CheckMate 9KD Trial CohortA2 Evaluating Nivolumab + Rucaparib for Chemotherapy-Naïve mCRPC - Daniel Petrylak

November 7, 2021

In this UroToday discussion, Daniel Petrylak joins Tom Keane highlighting the ESMO 2021 data on CheckMate 9KD cohort A2. This was the final analysis of nivolumab and rucaparib for chemotherapy- naïve metastatic castration-resistant prostate cancer. 


Daniel P. Petrylak, MD, Professor of Medicine (Medical Oncology) and of Urology; Co-Leader, Cancer Signaling Networks, Yale Cancer Center, New Haven, Connecticut, USA.

Thomas E. Keane, MBBCh, FRCSI, FACS, Department of Urology, The Medical University of South Carolina, Charleston, South Carolina, USA.

Read the Full Video Transcript

Thomas Keane: Good day, everybody. This is Tom Keane, coming to you from UroToday. And today, I think we have a very interesting topic. Of course, it's metastatic castration-resistant prostate cancer, but the speaker is someone well known to most people in the field. It's Professor Dan Petrylak, and he has very kindly agreed to go over his presentation, which he delivered at ESMO 2021. It was entitled, CheckMate 9KD cohort A2 final analysis of nivolumab and rucaparib for chemotherapy- naïve metastatic castration-resistant prostate cancer. As we know, Dan is professor of medicine and urology at Yale School of Medicine and co-director of the cancer signaling networks research program at Yale Cancer Center in New Haven, Connecticut. He's also an avid golfer, and I'm delighted to say a very good friend of mine. Over to you, Dan.

Daniel Petrylak: Thanks Tom, and it's certainly both a pleasure and an honor to be able to present this data on behalf of the investigators from the CheckMate 9KD study. So, this presentation is part of a larger trial that has several different cohorts. We're talking here about cohort A, but cohorts B, by those patients who were treated, who were naive to docetaxel, eligible to receive docetaxel therapy and have up to two prior next generation hormonal treatments. And these patients receive nivo and docetaxel. And then the third arm was nivo plus enzalutamide in those patients who've not had prior treatment with enzalutamide or apalutamide. So I'm going to be talking about the cohort A group, those patients who were treated with nivolumab and rucaparib.

So overall, there was 71 patients treated in this trial. The median time from diagnosis was approximately four years. The median PSA was about 38, but that ranged from 0.6 to more than 5,000. A quarter of patients had visceral metastases. If we look at the HRD status, about 49, 47% were HRD positive, about 50% were negative, and about 1% were not evaluable. Half of patients had measurable disease, and the prior treatments included abiraterone, enzalutamide or abiraterone low. The median follow up was 17.5 months, and the median treatment duration was 4.6 months for nivolumab, and 5.6 months for rucaparib. And 65 patients at the time of the database lock had discontinued treatment, and the most common reason for the discontinuation was progression. 2.8% of patients completed treatment, and four patients remained on treatment. So let's go to the response outcomes, because I think there's some very, very interesting patterns that have developed from this.

First, if we take all commerce, the response rate's 15.4%. So, this is basically telling me that if we're trying to look at increasing BRCAness, by giving a immune checkpoint plus a PARP inhibitor. And the concept behind that, is that the PARP inhibitor may induce DNA damage. Also, of course, it's going to affect those patients who have DNA repair mutations, but those patients may actually have more Neoantigens and that may lead to a greater sensitivity toward checkpoint inhibition. But the response rate's 15.4%, that's really predominantly driven by the HRD positive patients, and the HRD positive patients as we've seen in other trials, that's predominantly driven by the BRCA1, BRCA2s. So if we look specifically at the BRCA1, BRCA2s, three of nine patients who have measurable disease with BRCA1, BRCA2s had an objective response, but we also see, as we see here, BRCA2 is in orange, BRCA1 is the pink.

We also see an ATM patient who did respond and that's a little bit unusual because as we see with the other PARP inhibitors, we generally don't see objective responses. And these are really very, very small numbers, but that may be hypothesis generating. But also, when we look at PSA declines, we see that 11 of the 13 BRCA patients had PSA responses or PSA declines of more than 50%. And that's, I think better than what you would see with single agent rucaparib. But again, when we look at some of the other mutations, we do see some negative patients that are going in that direction, we do see some CHEK2s. So clearly we're seeing some interesting signals, but not enough numbers really to determine whether this is insignificant. But I think here this observation with the higher risk PSA decline rate with BRCA does need some further confirmation.

