Novel Therapeutic Targets in Metastatic CRPC


A broad discussion on emerging therapeutic targets in metastatic castration-resistant prostate cancer and where they may fall within the treatment landscape.


Rana McKay, MD:It’s exciting [to think of] the number of cell surface targets being looked at from B7-H3. There have been some very exciting data around various ADCs [antibody-drug conjugates]. Technically, B7-H3 is a checkpoint inhibitor. There could be combination strategies with I/O [immuno-oncology] therapy. What are your takes around B7-H3 that target?

Sumit K. Subudhi, MD, PhD:An antibody-drug conjugate appears to be active in prostate cancer. But in addition, they have an antibody that can cause ADCC [antibody-dependent cellular cytotoxicity]. It’s not a drug conjugate, but the antibody itself interacts with the complement system, and that causes tumor lysis. It’s been shown to be immunogenic. The question is, can we use that in the castration-resistant setting? What do we combine it with to make it more effective?

Rana McKay, MD:There are other agents, like KLK2 and DLL3. We haven’t talked much about prostate cancer and how to target that. Any thoughts about those targets?

Ulka Vaishampayan MD:Those targets show D differentiation. If the disease is taking that turn to the neuroendocrine path, the management deserves to be different. That’s why I was asking if there are multi-targeted radioligands that could prevent that crossover or disease state from forming. Even that disease state, which tends to be a terminal and dismal prognosis, needs novel strategies to address it.

Sumit K. Subudhi, MD, PhD:The 1 issue with DLL3 is that it can be heterogeneous within a patient. That’s intrapatient heterogeneity. A paper shows that in 1 patient, liver metastases has high expression of DLL3, but the primary prostate has very low expression. Whatever therapy you use would not be effective for the patient.

Scott Tagawa, MD, MS, FACP:Maybe. With radium, we ignored nodes. If we hit an important compartment, it can be successful, or in combination. I’m an advocate for theranostics. I’m not so strict about the therapy part. Let’s say you have imaging, and our friends at Memorial Sloan Kettering [Cancer Center] have a DLL3 imaging agent. That’s a way to look at the patient in vivo and what’s going on.

Rana McKay, MD:We’ve talked a little about targeting the microenvironment. Data came out of COSMIC-021 looking at cabozantinib-atezolizumab. There’s a large phase 3 that’s fully accrued, CONTACT-02. We’re eagerly awaiting the results. Any thoughts around that?

Sumit K. Subudhi, MD, PhD:Microenvironment is very important. It’s underappreciated in prostate cancer. The excitement last year at ASCO [American Society of Clinical Oncology Annual Meeting] was that 18 of 18 patients with colorectal cancer and mismatch repaired defects had complete responses. If you look at the data from Wassim Abida—he’s probably treated the most patients with anti–PD-1 therapy with prostate cancer and mismatch repair defects—you’d never see 18 of 18 patients. In fact, he shows that 50% of patients have primary resistance. Of the other 50% who respond, only 50% of those have a durable response. Of the total population, you get 25% durable responses. We’re talking about the same mismatch repair defect in 2 different cancers. What’s different is the microenvironment. That’s important. Cabozantinib has been shown to affect not only endothelial cells but also the myeloid population, as shown by Ron DePinho in Nature. This combination with atezolizumab looks promising.

Arash Rezazadeh Kalebasty, MD:One thing [to ask about] that trial is, can we look and see who responded and separate those patients? Don’t say, this is the hazard ratio; give it to everybody. Those are the key points that have to be considered in trial enrollment and have an open question answered because it’s important. Rather than just showing a Kaplan-Meier with a difference between the 2 groups.

Sumit K. Subudhi, MD, PhD:Much of the in-house molecular testing that we have is looking at the tumor cells themselves. BostonGene has a platform looking at the tumor cells. In addition to the microenvironment, they’re giving you some data on that. These aren’t data you can act on. We’re trying to use it in the context of clinical trials to help us stratify patients.

Transcript edited for clarity.

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