Prostate Cancer - Episode 15

Case 3: Personalizing Treatment for mCRPC


Alicia Morgans, MD:I wanted to circle back on the CARD trial data. I think it’s really important for us to emphasize to everyone who’s listening and thinking about this that not only was cabazitaxel better in terms of survival—there was a clear survival benefit, again, just out in theNew England Journal of Medicine—but we also saw that more patients had adverse events that actually, I think, resulted in deaths in the second AR [androgen receptor]-targeted arm.

So big problems I think, and that really should not be our first choice unless there is a compelling reason from a patient perspective, or they cannot take chemotherapy. I think what it doesn’t exactly answer though, and what some people have been talking with me about is, what is the next best agent? It’s not necessarily cabazitaxel just because we saw that it’s not another AR-targeted agent. And just to reemphasize, you don’t re-sensitize to AR agents by sandwiching. So AR, docetaxel/AR, not any better than docetaxel/AR, AR. So just putting that out there too.

I think that the change in mechanism of action is what’s going to be critical. But like Jorge said, this is the first third-line option trial that we have. And so, if we really want to rely on data in our clinical practice, if that’s how patients feel most comfortable, then cabazitaxel it is.

But you know, interestingly at ESMO [the European Society for Medical Oncology annual meeting], there were some other data presented just before the CARD data, which was looking at personalizing therapy by targeting DNA repair defects. And that story is really unfolding before our eyes as well. In the PROfound trial, these patients, many of whom had docetaxel and had also had either abiraterone or enzalutamide, were identified by having 1 of these DNA repair defects in a germline or somatic lesion, or alteration. They were randomized to the other AR-targeted agent, or olaparib, and the primary endpoint of this trial was radiographic progression-free survival. Olaparib had a superior radiographic progression-free survival in this population, again demonstrating that sequencing AR agents is probably not going to be beneficial to our patients, but really identifying that we can personalize and target patients who have a DNA repair defect. So I’m curious, Ken, are you using these data? Are you checking germline mutation status in your patients? What are you thinking about with this?

Kenneth Kernen, MD:I think that’s a great question. We started looking at that about a year and a half ago in high-risk patients. And so, we are doing genetic germline testing looking forBRCA1andBRCA2. We’re using some other agents now. We are using Foundation Medicine, and are doing some other things to get all that because that’s going to be the future—customization of cancer care, whether it’s newly diagnosed low-volume prostate cancer that can probably go on active surveillance and never need treatment, or someone like this gentleman who’s clearly failing multiple things and we need to figure out how we are going to make that better. Whether that’s going to be a PARP [poly ADP ribose polymerase] inhibitor, or whatever that’s going to be, I think that’s where germline testing is going to be critical to continue that customization of care.

Alicia Morgans, MD:Yes, and what you are thinking about, in regard to germline versus somatic. So, tumor testing and thinking about when to pull that in.

Neal Shore, MD, FACS:Yes. I think the PROfound trial is a landmark trial. Maha Hussain, MD, FACP, FASCO, did a great job in her presentation. This is going to revolutionize how we basically are looking at genomic profiling for all patients with metastatic disease, and this trial was the first. It’s truly remarkable. It’s personalized therapy. If you have a DNA repair damage alteration, you knowBRCA2, which kind of led the charge in this study. But we saw results withCDK12. We saw it withCHEK2. You saw it withBRCA1; and little bit of a signal, not great, withATM. That said, it clearly bested the switch to either abiraterone or enzalutamide. And as you said, about two-thirds of the patients also had received taxane therapy too.

And also, there was an 80% crossover. So the actual benefits are a little bit blunted by that 80% crossover. Why is this important to the listening audience? Basically, you’ve got to start testing. If you’re not testing, you’re never going to know. It’s both germline and it’s going to be somatic. If it’s germline, you kind of have your answer. But patients who are negative-germline, they could have DDR [DNA damage repair] defects as well. So getting biopsies, metastasis-directed biopsies—there’s a learning curve to that.

