Show notes
Recent approvals of PARP inhibitors mark the beginning of precision medicine for prostate cancer. Through patient case scenarios, Drs. Lisa Holle (Oncology Pharmacist, University of Connecticut) and Pedro C. Barata (Medical Oncologist, Tulane University) dive in-depth into appropriate use of olaparib and rucaparib in clinical practice, including patient and disease factors to consider. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us TRANSCRIPT [MUSIC PLAYING] ANNOUNCER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] LISA HOLLE: Welcome to the e-learning ASCO podcast on PARP inhibitors in prostate cancer. I'm Lisa Holle. I'm an associate clinical professor at the UConn School of Pharmacy, and I practice at UConn Health's Carroll and Ray Neag Comprehensive Cancer Center in Farmington, Connecticut. I'm joined today by Dr. Pedro Barata from Tulane University, New Orleans. PEDRO BARATA: It's great to be here with you. LISA HOLLE: Same here. PEDRO BARATA: So, Lisa, I know we'll be talking today about PARP inhibitors in prostate cancer. And it's kind of a kickoff, you know. What do approvals of the different PARP inhibitors for patients with advanced prostate cancer mean to you? LISA HOLLE: Yeah, this is a really exciting time in prostate cancer, because this is really the introduction of precision medicine in the treatment of metastatic castrate-resistant prostate cancer. So this is a group of patients, traditionally, who can benefit from PARP inhibitors that have not had good responses in the past to our traditional treatments. In fact, it really does allow these patients who would be eligible to receive PARP inhibitors to have an extended time on active therapy. Now, as we know with metastatic castrate-resistant prostate cancer, we can't cure the patients, but we can extend that time that they're on active treatment. In fact, in the two studies that were conducted, the PROfound study evaluating olaparib, and the TRITON2 study evaluating rucaparib, the progression-free survival time on average was about eight months. And in the PROfound study, which compared it to our new generation hormone therapies, that really doubled the progression-free survival time. And recent overall survival time was also improved by about five months. So this is really a significant advancement for these patients. And it really underscores the need that we have now for our metastatic patients to do germline and somatic mutation testing to see if they might be eligible for these treatments in the future. So Dr. Barata, who do you think could best benefit from the PARP inhibitors in prostate cancer? PEDRO BARATA: Yeah, and also, it's a great question, by the way, great introduction to the topic. And you indeed touched on something very, very important. And I think it's a perfect segue way for your question, which has to do with can you identify the good actors or the patients who are likely to respond, right? So when you think about how these drugs were developed, if we started by classifying this group of genes known as DNA repair genes, right, who have this job or function of repairing defects at time of cell replication. And so among these different genes, we start talking about BRCA, BRCA1, BRCA2, ATM, CDK, you know, RAD51, FANCA, et cetera. And so it seems like patients who harbor a defect in one of these genes are actually more likely to respond to these therapies. And these therapies, by the way, they inhibit the PARP and the enzyme that helps with burying the DNA, if you will. And so, you harboring a defect in one of these enzymes actually helps you to kind of amplify the benefit of this therapy. So what I'm really describing is a test who can find those defects, those gene differences. And we can do it in both ways. We can test the genes patients were born with. We call that germline testing. And we can also test a tumor for dose alterations. And that's also known as somatic testing, right? And we now know that germline doesn't tell you all the story and somatic doesn't tell you the full story. And so getting both tests seems to be helpful because it's a way of not missing the biomarker positive patients, or in other words, patients with DNA repairs, who are, again, likely to respond to these therapies. And so I would say, among these, definitely, patients with DNA repair defects. And we start learning a little bit more that not all the genes defects are the same, I mean the same in terms of efficacy signal. I guess we can talk about that a little bit later today. But I have to say, we expect somewhere 20% to 30% of patients who harbor dose genomic alterations. And so we are talking about a subset of patients within the group of advanced prostate cancer who really harbor those gene defects, and based on the data we have today, are destined to do better on these agents. Now if we don't test, we don't find, right? And so that's something that I think the clinics overall across the country and really, around the world, are now adapting to develop an easy way to start offering germline and somatic testing to those patients. Because