This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Sandhya Srinivas, MD: Hello. I'm Sandy Srinivas, host of the Medscape InDiscussion podcast series on prostate cancer. Today I'm delighted to discuss poly-(ADP-ribose) polymerase (PARP) inhibitors, genomic testing, and the combination of PARP inhibitors, and perhaps talk a little bit about proposed agnostic use of these drugs, as well. This topic is really relevant to our patients and their families if they test positive for germline mutations. We now have a variety of drugs we can use based on genomic testing and an understanding of the availability of these drugs for a broader group of patients.
It's my pleasure to introduce my guest, Dr Heather Cheng. Dr Cheng is an associate professor in the Division of Medical Oncology at the University of Washington and an expert in prostate cancer genetics. She's been studying ways to use genetics to guide the care of prostate cancer patients and family members who may be at risk for this disease. She leads several clinical trials on new treatments for prostate cancer. She's also developing new tests that could help physicians choose treatments for each patient. She's contributed significantly to our National Comprehensive Cancer Network (NCCN) panel on prostate cancer. It's my pleasure to welcome Heather to this podcast series.
Heather, before we begin, I'd love to learn a little bit about your journey. Tell us what led you to oncology and specifically to urologic oncology, and your interest in this whole field of genetics and genomics.
Heather Cheng, MD, PhD: Thank you so much, Dr Srinivas. It's a pleasure to be here. When I think about how I ended up in oncology and urologic oncology, it's a field that's exciting because of the pace of innovation and new drugs from a scientific perspective. I did my PhD in molecular and cellular biology, so I can appreciate the advances in that area. But also from a humanitarian perspective, one of the most rewarding parts about cancer in general is the fact that you can really get to know patients well to figure out what's important to them in terms of deciding on treatment. I have a number of family members with prostate cancer, including my grandfather, my father-in-law, and my step father-in-law. It's a cancer that affects my family very personally. I think that's why I ended up in urologic oncology.
Srinivas: You've certainly contributed a lot to this field, and the field has benefited from your work. Let's start talking about some basic terminology for germline vs somatic testing, and maybe you can comment about what specimens are used when we think about this specific testing.
Cheng: Yes. Thank you. That's a really great question and a really important question for patients and medical providers and doctors. The terminology we use is best broken down into the main question for testing. We often talk about germline testing, which refers to the inherited DNA or hereditary DNA, and these are the genes an individual inherits from their parents — from their father and from their mother — that are present in virtually all cells of the body. For example, we can test for germline or hereditary inherited variants or mutations using blood, which has white blood cells that contain DNA. Saliva is also an increasingly popular way to test because cheek cells and white blood cells can be shed into the saliva, and those can be tested, which is obviously very convenient for patients. In contrast is somatic or tumor testing, which is where we're trying to focus on the DNA from the cancer. As you might imagine, DNA starts off as germline or hereditary but then acquires additional mutations that lead it to become cancer. It resembles the germline but is not the same and has unique DNA features. In order to test the DNA of the somatic mutations, tumor mutations, or the genomic mutations, we would need to sample the cancer. Often this is through the diagnostic biopsies or from prostatectomy material or metastatic biopsies. Increasingly, we're also interested in circulating tumor DNA, or ctDNA. This is a concept that's similar to prenatal testing, where you can test fetal DNA from the blood. You can do the same for cancer as long as the cancer is high enough volume and being shed into the bloodstream — then we can assess cancer mutations in the blood. There are some additional nuances to doing this well that we're still learning about. Certainly, ctDNA is very exciting as a less invasive way of understanding what's happening with the cancer and the mutations that might be present.
Srinivas: I completely agree. It's so relevant for our patients, especially with prostate cancer, where more than 75% have bone metastasis. While I think the technology is getting better for taking a biopsy of bones and extracting DNA, having the availability of doing this liquid biopsy, so to speak, and to look at ctDNA has been such an incredible addition to our field. Many of our patients with prostate cancer, unlike other cancers, have had a prostatectomy, sometimes even 10 years back. Getting material from archival tissue from that long ago can be challenging. Having access to this liquid has been so incredibly helpful. Maybe you can start off by talking about who gets germline testing. I know you've been an incredible part of our guidelines in advising providers as to who should be evaluated for germline testing.
