Exploring the Impact of PEACE III on mCRPC: Insights and Implications

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 second part of this series, results of the PEACE III trial on mCRPC are discussed. The panelists give their insights on the trial and go over the implications of its results.

View the next segment of this roundtable series: Assessing the ARANOTE Trial: Role of Darolutamide in Enhancing ADT for HSPC

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Dr. Laccetti:
There’s a swath of data from the meeting this weekend that I think warrants some discussion points – you alluded to the PEACE III trial, which has the potential to impact patients in the metastatic castration-resistant setting.

As a review, the PEACE-III trial randomized men with metastatic castration-resistant prostate cancer (mCRPC) to receive either enzalutamide as monotherapy or in combination with radium-223.
An important point to note is that in this trial, patients must have not received a prior androgen receptor pathway inhibitor (ARPI), which does not reflect the majority of patients in contemporary practice who do receive that in the castration-sensitive setting. In addition, bone modifying agents were a necessary element for patients in the trial.

The primary endpoint of radiographic progression-free survival (PFS) was met in this trial, with a hazard ratio of around .69, which is very impressive, and there was also a trend towards an overall survival (OS) advantage with a very similar hazard ratio.

The safety profile reported in the study was excellent, with the most common observation being hypertension, most likely as a product of the enzalutamide.

So how are we approaching this data and what are our thoughts around it?

Dr. Efstathiou:
Radium-223 – an agent that came out of an older study – didn’t have those hard endpoints that we are looking at now. I typically do not employ this agent as much in the presence of lutetium and PSMA, because it is a direct theranostic.

Looking at this data, I may have done a disservice, because there may be a synergistic effect which we should look at with more detail, which makes absolute sense. We mentioned during our earlier discussion that there was a trial before that, ERA 223, where we completely failed to protect our patients from adverse events.

However, the PEACE III trial corrected the course and did the right thing, which we can now say is a no-brainer. The hindsight is 20/20, but it shows data that we need to look more carefully at.
I understand the dilemma and the nuance of thankfully most of our patients receiving any of the available ARPIs upfront, but let me give you this hypothesis – if I have a patient coming in the door who has responded for, let’s say three years, and is now showing bone-related progression, should I add or shift to enzalutamide and give him the radium-223?

Dr. Laccetti:
Dr. Vaishampayan, what is your take on the data?

Dr. Vaishampayan:
I was very impressed with it – it was a very active comparator. Frontline ARPI is very effective as we know from the PREVAIL study. Most other studies of radiopharmaceuticals have been done in comparison to second neoadjuvant hormonal therapy (NHT).

I think one of the other main points to consider is the OS difference; the median survival improvement of seven months is very robust and has not often been seen with any other agent in mCRPC. To me, that is a big take away from the study results, and the OS is pretty mature because they have adequate follow-ups.

About 80% of the survival events have occurred already, so this is a very mature study presentation of the PEACE III trial and that resonated with me. Meanwhile, we use a lot of ARPI upfront in the castration-sensitive setting. I feel like adding radium-223 in the second NHT – which is where most of us would likely use this in the mCRPC setting – will still be able to potentially enhance the efficacy and maybe provide that long term survival benefit. The additive toxicity was also very minimal, so that again is an attractive option to combine the two in mCRPC today.

Dr. Laccetti:
How do we factor in lutetium-177/Pluvicto in the face of this new data? As stated, radium for many of our practices has fallen out of favor. However, in light of this new data, there may be an additional role. Dr. Schweizer, do you have a thought on that?

Dr. Schweizer:
Yeah, it’s a tough one. We’re still waiting to see whether or not the PSMAfore study that looked at using lutetium pre-chemotherapy is going to actually lead to an approval. Assuming that does happen, you’re going to have these two approaches in the same space and it’s going to be tough to know exactly where to use it.

Radium is mainly going to affect bone disease by and large, so I think for patients who have any soft tissue disease, you’ll want to use lutetium-PSMA. But for patients with bone-only disease, you may still consider it.

I’ll also I’ll say, as far as access is concerned, lutetium-PSMA still isn’t available everywhere. I’m in Seattle, so I see a lot of patient referrals from Alaska and they need to come all the way to Washington State to get lutetium-PSMA, whereas I think radium is available up there. It’s a little easier to handle. There are practical considerations here too.

Lutetium-PSMA is a theranostic agent. My general impression is that it’s probably a more targeted and effective drug in many settings, but there’s no comparative data to really support that.

I also want to make a point regarding the PEACE III study, and that’s low toxicity. The requirement to achieve that is also giving a bone modifying agent, because we know from ERA 223 that for patients who get it in the absence of denosumab or zoledronic acid, they have really high rates of fractures. So you 100% need to give it with one of those drugs, otherwise you’re likely to have the same level of toxicity.