it does impact our decisions. And so I kind of-- I just alluded briefly. And you did say, Lisa, you did talk about PROfound and TRITON that developed, respectively, olaparib and rucaparib, right? Do you have any thoughts about factors that makes you choose one versus the other? Is that something that you kind of use in clinic and to go through that thought process? Tell us a little bit how it goes when you get to pick one agent. LISA HOLLE: Yeah, I think as we think about new agents that are available for each of our individual patients, we have to think about patient characteristics, I think is one big factor, such as comorbidities. For example, in the PROfound study, I think they had an instance of deep vein thrombosis and pulmonary embolism that was relatively small, but it was in the range of 4% to 7%. And so I think in a patient who might have a history of a recent PE or a thromboembolic condition, you might shy away from using olaparib if they could receive rucaparib instead. I think the prior therapies that they have received too is also really important. So both of these trials looked at patients who had advanced after receiving either enzalutamide or abiraterone. And then the TRITON study evaluating rucaparib, they also had to receive at least one taxane therapy. So I think you need to make sure that they've progressed on one of those therapies. You might try olaparib before a taxane in that patient population. PEDRO BARATA: So basically, you're saying-- because I think it's a very important message-- is not that we believe agents might be different mechanistically, right? But the way we develop drugs in the oncology world is based in the setting they were developed, right? So you're basically describing different patient characteristics that were enrolled in PROfound and TRITON, and how that led to different approval specifically regarding chemotherapy. Is that it? LISA HOLLE: Right, exactly. And so I think when you're trying to decide between two therapies that have similar outcomes, are used in a similar population, and trying to figure out which one might be better for that particular patient, I think these are some of the things that we think about. Certainly, insurance approval could be a possibility, although I would expect that insurance would cover both of these agents. They're FDA approved. They do have some different indications that we can talk about a little bit more specifically as we talk about the specific testing that's done and what mutations were found to be most beneficial from these agents. But also, I think performance status is something to consider. So when we get to later lines in therapy, sometimes, our patients have poor performance status. And as with all clinical trials, we enroll patients with good performance status. I think the PROfound trial enrolled ECOG 0 to 2, and TRITON2 enrolled 0 to 1 performance status on the ECOG scale. So again, well-performing patients. It doesn't mean that our performing patients can't receive these drugs, but they may not have the same outcomes and may have more toxicity. PEDRO BARATA: Now it's interesting that you brought up access. I don't know your experience with that. I actually had a story, and I can share now or later. LISA HOLLE: Yeah, absolutely. PEDRO BARATA: So here in our clinics, we do test everyone. And we'll talk a little bit about that in a minute. And so this patient was a BRCA, a BRCA2 positive patient. And we tried at the time, we applied for olaparib for him. And unfortunately, we were not able to get it due to insurance restrictions at the time. This was prior to the FDA approval. And so we got to be creative. And we went with a platinum-containing regiment as an alternative. And it turns out, it worked really well, as we know. I mean, there's significant data out there. But basically, demonstrating an increased activity of platinum-containing regimens for patients with DNA repair gene defects. And so anyway, so that patient did respond well. And so I think he completed-- he got some carbo plus cabazitaxel at the time. And he completed six cycles, went on observation for while, on a chemo break, as we call them. And then he progressed a few months later. And at that time, we reapplied for a PARP inhibitor. And it got approved that time, actually. So we got rid of the obstacle that we had the first time around, that we encountered the first time around. And so actually, that patient is still on olaparib and doing well. But I think that speaks a little bit to what you were saying or referring to, that sometimes, there are obstacles that we have to be aware of. And definitely, access to medication is one of them. LISA HOLLE: Yeah, absolutely. And I think this highlights a good point that we're having in all of our patients with cancer right now, is as the studies come out-- so GU ASCO was just a month ago. Data comes out and the guidelines aren't updated right away. And during that period, when we know we have an effective therapy that could be used, that's the time, I think, and even a few months after that is when we have the