Innovative Approaches in Prostate Cancer: From BiTEs to Estradiol Patches

A roundtable discussion, moderated by Andrew Laccetti, MD, MS, of Memorial Sloan Kettering Cancer Center, focused on the treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC), including insights on the integration of recent research and clinical trials, how molecular subtyping affects treatment decisions, the future of care, and more. Dr. Laccetti was joined by Eleni Efstathiou, MD, PhD, of Houston Methodist Cancer Center; Ulka Vaishampayan, MD, of University of Michigan; and Michael Schweizer, MD, of Fred Hutchinson Cancer Center.

In the final part of our roundtable series, the panelists discuss novel therapies for castration-resistant prostate cancer, such as AR inhibitors and testosterone suppression.

View the first segment of this roundtable series: Transformations in mPC: Risk Stratification, Therapy Approaches for Hormone-Sensitive Disease

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Dr. Laccetti:
My next question is in terms of novel therapies for CRPC. The landscape is wide open for antibody drug conjugates; we mentioned BiTEs earlier.

What’s everyone’s thoughts on the most promising novel mechanisms that we’ve either seen presented this weekend or that exists across the research landscape generally?

Dr. Schweizer:
You mentioned two big ones – that data was very impressive. It’s like the first time we’ve seen substantial PSA responses with any immunotherapy and prostate cancer aside from the small subgroup with microsatellite instability. So I would say stay tuned.

There’s a lot of these drugs in development, and I’m really excited to see how they pan out. I think some of the ADC studies coming out are very interesting too.

I think there’s also a lot of interesting epigenetic drugs which seem like they’re gaining some traction here, as well. These can potentially serve as novel combinations that can work in a post-ARPI resistant population – we don’t have a lot of good data to say that we have treatments that work for that population.

Dr. Efstathiou:
I want to make a comment regarding T-cell engagers; a lot of our urology colleagues or small community practices are really stressed, because right now the trials are happening with inpatient admission. This is the learning curve.

We can see from the toxicity profile that at least some of them look like we’re going to be able to have it on the outpatient. We were struggling when we were trying to develop ipi/nivo, and it was a learning curve before that even with cisplatin.

I think there is a lot of promise, especially potentially for this highly aggressive disease. I’m not talking about biochemically-recurrent patients, but the ones who need it. I hope it’s going to be a game changer.

Dr. Vaishampayan:
The AR degraders and PROTACs are looking very promising. Plus, they’re oral agents that are easy to tolerate and easy to deliver.

We reported a study of lenvatinib and pembrolizumab in neuroendocrine prostate cancer. To your point about chemotherapy, we actually allowed up to two prior chemotherapy regimens, and even then, we saw about 25% response rates with about 30% of the patients staying progression-free at six months. It had a short follow-up, but this is a really tough disease to treat, and we’re seeing some promise.

Dr. Schweizer:
Going back to PROTACs, I’d be interested in everybody’s thoughts on whether we think it’s going to become an approved option for patients in the absence of an AR ligand-binding domain mutation. The data that was presented today showed that in the wild type groups response to around 25%, which is strikingly similar to what you get with enzalutamide close to abiraterone.

I think it’s a really effective AR signaling inhibitor, probably better than the currently approved drugs. But as far as fitting it into the treatment landscape, how do you get that phase III trial that’s positive? It’s going to be challenging.

Dr. Laccetti:
I agree. I think that the value is in the selected population, but patient selection from clinical criteria is also critical because the studies are starting to be designed favoring the prechemotherapy population in which you’re enriching for more AR-driven disease.

I think in absence of a validated biomarker and a well-designed, personalized study in that way, I think rational application in the prechemotherapy setting is a reasonable surrogate. But we’ll see how the studies are designed.

Dr. Efstathiou:
Do you anticipate it to be like a non-inferiority across all?

Dr. Schweizer:
I’d be doubtful of them having a have a non-inferiority castration-resistant setting; there’s no precedent for that. And to pull that off, you would need thousands of patients.

Dr. Efstathiou:
I think it’s going to be stuck with mutations.

Dr. Vaishampayan:
I feel that the strategy to market would be to do the study on resistant mutations, and then maybe they can expand into the frontline setting.

Dr. Schweizer:
True, because if it really is the most potent AR inhibitor, maybe can move it up into an earlier strategy.

Dr. Efstathiou:
Well, I would go to high-risk localized; we’re still waiting for a report, but high-risk localized is still uncharted waters.

Dr. Schweizer:
One other study I’m just curious of people’s thoughts on was the patch trial; are there patients who you may offer estradiol patches to instead of leuprolide and ADT, and would you take those results and extrapolate to the metastatic setting too?

Dr. Laccetti:
I think it’s a tough sell in the metastatic setting where the majority of patients are going to receive combination therapy, so they’re either going to have a potent AR antagonist or another androgen suppressant drug like abiraterone.

But I think it has value for intermittent therapy, potentially in the M0 population or for those select few with low-volume disease who can’t tolerate ADT. You can offer a sort of intermittent therapy for them.

Dr. Efstathiou:
I have to be honest, I didn’t look carefully at the adverse events. How was cardiovascular?

Dr. Schweizer:
It was no difference. They basically cut hot flashes in half, and the risk of skeletal events was lower too. They didn’t see any effects on anticoagulation, arguing that because you avoid that first pass metabolism with oral drugs that you don’t have the increased thrombogenic potential.

So I would agree with you, I think that in general, the patients you described are the ones I’ll probably look at. But in a patient who otherwise might have bone health issues or concerns, or in somebody who’s struggling with hot flashes, use it for all those patients because it’s still going to help mitigate some of those concerns.

You’re still going to mitigate the hot flashes by giving the estrogen back, and I think it would help bone density too. So it’s hard, but I think you’re going to start hearing patients asking for it because of this.

Dr. Laccetti:
I think it’s a very intriguing study trading hot flashes for gynecomastia.

Dr. Efstathiou:

I hope that we’ll soon embark on this trial, I’ve been looking forward to one with a new neurokinin 3 inhibitor that is approved for women for hot flashes and it really works.

I’ve been able to squeeze in for some of my patients. It really works, and I think we should do a quick study to get it approved for men. I agree with you, it has some limited liver toxicity, but we monitor these men about once every three months.

Dr. Vaishampayan:
But it’s also attractive to use the patch for patients with mCRPC where you’re just continuing that, especially with marrow infiltration.

Dr. Schweizer:
The one sort of thing that is going to be an issue if we start using it though is I don’t know how that’s going to impact patient trial eligibility because now they’re not on an LHRH analog. They’ll have castrate-level testosterone, so it should be ok for men.

Dr. Efstathiou:
Now with the oral antagonist being present, they’ve kind of loosened up because now that it’s been in the market for four years and some countries are engaging more and more, they’ve loosened up and they’re going just by the T suppression. So I think we’ll be able to.

Dr. Vaishampayan:
But also we need to modify with the times too, correct? You know our clinical trial design, we don’t, we changed the trial design for the patients.