Cheng: This has really changed dramatically over the last few years. We have known for a long time that prostate cancer is very heritable, and if you have a father or a brother with prostate cancer, it increases your risk. There wasn't as much actionability of that until recently, and it stemmed from some landmark papers in 2015 and 2016. The first one showed that about 10% of prostate cancers have inherited cancer predisposition — these are men with metastatic disease, or cancer that has spread outside the prostate involving the bone, lymph nodes, or other sites, irrespective of the age they were diagnosed or family history of cancer. This was validated in a larger confirmation study in 2016 in The New England Journal of Medicine that showed it was close to 12%. The details depend on the population you're looking at, but it's approximately 10% in most of the series. This is the basis for the NCCN guidelines recommending that all patients with metastatic disease, irrespective of their family history or age of disease onset, should be offered germline and genetic testing. This is because it's important for their treatment implications, which we'll talk about later in this podcast, but also because if they carry an inherited or germline variant or mutation associated with their metastatic prostate cancer or advanced prostate cancer, it has important implications for their family members. These are genes people are often familiar with in respect to breast cancer and ovarian cancer. Increasingly, we're aware that there's importance for pancreatic cancer, as well. The family members have important options for understanding their risk of developing cancer, which can potentially be lifesaving. There is also a recommendation for testing people with node-positive prostate cancer and high-risk localized prostate cancer. For these diseases, this is something newer for folks to think about, but it's also important, as there's increasing clinical trial possibilities for these patients as well. Of course, for anyone with a strong family history of cancer, breast cancer, ovarian cancer, pancreatic cancer, colon cancer, or melanoma — even if they have low-risk disease or Gleason 6 cancer or they are on active surveillance, it's still important to think about testing because of the family implications and potentially prognosis.
Srinivas: Thank you so much. That's definitely something new that our listeners would benefit from. Now, prostate cancer has so many different states. We have localized disease as you just said. Then we have hormone-sensitive metastatic disease and castration-resistant disease. For somatic testing, in your practice and whether it's on the metastatic sites or liquid biopsies, as you had just discussed, what do you find is the optimum time for us to recommend when testing should be done on the tumor?
Cheng: At the present time, testing should certainly be done on patients with a diagnosis of metastatic prostate cancer, especially now with the expansion of the availability of PARP inhibitors, which we can talk about more. Certainly, in the metastatic castration-resistant disease setting, there should be consideration of testing for investigating whether a patient may receive PARP inhibitors as a treatment option. We haven't talked about this yet, but for patients with advanced or metastatic prostate cancer whose cancer is microsatellite instability–high, tumor mutational burden–high, and who have mismatch repair deficiency similar to that in colorectal cancer — there are a smaller fraction of patients, but an important fraction of patients who are eligible for pembrolizumab. Certainly, the PARP inhibitors are also very exciting and a clear treatment option that isn't otherwise available if there isn't evidence of a DNA repair mutation, at least at this time.
Srinivas: It sounds like while the drugs that we have today are approved in metastatic castration-resistant prostate cancer (mCRPC), we would certainly want testing done at that time so physicians can pick appropriate treatment choices. What I'm also hearing is that there are clinical trial possibilities these patients may be eligible for. It may be a good choice at some point to have the testing done, so it could be of use for patients and providers down the road. With that, there are so many PARP inhibitors now. Could you highlight the ones that are approved in prostate cancer and, briefly, the trials that led to their approval?
Cheng: It is important to consider that somatic testing does take a little bit longer, so both germline testing and somatic testing can take a few weeks to a month or more. It's helpful to plan ahead. This goes back to thinking about when you'll use it and how soon it will be that you may need the information. It is important to think about this at the advanced disease setting. Going back to your question about the current PARP approvals, the first one was from TRITON-2, which led to the approval of rucaparib, which is approved for people with mCRPC with tumor mutations in BRCA1 or BRCA2. It's limited to those two genes, and it can be either germline or somatic mutations. Patients were eligible if they received a prior next-generation androgen receptor signaling inhibitor like abiraterone or enzalutamide, and they received docetaxel or taxane chemotherapy. Then, within a week after that approval was the approval of olaparib, which was based on the phase 3 PROfound study. That population was patients with mCRPC after an androgen receptor signaling inhibitor. In that case, patients were not mandated to receive chemotherapy. Some patients received a taxane. There were two cohorts in that study. Cohort A had patients whose cancers were associated with either a germline or somatic mutation in BRCA1, BRCA2 or ATM. Then the second cohort, cohort B, had a longer list of more rare or less commonly observed mutations. Those included CHEK2 and PALB2 and a number of other genes in the FDA approval for olaparib. Very recently, there was an approval based on PROpel for the use of abiraterone in combination with olaparib in the metastatic hormone-sensitive setting just for patients with BRCA1 and BRCA2 mutations at this time. It looks like patients with these mutations are very sensitive to PARP inhibitors, similar to what we've seen in breast and ovarian cancer. I think the biology and features of these cancers are similar — maybe not exactly the same, of course, but there is a lot to be learned from the experience we have in those cancers.
