The Evolving Treatment Landscape of Metastatic Castration-Resistant Prostate Cancer - Episode 11

Defining Unmet Needs in the Management of mCRPC

, ,

Experts share insight on the greatest unmet needs in treating patients with metastatic castration-resistant prostate cancer.


Scott Tagawa, MD, MS, FACP: For our patients with advanced prostate cancer—all stages and lines of therapy, including noncastrate, what some people call castration-sensitive, hormone-sensitive, and definitely for castration-resistant disease—we don’t have any curative therapy. Maybe a very small subset has deep durable responses. There are case reports of people who have been able to come off ADT [androgen deprivation therapy] with immune checkpoint inhibitors, but those are few and far between.

The major unmet need is the fact that we don’t have curative therapy. It’s great that we have a growing number of therapies that may be used sequentially or in combination that lead to improvements in overall survival, symptoms, and quality of life. But we don’t have any cures. There are 3 general ways that we look to improve upon what we have in terms of standard of care. That’s taking the existing agents and using them earlier with the hope that there’s an improved benefit. We’ve seen that very clearly with the AR [androgen receptor] pathway inhibitors and chemotherapy. Simply by moving them from CRPC [castration-resistant prostate cancer] to the noncastrate setting, the hazard ratios are significantly improved. That translates into years of benefit rather than months in terms of median.

We may see additional advantages with combinations of therapy. For a long time in hematology oncology, we’ve looked at combinations or alternating non–cost resistant drugs that don’t have complete overlap in terms of AE [adverse event] profiles. That’s another way to go: to look at different combinations or moving the same drugs up. And then additional drugs, whether they’re in the same realm as others, including more hormonal therapies, newer molecularly selected therapies, and antibody-drug conjugates. Or new radionuclides, whether they’re bone targeted or PSMA [prostate-specific membrane antigen]–targeted or targeted against other cell surface targets. There’s a lot happening right now in the realm of clinical research, much more than was happening a decade or 2 ago. It’s rewarding to see. We hope to get additional agents out there in the near term.

Oliver Sartor, MD: There are many unmet needs for men with advanced prostate cancer. First of all, we’re not curing anybody with metastatic disease. The truth is that if you have metastatic disease, you have an incurable disease at this point. We need to be able to bring these new agents earlier in the course of therapy. In the VISION trial, we only enrolled patients who have been treated with novel hormones and a taxane. But now we’re going to be looking at metastatic CRPC that hasn’t been treated with a taxane, only with a novel hormone. Then we’re going to be bringing PSMA-lutetium all the way up front to look at hormone-sensitive metastatic disease in a trial called PSMAddition. We also have the PSMAfore trial with metastatic CRPC [after therapy with] abiraterone, enzalutamide, apalutamide, or darolutamide. That’s moving forward as we speak.

I’ve emphasized PSMA-617-Lutetium-177, but there’s also another compound called PSMA-I&T-Lutetium-177. That’s moving forward in trial called SPLASH. That’s going to be for metastatic CRPC in the pretaxane space. We have other agents incorporating lutetium that are also moving forward.

What do we need? We need to bring these trials closer to the front of the disease so people don’t have to wait so long. Quite frankly, we’re going to need novel isotopes and novel targets. We need things potentially like HK2 as a target. Maybe we need things like actinium-225 instead of lutetium. There are a lot of patients who can benefit from this type of therapy, but it’s not the answer for everybody, and continued progress is required.

Andrew J. Armstrong, MD, MSc: As we mentioned, the standard of care is changing rapidly. Many patients are being treated with a potent AR inhibitor, such as abiraterone, darolutamide, enzalutamide, or apalutamide in the hormone-sensitive setting or even in the nonmetastatic CRPC setting. By the time a patient has mCRPC [metastatic castration-resistant prostate cancer], they’ve often had a potent AR inhibitor. Identifying agents that aren’t cross-resistant and could be active is an unmet need.

There’s a great movement toward developing newer AR pathway inhibitors, such as CBP/p300 inhibitors; AR degraders, downstream effectors of AR; immunotherapy combinations, such as PD-1 combinations; and PARP combinations. The standard of care is to switch to a different mechanism of action, but we’re limited to docetaxel, cabazitaxel, PSMA-lutetium, and radium. Looking at combinations that may optimize those agents is part of the ideal.

Getting more patients molecularly tested, both germline and somatic, should open the door to many of these approved therapies to improve their survival. I’m still seeing many patients who haven’t undergone the standard of care testing, even though it’s been recommended for many years in the NCCN [National Comprehensive Cancer Network] guidelines. Implementing those standards of care will allow many patients to have more open doors and access to these phase 1 and 2 trials in the future.

Transcript edited for clarity.