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Mary-Ellen Taplin: So here are my disclosures. So PSA—you know, what's old is new. And I was asked to speak on a very specific topic. That is, when a patient with metastatic hormone-sensitive prostate cancer is on therapy, which includes hormone therapy, and they reach a PSA—if they don’t reach a PSA nadir of 0.2, should we change their therapy?

So I want to start by saying unfavorable PSA decline does not equal progression. And I’ll start this talk talking about this PSA biomarker—the history of it, how we got here. And then I’ll end with a few of my clinical pearls, if you will, when a patient is in this situation.

So Bertrand just introduced this, I guess, really important study because we’re still talking about it all these years later. But this is the SWOG 9346 trial. And what this trial was—excuse me—patients with metastatic hormone-sensitive prostate cancer were randomized to continuous versus intermittent hormone therapy.

And when they got to the 7-month induction of hormone therapy—in retrospect, this analysis was done for patients who reached a PSA of 0.2. And why 0.2? Because we have assays that go much lower than that now. But at the time of the study, that was the assay that was used and the lowest that was measured.

So these patients, the survival was analyzed by patients at 7 months who got to 0.2 or less, were between 0.2 and 4, and were over 4. And you can see that this biomarker holds up very well for how these patients did.

So then Dr. Sweeney and his team looked at something similar, and CHAARTED looked at the PSA nadir at 7 months of ADT on this trial. And you can see with the blue line that, again, it’s very prognostic for survival either with ADT alone or ADT and doce, or all the patients shown here.

So then going into our next generation of therapy and the debate about what we could call them—I’m going to call them the AR axis inhibitors. And you can find in the literature the same analysis, or very similar analysis, for apalutamide and abiraterone.

And then there’s a whole slate of—I’m going to call it “wide world” instead of “real world” because I have a thing with the real world term. But there’s a lot of studies here, and this is one that represents them from the LATITUDE trial, where they looked at PSA of 0.1 at six months or 0.1 at 12 months, and it stood up as a biomarker for radiographic progression, overall survival, and in PSA progression.

So there are unanswered questions about this PSA biomarker, which include—which is the time point we should be assessing? Seven months was what was used in the SWOG trial, but obviously, that’s not written in stone. Should we be using 12 months? Should we be using the true nadir?

And then what is the target? Should we stick with 0.2—or many of the assays now go to 0.02—or is there some other number? And how do genomics fit into this assessment? Our patients are all individual and heterogeneous—have very different makeups of their tumor. Should that be assessed in conjunction with a single biomarker like PSA?

This is just one slide on genomics. And this is from the Stand Up to Cancer International Dream Team, published by first author Wassim Abida here. And this just shows that there are genomic biomarkers that correlate with response, and RB1 and P53 mutations correlated with a very short time of response on AR axis signaling inhibitors.

What do we do with these patients? And I want to just repeat to answer the question I was asked to answer: no data exists to change systemic therapy if your patient doesn’t reach an optimal PSA nadir. However, this point in time would be a good clinical trial strategy for randomization at this point.

So here are my clinical considerations—the take-home message. I want everyone to be aware that this is an important biomarker. And your patient should be assessed for their response to ADT probably around 6 to 7 months.

What I would say is, if you have a patient in this situation, the first thing to ask is, is the ADT optimal? Check the testosterone level. If the testosterone isn’t in the castrate state where you want it, I would suggest testing it in a second laboratory because I’ve seen a lot of erroneous testosterone levels.

If the testosterone is measurable, then please consider changing your ADT if it’s injection, or assessing the patient’s if they’re taking orals such as relugolix. And if they’re on AR axis inhibitors, a lot of times, we dose-reduce them over time for a variety of reasons. It might be a good point to assess whether a patient could be titrated back up to full dose if they’re not having a PSA optimal response.

If they were candidates for prostate radiation that hadn’t been administered, please consider that. If they were candidates for SBRT to mets and didn’t receive that, you could do restaging at this point and reconsideration of SBRT to their mets. If they were a candidate for triple therapy but didn’t receive triple therapy—again, this might be a good time, especially if it’s inside of six months, to consider intensifying standard-of-care therapy.

If it hasn’t been performed to date, I would recommend doing germline testing because this is a patient you know is going to be considering other therapies, probably in the short term. And similarly, if you haven’t done somatic testing either on the original biopsy tissue or a new metastasis biopsy, this is a very good time to get that done.

And then, I think, as Bertrand just noted, the importance of patient input into their care—I think if we have patients who are receiving suboptimal PSA nadirs—because often the patient’s PSA goes down from 60 to 5, and they’re really happy, and we’re kind of like, oh, my goodness, we know what’s coming.

So I think educating the patients and sharing your concerns and shared decision-making for what are the optimal repeat PSA schedules and reassessment schedules. So, in conclusion, PSA nadir is prognostic for rPFS and OS. PSA nadir is not a validated endpoint to change systemic therapy.

Recognition of suboptimal PSA nadir is an opportunity to evaluate if all available standard-of-care treatment options have been maximized. And recognition of suboptimal PSA should prompt careful consideration of the patient’s future assessment schedule. Thank you very much.