SPLASH Trial Findings: Balancing Enthusiasm and Realities of PSMA Radiotheranostics

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 fourth segment of this roundtable series, the panelists discuss the SPLASH trial which analyzed 177Lu-PNT2002 for the treatment of patients with mCRPC who progressed on an androgen receptor pathway inhibitor, and weigh the realities of the trial’s hazard ratio and overall survival results.

View the next segment of this roundtable series: CONTACT-02 Highlights: Immunotherapy, Biomarkers, and the Need for Better Treatment Options

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Dr. Laccetti:
Another trial that was reported was the SPLASH trial, looking at another lutetium-177 mediated PSMA-directed radiotheranostic. I think this study requires a little bit of attention. Eleni, do you want to give us your opinion?

Dr. Efstathiou:
I have to be honest, I expected more from the trial and I am one of those who have fallen victim to the enthusiasm surrounding the theranostic era. It was a positive trial, but we’re used to more impressive outcomes – when you look at the statistical design, the primary outcome was there. But I believe overall survival was not there and the hazard ratio was not impressive to the point that we are used to.

Theranostics are a phenomenal new space, but we should be more selective regarding who we’re treating. I had a recent patient with a germline BRCA2 mutation who received a second opinion that recommended PSMA PET, and he was adamant that this was the best treatment for him. He also had a high SUV.

I allowed him to get the PSMA treatment, but it didn’t work and his marrow was affected. So will I now be able to give him the one treatment that I should have given him to begin with? This is just one of many examples of how we should be more thoughtful, but again, this is a discussion to have with our patients, who are also very excited about lutetium treatments right now.

Dr. Schweizer:
I think it’s worth pointing out that the overall dose of the lutetium I&T was quite low; my understanding is that it was mandated by the FDA, and I think that’s probably a big reason we’re not seeing more robust outcomes with this.

In contrast, PSMAfore looked at lutetium PSMA in the same disease space, and they had a PFS of about 12 months versus splash at around 9, I believe. So it’s not fair to compare across trials.

But at the end of the day, it makes you question whether or not the FDA’s edict that they use a lower dose of the INT potentially could have been the reason they weren’t able to show more robust clinical activity there.

 Dr. Efstathiou:
But just to come back to you, PSMAfore has not given us OS either.

Dr. Schweizer:
It has not. You’re right. The hazard ratio at least is falling on the side of benefit, whereas I think SPLASH was still 1.1, which favored the control. Which is concerning, right?

Dr. Laccetti:
I think an important reason for that is the high crossover rate exhibited by both trials. So I think the OS will wash out by design rather than by drug ethic.

Dr. Vaishampayan:

For PSMA lutetium treatments, the extent of PSMA expression has been very poorly studied, let’s face it. There is some data to show that the SUV max or maybe SUV mean of 20 or higher has a better chance of response.

Now with the P3 data, does that allow us that flexibility to sort of pick and choose who gets radium-223 versus other treatments for patients with high PSMA expression. Radium-223 has OS data, which PSMA lutetium does not have as of now.

Dr. Schweizer:

But even in the lower PSMA-expressing patients, there’s still some benefit from these drugs. It’s just that the most pronounced isn’t that high SUV cohort.

It’s tough, because the bottom line is, we need biomarkers, right? And there’s no good prospective data here. I mean, to your point, I think people look at PSMA expression as the main one that we know about, right? I think there’s some data on liver metastasis that are also bad actors, but there is some emerging molecular data too showing that perhaps genomic subgroups can really help to stratify who’s going to do well or not.

We published some data with UCSF and University of Colorado looking at patients who have different mutations in their cancer-resistant prostate cancers, and it showed that the HR-deficient population actually does pretty well with lutetium PSMA.

Dr. Efstathiou:
I want us to keep in mind, that the driver progression is going to be what it’s all about. The concern that I have with PSMAfore is that we’ve seen repeatedly in trials with androgen signaling inhibitors that if we allow the time for maturity, we see that overall survival benefit even when we have crossover. We saw this in the ARCHES trial.

Dr. Laccetti:
My only rebuttal would be that with such a weak comparator arm, really you’re looking at a median PFS of three to six months. So if you’re getting lutetium three to six months later, is that going to dramatically change things for these patients? I don’t know.

Dr. Vaishampayan:
Also, I do worry about the people who were screened out, like in the VISION trial for instance, about 15 to 20% of patients never made it because they didn’t have adequate PSMA expression. So we haven’t looked very carefully at those kinds of things as well as you know, markers or scans in between to see whether progression or response on the PSMA PET scan means anything during the treatment. And the response determination has been a big challenge with all radiotheranostics.

With radium-223, we have no idea because PSA is not a good marker and the scans may or may not change. And I think similarly for PSMA PET scans with lutetium.