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Phillip Koo: Hi, this is Phillip Koo. I'm joined today by Dr. Zach Klaassen from Wellstar MCG Health. Today we're going to talk about the sequential lutetium-177 PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer. This is the UpFrontPSMA study that was recently presented at ESMO 2024.

So here's the study. It was published in Lancet Oncology recently, looking at the use of lutetium-177 PSMA-617 in the hormone-sensitive setting, which is something that is being studied. And it's something that we do not currently have a label for, but I think we're all very optimistic and hopeful that we get an indication for this in the near future.

So just some background. What we know about lutetium-177 PSMA-617 is that it improves overall survival in patients with metastatic castration-resistant prostate cancer post-chemotherapy. Whether it confers a benefit in hormone-sensitive disease is unknown. So this study was designed to evaluate PSMA-617 before docetaxel treatment in patients with de novo high-volume metastatic hormone-sensitive prostate cancer. So this is a very aggressive patient population or diagnosis, and it's really seeing if lutetium adds any clinical benefit to those patients with this aggressive disease, especially when compared to docetaxel.

So the hypothesis was that lutetium-177 PSMA-617, followed by docetaxel, would be better compared with docetaxel in patients with de novo high-volume disease. And obviously, the study wanted to look at the adverse events and the toxicities, because that's obviously a very important piece when we're selecting treatments for the patients in this specific group.

So this was a randomized multicenter Phase 2 trial comparing ADT plus docetaxel plus lutetium-177 PSMA-617, compared to ADT plus docetaxel in patients with de novo high-volume metastatic hormone-sensitive prostate cancer. So these are patients who presented with high-volume metastatic disease, defined as either visceral and/or bone mets—at least four bone mets, one being outside of the axial skeleton. This was an investigator-initiated, open-label Phase 2 trial at 11 Australian hospitals. So again, a Phase 2 trial, which we should always keep in mind.

So this was the trial design. And I think this graphic that was published in Lancet Oncology really provides a great graphic with regards to the design of this trial. The participants included patients with prostate adenocarcinoma who had less than or equal to four weeks of ADT. So you couldn't have been on chronic ADT less than or equal to 12 weeks since diagnosis, and needed to have mets on CT and/or bone scan, and a PSA of greater than 10 nanograms per milliliter, the definition for high-volume.

And then in the pre-randomization setting, the patients underwent PSMA PET plus FDG PET. So this is something that the Australians have really, really capitalized on, is using a lot of this imaging to really select the patient population, which I think we need to keep in mind that in the U.S. and other global trials, the inclusion of FDG PET is not routinely incorporated. So the VISION trial did not have FDG PET. The PSMAfore study, pre-chemo, did not incorporate FDG PET. And then the PSMAddition trial, exploring the use of lutetium-177 PSMA-617 in the hormone-sensitive setting, did not include FDG PET as well.

And then on PSMA PET, that's where the patients needed to have that high-volume disease and also high tumor uptake. And the definition of high tumor uptake was an SUV max of greater than 15. And through the use of FDG PET also stratified patients with regards to making sure the patients did not have discordant disease. So they did not want patients who had PSMA-negative disease and FDG-positive disease.

So the patients were randomized in a one-to-one ratio to receive either two doses of lutetium-177 PSMA-617, followed by six cycles of docetaxel that were three weeks apart versus the control arm, in which the patients received docetaxel. And in both of the arms, patients received ADT, which would be standard of care. One point I like to emphasize is these patients received only two doses of 617. So it was a relatively arbitrary choice with regards to the number of 617 doses that patients received. And if you talk to the authors and you read the paper, you realize that part of this was they didn't want to delay the initiation of docetaxel too much, because that was the approved standard of care at the time the study was designed.

And then the primary endpoint was an undetectable PSA at 48 weeks. And then you had secondary endpoints of PSA progression-free survival, time to castration resistance, radiographic progression-free survival, overall survival, quality of life and pain, and then adverse events.

So the methods, all patients received ADT, either an agonist or an antagonist. And then the study treatment and procedures continued until unequivocal disease progression, whether that was by imaging or clinical progression, and then the development of unacceptable toxic effects or withdrawal of consent.

So no race or ethnicity data were collected in this study. And again, this was at 11 Australian sites, a relatively small Phase 2 trial. Patient-recorded outcomes and conventional imaging were done at baseline and every 12 weeks until unequivocal disease progression. So these patients weren't necessarily followed by PSMA PET, though there was PSMA PET performed at baseline, including an FDG PET. And then at 12 weeks from Cycle 1, PSMA-617 or docetaxel was started in this patient population. The patients did receive planar and SPECT-CT 24 hours after each cycle of lutetium-177 PSMA-617.

Outcomes. As we discussed earlier, the primary endpoint was the number of patients who had undetectable PSA at 48 weeks. And again, we talked about those patients who fell off who either had unequivocal radiographic disease progression, clinical disease progression, or both, all within 48 weeks. And those then would not qualify as undetectable PSA.