Srinivas: Clearly, two drugs are approved as a single agent, olaparib and rucaparib, and I think we had the TRITON-3 data confirming rucaparib use in CRPC, but you touched upon the use of combinations, and that's really been a very interesting aspect for our field. There have been a number of drugs now combining nonhormonal therapies (NHTs) with these PARP inhibitors. Interestingly, all of the trials are designed not just to select patients with mutations but look at a broader population and see if the combination of NHT with PARP inhibitors would benefit a larger group. Maybe you could comment a little bit about the history behind why they selected these two drugs and the recent approval for olaparib with abiraterone just in the population with BRCA mutations. Maybe you can give our listeners a little bit of a history behind the design for these trials. It hasn't just been one trial — we have several PARP inhibitors and several phase 3 trials, and I would love your thoughts on these combinations.
Cheng: Sure. I'll clarify, the new FDA approval for the combination of abiraterone and olaparib is for first-line mCRPC. There are a number of studies — the first one that just read out and the most mature is the phase 3 study called PROpel, which is the combination of olaparib with abiraterone in the first-line mCRPC setting. The design of the study was to look at all comers. Patients were not selected for BRCA1 or BRCA2 mutations or homologous recombination deficiency. The hypothesis was based on laboratory studies that indicated there might be synergy to this combination because there is cross talk between inhibiting the androgen signaling pathway and the effects on DNA damage response. The hope was that there would be a signal, even in patients whose cancers did not have homologous recombination deficiency, or in other words, a mutation or deficiency or inactivation of BRCA1 or BRCA2 or something like that. That was the original design of the PROpel study. There was a similar study called MAGNITUDE, which was a phase 3 study using niraparib with abiraterone. In that study, they designed the randomization a little bit differently. In some ways, it was a very elegant study because they set out at the very beginning, prior to randomization, of identifying whether or not a patient had a DNA repair mutation that was either somatic or germline. They assigned patients prior to the randomization into two groups. They either had evidence of mutation, which would lead a patient to be particularly susceptible, or they did not have that mutation, and then the patient was randomized after that to either abiraterone with the PARP inhibitor — in this case niraparib — or not. There was a futility analysis. In the MAGNITUDE study, they did not see benefit in the patients whose cancers did not have evidence of homologous recombination deficiency. It suggested that the patients who did have one of those mutations were the ones that especially benefited. That, I think, was similar to the previous studies like PROfound, TRITON-2, and TRITON-3 but seemed to suggest that patients who did not have those mutations did not benefit. The study TALAPRO, which investigated talazoparib with enzalutamide, was also similar in concept, in that there was an androgen receptor signaling inhibitor and then a PARP inhibitor. What's different is that they didn't necessarily assign the presence or absence of a homologous recombination deficiency prior to randomization. One of the discussions is whether or not we really understand this because some of the testing may have been with ctDNA potentially at different time points in the disease. Or, the tumor sequencing might have been insufficient or the methodologies to assign whether or not a patient's cancer was associated with those features may have been different between the two studies.
That's where there's still some uncertainty about how much benefit the unselected population has. I think there may still be some benefit. But there's no question that the people who benefit the most are the people whose cancers have the BRCA1 and/or BRCA2 mutation, which is the basis for the FDA approval just in that population from the PROfound study in the frontline mCRPC setting.
Srinivas: Thank you. There are a lot of data here, combining so many of these studies. I also find one of the challenges to be that these patients all had mCRPC and no prior exposure to our NHTs. The field is changing so rapidly that today, we use these NHTs in earlier and earlier lines of therapy. Clearly, your message is that patients who test positive for a BRCA mutation benefit the most from these drugs. It comes back to your point of testing these patients, and if they are positive for a BRCA mutation, we clearly want them to have the opportunity to have this combination if they have never been exposed to an NHT.
Cheng: In the midst of a lot of data, the take-home point is exactly what you said, which is, testing early, testing both for family implications and early treatment implications, and understanding that PARP inhibitors will be part of the treatment toolbox. Deciding when to use PARP inhibitors in the disease course is something we're still clarifying because there are data to suggest there may be a benefit to treatment synergy, but in some patients, it may be that sequential therapy is also okay. The combination of the two may have some more toxicity, so it may be reasonable for some patients to either receive combination upfront or consider doing the monotherapy sequentially if it's challenging.
Srinivas: Thank you so much, Dr Cheng. We always learn from you. You've made some really important points about both germline and somatic testing and the drugs we have available for our patients today. Thank you so much. We thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on prostate cancer. This is Sandy Srinivas for the Medscape InDiscussion podcast.
Medscape © 2023 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Germline vs Somatic Testing for Patients With Prostate Cancer: Which Patients Should Be Evaluated and When? - Medscape - Aug 23, 2023.