Dr Petrylak Discusses the Latest in Prostate Cancer Research

In honor of Prostate Cancer Awareness Month, Targeted Oncology has an exclusive interview with Daniel Petrylak, MD, professor of oncology and urology at Yale School of Medicine. Dr Petrylak is a renowned expert in genitourinary cancers, and in this interview, he discusses significant recent advancements in the field. He sheds light on the growing importance of genetic mutations like BRCA and the therapeutic potential of PARP inhibitors. Dr Petrylak also addresses the biggest unmet need in prostate cancer—the proper sequencing of the many newly approved drugs—and shares his excitement about the future of PROTACs, a revolutionary class of drugs that leverage the body's natural protein degradation system to combat cancer.

Targeted Oncology: What are some recent advancements in prostate cancer that you think clinicians should be aware of?

Daniel Petrylak, MD: There are a lot of areas of prostate cancer that have really come into the forefront. Firstly, the identification of genetic mutations, particularly the identification of BRCA and the related DNA repair enzymes and deficiency. I think those are important from a therapeutic as well as a family standpoint.

From the familial standpoint, we know that the germline mutations can be passed down from generation to generation. Not only is the patient who has prostate cancer afflicted by that, but the family members potentially can be afflicted, and they need to be properly genetically counseled, including screening for breast cancer, ovarian cancer, and pancreatic cancer, amongst other cancers.

From a therapeutic standpoint, we're now seeing the DNA repair does play a role as a target for those patients with metastatic prostate cancer. We know that the PARP inhibitors have activity in those BRCA mutation-positive patients. There's a potential synergy between PARP inhibitors and next-generation antiandrogens. As we've seen recently, moving these agents earlier in the hormone-sensitive state shows an improvement in radiographic progression-free survival, and perhaps we will see an overall survival benefit eventually.

The other theme that dovetails with that is using our agents in metastatic disease earlier. We know androgen deprivation therapy is the backbone of treatment for metastatic prostate cancer, but adding antiandrogens upfront does show survival benefit. The question is whether that should be combined with chemotherapy or not, and there's a lot of controversy over that as to who the right patient to treat in that fashion. But now, as I mentioned before, the PARP inhalers are moving up. The PSMA targeted agents are moving up, so intense treatment initially is something for the appropriate patient that needs to be considered.

What do you consider to be the biggest unmet need in prostate cancer?

The biggest unmet needs are sequencing. How do you sequence drugs properly? Twenty years ago, when I helped to get docetaxel approved, it was pretty easy. Then, you only had 1 drug that showed a survival benefit. Now you have immunotherapeutic agents such as [sipleucel-T (Provenge)], pembrolizumab [Keytruda] for select patients who have microsatellite instability, the PARP inhibitors, other chemotherapeutic agents, [lutetium Lu 177 vipivotide tetraxetan (lutetium-177 PSMA; Pluvicto)]—all these agents are approved in various states of prostate cancer, and there's some overlap. So, what's the right treatment to give at the right time? And then, by giving a treatment, do you preclude patients from receiving other treatments later on?

In terms of molecular markers, we need to develop more targeted therapies for prostate cancer. We have the PARP inhibitors. We have lutetium 177-PSMA for those patients who make PSMA. Perhaps in the future, the androgen receptor mutations will be targeted, and we're working on those particular areas right now.

What are you most excited about in the field?

I’m excited by the trial we're about to open at Yale. This is taking a drug that was actually developed on the Yale campus. It’s a [proteolysis targeting chimera (PROTAC)]. PROTACs exciting drugs. They're completely different than other drugs we've used in the past. What they do is they take the natural protein degradation system and amplify that. So, the PROTAC will target the androgen receptor, and it's sort of like a mark on that receptor for it to be destroyed by the proteasome. That's a natural process, but it's accelerated, and we have presented data at [the American Society of Clinical Oncology (ASCO) Annual Meeting] looking at a protect called ARV-766, which has activity in patients who have mutations in the androgen receptor.

The other thing that's been found with the PROTACSs is that they actually have a very vigorous up regulation of PSMA. We’re about to own up a trial Yale looking at the PROTAC combined with lutetium 177-PSMA with the thought that we potentially can make this more effective.