These are the survivals in our patients. So this is the rPFs, a Radiographic progression-free survival, as one would expect the Radiographic progression-free survival was better. And those patients are HRD positive, 11 months and the overall survival's, approximately 23 months. We didn't see any treatment related adverse events that really were unique to this combination. In fact, what we're seeing is basically the individual treatment related events about a quarter of patients had a treatment related adverse event that was led to a discontinuation, the most common, and we've seen this before is anemia and no treatment of related deaths were reported in this trial.

So in conclusion, we found that nivolumab with rucaparib demonstrate clinical efficacy with noteworthy activity in patients harboring BRAC alterations, we need more follow up to determine the clinical benefits of adding nivolumab to rucaparib. The activity seems to be in patients who have DNA repair mutations and the safety profile was expected and there were no new safety signals that were seen. So these are acknowledgements of the patient and families, of course, the clinical study teams and then a ranch campus from Bristol Myers who served as protocol manager and also Richard Daniel who provided writing an editorial assistance. So questions?

Thomas Keane: As I've looked over the last five to seven years at the really phenomenal improvements that have taken place, breakthroughs that have occurred, realizations of just how nasty, or how benign some of these conditions can be. I can't help, but ask, do these defects, the DNA repair defects, et cetera, are we causing some of these based on the treatments that we're delivering? Are these inherent in the tumors when we first start out? Because you can see such changes in both the aggressiveness and in basically, the structure of these tumors. As we move along our pathway of treatment, obviously surgery is not going to make one difference between them but the treatments, particularly from medical oncology and from radiation, are we causing some of these?

Daniel Petrylak: Well, that's a great question. There's no clear answer to that, but, when you look at the microsatellite instability data, there does seem to be in a very, very small number of patients. There does seem to be some upregulation of that particular marker. And even though it's only two to three% of all men with advanced prostate cancer, there is in the study for Memorial three of six patients. Again, very small numbers develop microsatellite instability. Now is that associated with a particular agent? Not clear, is that associated with... Do we see the same thing for BRCA? I tend not to think that. I think that if it's there early, it'll still be carried through. And I think that's why we need to look at different genetic markers when we see changes in a clinical state. So if somebody develops visceral disease, when they didn't have it, where did that [inaudible 00:09:09] arise from? And can we treat that with some of the newer target therapies?

Interestingly, PARP is related to a DNA damage. There's upregulation of the enzymes involved as patients become castrate resistant. So, that may also be a factor. We know that administration high dose of testosterone can actually cause DNA breaks. So there's just a very, very interesting little interaction between all these different agents.

Thomas Keane: And this may be a simplistic view, but do you feel that we are changing the makeup of the tumors based on the treatment that we are giving? What I mean is, we have patients who've been treated with ADT and all the variants of ADT and then they develop a Neuroendocrine type tumor profile, and then we switch back again. So we give them chemo and then we switch back and suddenly they're back having an androgen type profile, androgen receptivity. So is that where we're going to be going? Do you think, is it going to be a kind of a left, right, left, right where we move from one treatment to the other treatment and bounce back again?

Well, you're raising a really, really important question. How do we, in real time measure genetic and phenotypic changes? Because when we're looking at tissue biopsy, we're looking at one slice at a time. Liquid biopsies, I think is a little bit better, but how many liquid biopsies do you need to do? What's the efficacy of doing multiple biopsies? Are you getting any more information to take care of the patient? I think without question, you are changing not only the tumor, but you're changing the microenvironment around the tumor, such that, the treatments may act very, very differently. And this is why I'm always wary of studies that are looking at archival tissue, because that may not reflect the microenvironment of a given time, it may not reflect upregulation of different markers. I mean, it only makes sense.

This is like if you take the analogy of infectious diseases, it may be a little bit simplistic to say this, but you give a antibiotic for infection and then the bacteria develop resistance, and then you have to change your antibiotic. And then of course you develop bugs that are resistant to everything, eventually super bugs. So that in some respects is what's happening here, but you also have a micro environment to worry about in terms of the intracellular matrix, how that interacts with the tumor. I think we've kind of forgot about that and focused on the epithelial cells. Now we're looking more at the environment around the tumor and how we can change that, and how that affects gene expression.

Thomas Keane: That's a great answer. I always learn something whenever I listen to your presentations. And this is one of, I think the most useful things that we can have is getting someone like you to explain it, because I'd understand it for probably for five or 10 minutes, and then I go, what did he say again? But it really is a pleasure to hear this. And, once again, in the interest of time, we'll wrap this up, but I think, people like you, are what's making the huge improvements that we're seeing in this. And please, God, they'll continue. As always, it's wonderful to have you on Dan. Thank you for this presentation.

Daniel Petrylak: Thanks, Tom. Greatly appreciate it.