Transformations in mPC: Risk Stratification, Therapy Approaches for Hormone-Sensitive Disease

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 first part of this series, the panel discusses how to best sequence treatments for mHSPC and which patients are best suited for new therapies, along with decision-making for patients with mCRPC.

View the next segment of this roundtable series: Exploring the Impact of PEACE III on mCRPC: Insights and Implications

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Dr. Laccetti:
Metastatic prostate cancer has experienced some really dramatic shifts over the last decade with the advent of novel therapies and novel applications including drugs like androgen receptor pathway inhibitors, chemotherapies, and targeted therapies like PARP inhibitors and radiotheranostics.

So really critical to this evolution is a determination of how we should best sequence treatments and determine which patients are best suited for these given therapies.

To give us a little bit of a background, Dr. Vaishampayan, I’ll ask you, how do we characterize hormone sensitive prostate cancer and really think about the risk stratification for our patients?

Dr. Vaishampayan:
Hormone sensitive prostate cancer is typically how a patient initially presents within that metastatic disease. Conventionally, we talk about metastatic disease when you see signs of spread outside the prostate on our typical imaging, which is CT scans and bone scans.

So far, we have not quite made the switch, at least from a clinical trial standpoint, to use molecular imaging as a staging mechanism. However, a lot of decisions now are gradually being made more and more with the PSMA PET scans or some kind of molecular imaging techniques that will probably stage the patients to an advanced stage sooner.

The main basic definition of metastatic castration-sensitive prostate cancer would be where the cancer has spread outside the prostate and if that patient has a normal testosterone level – which typically is considered about 150 or so for the minimum testosterone level – and the patient is typically just starting therapy.

Dr. Laccetti:
Well, that’s excellent; it’s a really comprehensive and detailed overview. That leads me to my next question. In understanding the risk stratification approaches, how do we approach therapy selection in the hormone-sensitive setting given the evolving landscape of available therapies?

So, Dr. Efstathiou, I’ll ask you for that.

Dr. Efstathiou:
You know, I think we all have voiced the fact today that we do not have the markers that we should have, right? We don’t have these prognostic and predictive markers that you have in lung cancer or in breast cancer, so we have to use the equivalent.

The surrogates at least that have been defined based on some assumptions which have to do with volume mainly, presentation, and time of presentation. And these are poor surrogates, because of course, the progression of prostate cancer is a dynamic event.

And the reason I’m saying this is that is you may be lucky enough to catch it where – only on PET imaging for instance – there are few findings, but this may be a highly aggressive disease that is in the making, so they’re not fail-proof.

But having said that, that’s the best we have right now. The definition that started back in the day when we had the class classification, such as in the CHAARTED trial, was mainly based on the number of metastatic lesions and the presence of visceral metastases.

Those all would put you, in a simplified way, in the high-volume category. And then you have the low-volume category that may be more lymph node-only disease or limited bone metastases.

But then you also had a new definition that came about with the LATITUDE trial, which looked at high risk and low risk disease and also incorporated the Gleason score. On top of that, we now know that if the presentation is de novo and especially high volume, then that prostate cancer will be a top priority for treatment.

There’s a number of different morphologic and tumor characteristics to take into consideration, as well as patient characteristics. When we decide what treatment to give, at the end of the day, we’re treating a man, not a disease. So I think we should combine everything in lack of those markers that we hope to get, and we saw some new data at ESMO.

Dr. Laccetti:
Well, that leads me into my next point. Unfortunately, despite the advances we’ve made in metastatic hormone sensitive prostate cancer, castration resistant disease is an eventual course for the vast majority of our patients.

So Dr. Schweizer, I’ll ask you, how are you approaching metastatic castration resistant prostate cancer given the increasing multitude of treatment options we have in the current landscape?

Dr. Schweizer:
First of all, I’m benefited by the fact I’m at an academic center, so clinical trials are always high on my priority list. But in the absence of that, you’re right. I think we’ve got a lot of options, which is great, but it makes decision-making hard.

We clearly know that for patients who get upfront treatment intensification with an ARPI, they’re not going to have as great a response to a subsequent ARPI in that castration-resistant setting, as response rates are lower. For instance, drugs such as enzalutamide after abiraterone only have about a 20-25% chance of granting a robust PSA response.

That being said, there are still a subset of patients who would still want that treatment. They may be low-risk or low-volume disease patients where, if it doesn’t work, then they still have options of moving on to the next line of therapy. In my practice, I do this for some patients – it has to be highly selected, however.

For higher-risk patients in the early castration-resistant setting, I tend to use docetaxel with chemotherapy as one of my more common treatment options.

It’s interesting to take that framework into context with some of the data coming out of the ESMO presidential symposium, which showed that radium-223 plus enzalutamide looks like it has better progression free survival and overall survival rates compared to enzalutamide alone.

I think it’s important to understand that most of the patients who were enrolled in that study did not have intensified therapy upfront with an ARPI, so it may not be as applicable for many of the patients that I know I’m seeing in clinic. But that being said, if I have a patient who is otherwise thinking about enzalutamide, I’d be tempted to think about adding radium-223 on top of that.

Will it work for those patients? I think it’s a bit of a data-free zone, but at the same time, the combination is fairly well-tolerated, so I don’t think you’re losing that much. For somebody whose goal is to try to be as aggressive as they can, albeit maybe they’re not ready for chemo, it seems like a reasonable thing to consider based on these data.