Ep. 14: Emerging Agents in the Management of Prostate Cancer

Transcript:

Neal Shore, MD, FACS: For purposes of time, Nancy, I wanted to get to you about this notion about another class of drugs that’s going to hopefully be approved in 2020 for patients with mCRPC [metastatic castration-resistant prostate cancer], and those are the medications known as PARP inhibitors. Pedro did a great job earlier reviewing the importance of genomic profiling with germline, somatic, tissue, and liquid testing.

There’s actually a Medicare code for tissue testing for somatic tumors. I think there’s going to be liquid testing approval relatively soon, which is going to be great. Germline testing, as you said, is recommended by the NCCN [National Comprehensive Cancer Network] Guidelines for anybody with metastatic disease: hormone sensitive, castration resistant, or even high risk and newly diagnosed with a family history. But what role will PARP inhibitors play, assuming they get approved?

Nancy Ann Dawson, MD: The PARP inhibitors, which are oral drugs, are pretty exciting. As you mentioned, you’re testing all your patients to see if they have these DNA-repair gene abnormalities: BRCA1, BRCA2, ATM. The PARP inhibitors are very specific for patients who have these DNA-repair gene abnormalities. They do have activity, and they’re going to become very important for those patients. We should be testing all these patients, so we can identify who those patients are early on. But the PROfound study, which was with olaparib, included patients who progressed on hormonal therapy. For second-line androgen receptor [AR]—targeted therapy, they received the other agent: if they received abiraterone, they got enzalutamide, or vice versa. They were randomized with that second-line AR-targeted therapy or to olaparib, the PARP inhibitor.

There was about a 3½-month improvement in progression-free survival. There was a response rate of about 40% in those patients. I would point out 1 thing, though: all DNA-repair gene abnormalities are not equal. If you have a BRCA mutation, your response rate may be a lot better than if you have an ATM mutation, which although included, were not quite as responsive. Olaparib is probably going to have an approval very soon. It will have a role for these patients as another second-line option after they fail on 1 of the androgen receptor—targeted drugs.

Then there was the TRITON2 study, which was with rucaparib. That was a different population. Those patients could have had abiraterone or enzalutamide, plus they had to have had a taxane in the castration-resistant setting. Those patients also had very good responses. The preliminary data have been presented, with response rates as high as 50%. We don’t have the long-term data, but there were good response rates. Very exciting data. It was not as good for patients with ATM mutations, but mostly beneficial for patients with BRCA mutations. But those are going to play an important role.

Now, the patients who have these mutations make up a smaller percentage of the total, up to 20%. I’ve heard different numbers. But if we identify them up front, you will know when it comes time to decide on therapy. You can sit down with your patient and say, “All right, you’ve got a BRCA2 mutation, and I’ve got this treatment option.”

Neal Shore, MD, FACS: You summarized it greatly. We have to know their status. You have to identify that so you have to test. You have to test the germline, and you have to test the somatic if the germline is negative. You can test the somatic through tissue biopsy, and hopefully soon, liquid biopsy as well because it’s easier. Or you can use archival tissue. But if you don’t test, you don’t know, and then you can’t provide therapy and you can’t enroll these patients on upcoming clinical trials, which we’ll talk about in a minute. Thank you for that summary, Nancy. At this point, let me turn it back to the panel and ask, what is out there in the pipeline that you’re particularly excited about? We’ll start with you, Alicia.

Alicia K. Morgans, MD, MPH: Good, I have the easiest job then. I think all of us are really excited about the radiopharmaceuticals. The VISION phase III trial for mCRPC, where we looked at lutetium-117 plus best supportive care versus best supportive care, has finished enrollment and will hopefully give us some data in the next year or so. But there are others—actinium-225, thorium-227—and combinations that are coming. I think they’re tolerable and really exciting. That’s what I’m most looking forward to.

Neal Shore, MD, FACS: The radioligand conjugates as a class are very exciting.

Pedro C. Barata, MD, MSc: I share your thoughts, Alicia. On top of that, I would add that after our disappointment with immunotherapy, we have basically been testing immune checkpoint inhibitors everywhere. We’re starting to tease out the select group of patients with prostate cancer who will likely benefit from these therapies. I’m obviously thinking of the 2% or 3% of patients with microsatellite instability [MSI]. I’m thinking of data that were presented at the ESMO [European Society for Clinical Oncology Congress] meeting last year by Emmanuel Antonarakis on CDK12, which we learned is not a good biomarker for PARP inhibition but might be something to pay attention to in terms of immunotherapy.

I’m thinking about the data that were just presented on the combination of cabozantinib with atezolizumab for patients with prostate cancer and soft-tissue disease. We have immunotherapy use in prostate cancer, so it’s going to be interesting how this will tease out. To Nancy’s point, we’re starting to learn that not all DNA-repair gene abnormalities are the same. The signal seems to be driven by BRCA2. Perhaps other than ATM, I’m thinking about RAD50, etc . We’re going to learn in the next several months or years that some DNA repairs are going to be strong predictors of response to these therapies. We now have 2 agents in priority review, olaparib and rucaparib. We do expect approvals in the near future.

Neal Shore, MD, FACS: Great. Nancy?

Nancy Ann Dawson, MD: Being No. 3 is probably better than being No. 4. I’ve always been really excited about the PSMA [prostate-specific membrane antigen]—targeted therapies, so I’m with you on that. We’ve got the ARROW trial, in which we’re adding in iodine-targeted therapy. That’s exciting. The checkpoint inhibitors are getting looked at from the earliest hormone-sensitive setting to the latest castration-resistant setting. I’m very interested to see how those turn out. Those are big phase III trials.

I’m excited that there are things I haven’t heard of yet. I’m most excited about that. I’m probably the only person on this panel who, when I go to ASCO [American Society of Clinical Oncology Annual Meeting] or GU ASCO [Genitourinary Cancers Symposium], I don’t read all the abstracts in advance. I want to be surprised. I would say I’m most excited about what I’m going to learn at the next meeting and that it’s going to be something really exciting.

Neal Shore, MD, FACS: Great. William?

William Oh, MD: I remember when I was training as a fellow. Lung cancer was a disease where we gave everyone the same chemotherapy of paclitaxel—platinum-based therapy, the response rates were terrible, and the patients ultimately progressed and died. Lung cancer now has become a disease of multiple molecular subtypes. It’s embarrassing to me as a GU [genitourinary] cancer doctor that we have not been able to subset our patients in the same way. It’s a complicated disease, but we know there is a “triple-negative prostate cancer.” We don’t know what to test for, but we know there are different subtypes, which are probably molecularly defined.

We’re hearing about this, whether it’s DNA damage repair, immunotherapy-sensitive patients, or the resistance markers that we didn’t talk about today. But I do think I’m most excited that we’re moving past blanket treatment for everyone and starting to subset patients. Olaparib will probably be the first drug in this setting where a patient is selected for the treatment. We know MSI-high tumors are very rare in prostate cancer, but we can give those patients pembrolizumab. We’re starting to take the science and look at patients not just as having prostate cancer because that’s too heterogeneous a disease. We’re also starting to be able to molecularly define patients and will be able to treat them in a targeted way.

Neal Shore, MD, FACS: Absolutely. It’s the precision medicine that we all like to practice. This has been great. On behalf of our panelists, we hope you found this Peer Exchange® program to be useful and informative. Thank you very much.

Transcript Edited for Clarity