You have to work well with your interventional radiologist. This is all, again, part of the whole rubric of the multidisciplinary team. Whether it’s your pathologist, or your cardio-oncologist, or your interventional radiologist. Maybe we’ll get to the point where we use liquid testing, but we are not there yet. But there is a differential with patients. You ultimately have to be looking for somatic as well as germline mutations. And now we have Level 1 evidence. This drug almost assuredly is going to get approved. It will be the first PARP inhibitor. I’m sure that pretty soon we’ll be able to offer it to patients. And the good news is, there are several other PARP inhibitors that are being explored in trials with enlarged significant phase III studies. It’s going to really turn the field on its ear, because most of our colleagues, when patients present with metastatic disease—and it’s in the NCCN [National Comprehensive Cancer Network] guidelines—they’re not getting tested. So this is a big unmet educational need.

Alicia Morgans, MD:And what are you thinking about regarding cascade testing? Part of the reason I think that people are hesitant is they don’t always know what to do with the information. They don’t know which tests to choose. And then, they’re also concerned about the implications for family members. What do you think about that?

Jorge Garcia, MD:In our group, we have designed our clinic, we have a prostate cancer genetic counselor specifically for our prostate patients. But I think that you’re right, Neal. If you look at the NCCN guidelines over the last 3 years, specifically, we have adopted and changed every year, right? We used to say that people with a family history raise a flag for a DNA repair. Then we talked about all patients walking in the office with de novo metastatic disease; or men of younger age with high-volume localized disease. But now it’s clearly every patient.

Now, just to be provocative again, I think this is the most compelling trial that we have done in many years in prostate cancer. It’s biomarker-driven. Indeed, it’s a landmark trial, in my opinion.

Hopefully this is the beginning of that molecularly driven therapeutic era that we’re looking for. My only concern with DNA repairs is in regard to the utility of these PARP inhibitors, in my opinion. And I always use the example that if I were to walk into one of your offices as a 50-year-old guy with a knownBRCA2mutation, right? You tell me, “Well, Jorge, you’d know it. And if you didn’t know, we’re going to have to work on counseling you and your family—breast cancer, pancreas cancer, ovarian, breast for your sister’s family or children. And then, by the way, you do have more aggressive prostate cancer because DNA repair patients have more aggressive prostate cancer. Oh, and by the way, I’m going to be able to put you on oral agent—1 of maybe 3 in the future—that may actually be effective in your disease.” The problem is that we just didn’t know when to trigger that, when to put me on a PARP inhibitor.

Right now, we develop these agents in the castration-resistant space, which is pretty far out, right? The bigger question in my mind is, should we actually start testing? Undoubtedly, every man with prostate cancer should get tested. But should we start using these oral agents earlier? And we should not, because we don’t have that Level 1 evidence. But it raises the question of maybe earlier management of these patients, which may, in fact, be more effective for some of these patients.

Lastly, is that if you look at the data, the incidence of true germline mutations is probably less than 9% for most men. It’s not a huge patient population. Therefore, we see the importance of capturing somatic changes. We also know thatBRCA2appears to be exquisitely sensitive to PARP inhibitors, which doesn’t appear to be the same forATM, or maybe even forBRCA1. There are other somatic changes that also appear to be quite exquisitely sensitive to these PARP inhibitors.

I do know that not all DNA repair deficiencies are made the same and will likely respond to the same treatment the same way. I think that’s something that the field, over time, will have to spell out for us in clinical practice.

Alicia Morgans, MD:I completely agree. I think that we may find some of the PARP inhibitors to be more effective than others.

Jorge Garcia, MD:Correct.

Alicia Morgans, MD:What was fascinating to me in the PROfound data was that theBRCA1patients didn’t seem to necessarily have the same benefit. SoCDK12, yes.PALB2were not even reported because they were so rare. They were actually in the TOPARP-B study, and seemed to have similar effects as theBRCA2patients. So I still think there’s so much for us to dig into here. I’m excited that it is in the guidelines. And really, just to emphasize, anybody with metastatic disease gets germline testing. And then in my practice, at least, I try to work in somatic testing as well, because there are clear therapeutic implications, and we can increase the number of patients who actually end up being eligible for these treatments if we find them in the somatic testing. They do not need to be double-hits in germline and in somatic.

Transcript edited for clarity.