitor trial up and going here at Tulane. I know a number of other centers are working with those. So that would probably be about 2% or so of the prostate cancer patients, which may not sound like a lot, but if you're in that 2% it's very, very important.

So we're evolving our understanding of genetics, not only in the application of different therapeutics but also in understanding the monoallelic, biallelic proportion and also understanding the different assays that are optimal. And so, a really fascinating field right now. The field is in flux and gosh, we're learning so much so rapidly right now.

Alicia Morgans: Absolutely. It reminds me of when I was a fellow, and I'm dating myself, but a decade ago we watched lung cancer be spliced into all of these subsets when everyone just said, "Well, non-small cell lung cancer is just adenocarcinoma. That's all it is." And we are watching that happen in prostate cancer now and so it's so exciting.

One point that I did want to make sure we emphasize, that you mentioned, is that I think it was around 80% of patients who were on that control arm actually crossed over to receive the PARP inhibitor treatments and still we did see a press release that demonstrated an overall survival benefit. Now we have not seen that data, but it's not hard to envision that those curves could continue to stay separated and that the P-value may become significant, which is what I expect happened. So do you have any comment on that? I think that just speaks to the strength of the data.

Oliver Sartor: Yeah, absolutely, Alicia. I was actually surprised to the extent that the overall survival was positive, 0.64 hazard ratio in Cohort A, 81% cross-over. Eighty-one percent! When I was initially thinking through the trial design, I had very little in the way of hopes that the overall survival would be positive, but it is. And I think that underscores the importance of this therapy and quite frankly raises the issue about whether or not earlier PARP inhibitors might be even more effective because here you're not delaying the PARP inhibitor that much. You're just waiting for rPFS plus abi/enza, although 40% or so had taxane pretreatment as well. But it really amplifies, I think, the importance of some of the earlier trials.

And I also like to mention trials in combination with abiraterone and enzalutamide that are unselected patients. Noel Clarke, one of the investigators in the UK who's a fabulous investigator, has published some preliminary data looking at abiraterone/olaparib combinations in unselected patients. And quite frankly, there were strong trends toward positivity in what was basically a randomized Phase II. So we need to watch for the utilization of the PARP inhibitors coming into unselected patients or earlier in the disease in combination with our novel hormonal agents. So it's really a rapidly changing space right now, and again, we're going to learn so much more in the next couple of years.

Alicia Morgans: I think that's so exciting, Oliver. And we saw in Noel's data that there were wild type patients, so in other words, patients who did not have HRR mutations that seem to also benefit from that combination of olaparib and abiraterone, which suggests that we may be able to induce a BRCAness or some sensitivity to these PARP inhibitors. And it's really exciting as we think about moving therapies into the future.

Oliver Sartor: Yeah, absolutely, Alicia, I agree. And the full mechanisms, to me, are a little bit elusive whether or not it's the induction of BRCAness, I don't know. Or is it simply that there's synergy in the apoptosis that you can achieve with the novel hormonal agents and the DNA repair when inhibited through PARP it had synergy through the inhibition of DNA repair. So I honestly don't know the mechanism of the synergy, but I've seen the data and I've seen the concept presented from multiple angles and I think it will have to be clinically proven before we can really accept. But the good news is there are multiple trials underway to test these concepts.

Alicia Morgans: Yes, it is definitely very exciting. So as we wrap up on the PROfound data, I did want to mention and make sure that we note that it seemed like olaparib in this population also prolonged that time to pain progression and improved the way that patients lived, also. Not just helping them live longer, but really helping with some of their symptom relief.

Oliver Sartor: Absolutely, Alicia. And that's actually very important just due to the limitations of time, I did not present the time to pain progression. It was profoundly positive if you don't mind the pun. And there was a clear benefit in terms of the olaparib, not just in the rPFS, but in patient-reported outcomes as well.

Alicia Morgans: Wonderful. So one final message, and I try to drive this home whenever we see a control arm that's an AR followed by another AR as that control arm. Just to mention that, I think that it looks to me, in this setting as we have seen in other trials, that if patients progress on an AR-targeted agent, it will be a very short period of response, if any response at all, to a second AR-targeted agent. I think the radiographic progression-free survival in this population, similar to the CARD trial that we've seen, was very short, maybe three and a half months or so. Can you comment on that as we wrap up?

Oliver Sartor: I agree completely. The AR followed by AR might have an asymmetry that could be notable. The abiraterone post-enzalutamide response rate is probably 2% at best, it really is inactive. You end up with about a 30% PSA response rate with enzalutamide after abiraterone. In general, these are short-lived responses. I know there's a tendency for people to be reluctant to move on to chemotherapy, but chemotherapy is almost certainly a better choice, as shown in the CARD trial. And I also believe that these patients could be superb for clinical trials with novel agents as well. And the variety of trials now in the works to look at PSMA-targeted therapy, particularly the radiopharmaceuticals, in this phase as well. So things will continue to evolve. And the good news is that when we learn more, patients get better. So the good news is we're learning more.

Alicia Morgans: Wonderful. Well thank you so much for reviewing the PROfound trial data, talking with us about PARP inhibitors, both in terms of olaparib, and more generally, rucaparib, as you said, also expecting a PDUFA date and one way or the other, decision by the FDA. Certainly reminding us about MSI-high, pembrolizumab is important, but at the end of the day we see more treatments coming down the road for men with metastatic castration-resistant prostate cancer and things are looking good. So thank you so much for sharing all of your knowledge and reviewing this data with us.

Oliver Sartor: Thank you, Alicia.