most difficult time with insurance approvals. And then, of course, the FDA indication also can cause a lag in insurance approvals. But certainly, I think that also shows that we can, as many of us have done, had a peer-to-peer with an insurance company to ensure that they understand the data and can approve these therapies. That's another way that we can go about that. I think one other really important thing to think about these drugs are that they're dosed twice daily. So adherence could be a problem for some patients. Most of our patients have significant comorbidities. They're older adults, have multiple medications. So it's just an additional pill burden. And as we know with targeted therapies, adherence is really important to try to prevent the resistance that will ultimately develop, but try to prevent it from happening sooner. PEDRO BARATA: Right. LISA HOLLE: So I guess we probably should talk a little bit more about the testing that needs to be done and how we go about testing our patients. So could you share your experience with that, Dr. Barata? PEDRO BARATA: Yeah, for sure. I mean, that's truly, truly important. And thank you for highlighting that again. So as I was referring to earlier today, there are two types of testing, right? Germline and somatic testing. So the germline can be done with, for example, a simple blood test. And there's a bunch of commercially available assays that can do that for us. In regard to somatic testing, we can do it in the tissue. We can use a fresh biopsy or archival tissue, or we can do a liquid biopsy where we basically find circulating tumor DNA that's at the time of-- it's also a blood drawn, basically. So in prostate cancer world-- and I think that that's familiar to a lot of folks who treat prostate cancer-- they do know a lot of times, archival tissue is available from many, many, many years ago. And a lot of times, we cannot get fresh tissue or tissue that we feel represents the reality of the tumor today when we have the patient coming in to see us, for example, right? So I guess access to tissue is often a problem. And as you were saying, Lisa, both PROfound and Triton and other really biomarker positive studies, they often start based on tissue, not based on liquid biopsy, right? So the question is, in the absence of tissue, what can we do? And there's an emergent number of studies have shown good concordance between liquid biopsy and tissue. So I'll tell you what I do. We do favor tissue sequencing. And there's also a number of commercially available assays out there. And when I don't have tissue available and I really think we should do somatic testing, I use the liquid biopsy as a surrogate, if you will. It's not perfect, right? Because unless the tissue and liquid biopsy are kind of collected around the same time, and even though the panels are different-- so there are all these differences in there. But I think if we find, in this case, a gene defect with a good allele fraction, at least in my experience, I had that a few times. I did not encounter obstacles to access to a PARP inhibitor. But I still favor tissue because that's where the data was developed. And so that's just my style, right? I try be data driven as much as possible in all germline, right? If I have a germline that more than likely is going to be the tumor, right? Because all the cells wouldn't have it, but not necessarily. But anyhow, if I have a germline test positive or tissue positive, I'll use it. If I don't have tissue and I have liquid biopsy, I would still try it. But that's kind of my go-to, right? Now I do-- based on my conversations with my colleagues from the community, there's a little bit of concern about what to do with the results, meaning if you don't test, you don't know. But if you test and something positive comes back, you need to sit down with your patient or at least provide some kind of explanation and understanding. And some of us more than others are a little bit less familiar with some of the genomic alterations we can find. And I don't know all of them, to be honest. And they can create a challenge. So sometimes, we don't test because concern about the results. I would like just to highlight the fact that these commercially available assays, they do a good job, even a better job now than before, in terms of providing genetic counseling sometimes online or over the phone. And actually, some of my patients have used that in addition to just kind of go through the results with me. So that's something to be aware and it's simple to do, right? And we talked a little bit about reimbursement, especially before the approval. So approvals is based on the setting, right? So if I want to do, for example, rucaparib to patients who did not get chemotherapy, it can happen that insurance will, the payer will say, this patient needs to receive chemotherapy first. Because that's based on how TRITON was designed, right? And so you have an alternative, which would be olaparib, that doesn't require prior chemotherapy. And that doesn't…
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