Secondary endpoints we discussed, I think a few to highlight are the freedom from castration resistance, which was measured from the interval from random assignment to the first evidence of castration resistance. So I think this is something that's important, because as we all know, castration resistance, the prognosis decreases—gets worse when they are castration-resistant. Then you have PSA progression-free survival, and then radiographic progression-free survival, among other secondary endpoints.

So I'll turn it over here to Zach for more details about results and discussion.

Zachary Klaassen: Phil, thanks so much for a great intro, especially breaking down that trial design. And I think when we look at this study, this is the consort diagram from UpFrontPSMA, and you can see 166 patients were assessed for eligibility, ultimately 130 randomly assigned—63 to the combination of lutetium plus docetaxel arm and 67 to the docetaxel-alone arm. 63 in each arm underwent treatment. 50 in the combination group completed treatment. 53 in the docetaxel-alone arm completed treatment. And essentially, 61 were assessed for the primary endpoint in each group, and 63 from each group for the secondary endpoints that Phil highlighted.

When we look at the baseline characteristics, these are well-balanced even for a Phase 2 trial. So the median age, roughly 69 years of age for each. Excellent performance status for nearly all these patients; they were ECOG zero or one. When we jump down here to the clinical M stage at diagnosis, majority of these were M1 (not specified). You can see M1b roughly two-thirds of patients. And when we look down here to the maximum SUV max, the median was 33 in the experimental arm and 35 in the docetaxel arm. The last point on this slide I'll note is that for the FDG PET in terms of tumor volume was 43 for lutetium plus docetaxel, compared to 56 mLs in the docetaxel-alone arm.

This is the primary endpoint for the study, as Phil said. Undetectable PSA at 48 weeks, and this was statistically significant—P-value of 0.002 favoring the lutetium plus docetaxel arm. 41% of patients reaching undetectable PSA at 48 weeks for the combination, compared to just 16% for docetaxel. We also see undetectable PSA at any time, a benefit for lutetium plus docetaxel, 51% versus 32% for docetaxel. P-value of 0.042. Again, in the early evaluation PSA at 12 weeks, there was no difference between the two arms.

In terms of PSA response, the top part of this figure is looking at a maximum PSA change from Cycle 1, Day 1. We see for docetaxel PSA 90 response of 63%. For lutetium plus docetaxel, this was 76%. On the bottom part of this figure is PSA change from Cycle 1, Day 1 to Week 12 for docetaxel PSA 90 response of 31%, compared to 40% for lutetium plus docetaxel. Also of note, for objective response rate, numerically higher for lutetium plus docetaxel at 97%, compared to 83% for docetaxel. But this was not statistically significant—odds ratio of 0.14 with a wide confidence interval that was not significant.

The next several slides will look at time-to-event outcomes. So some of these secondary outcomes—PSA progression-free survival, you can see lutetium plus docetaxel in red and docetaxel in blue. And this did favor lutetium plus docetaxel—hazard ratio of 0.60 and a 95% confidence interval of 0.37 to 0.98. Also significant was freedom from castration resistance. Again, similar schema for these two arms, again favoring lutetium plus docetaxel—hazard ratio of 0.60 and a 95% confidence interval of 0.38 to 0.96.

Radiographic progression-free survival did favor the lutetium plus docetaxel arm, but this was not statistically significant. You can see the hazard ratios crossing one. And again, when we look at overall survival, small Phase 2 trial with limited follow-up, no difference between the two arms—hazard ratio of 0.83. So this table just essentially summarizes all of these time-to-event outcomes. I have asterisks listed on the two secondary outcomes that were favoring lutetium plus docetaxel. Again, this was PSA progression-free survival, as well as freedom from castration resistance.

When we look at treatment-related adverse events, essentially, to summarize this table, this was consistent with a population that was receiving six cycles of docetaxel. And so when we look here, we see febrile neutropenia, 11% Grade 3 for lutetium plus docetaxel, compared to 10% for the docetaxel-alone arm. A majority of these events were Grade 1/2. A smattering of Grade 3 events, but relatively well-balanced. It did not appear that two cycles of lutetium-177 PSMA-617 was adding to the adverse event profile for a population that was all receiving chemotherapy.

In terms of post-protocol systemic therapy, the most common was enzalutamide for both groups—48% in the lutetium plus docetaxel arm, compared to 40% in the docetaxel arm. Fair number also received abiraterone, 40% in the combination arm and 24% in the docetaxel arm. And of note, 7% of patients in the docetaxel arm did receive lutetium-PSMA in a subsequent line of therapy.

So by way of discussion, this trial shows that lutetium-177 PSMA-617 prior to docetaxel had greater activity and a similar toxicity profile compared with docetaxel alone in the metastatic hormone-sensitive prostate cancer setting. As we discussed, the primary endpoint of undetectable PSA at 48 weeks favored the combination arm of lutetium plus docetaxel, along with improvement in several secondary endpoints. This activity of lutetium-177 PSMA-617 in the metastatic hormone-sensitive population is notable, given that this was only two cycles of radioligand therapy, as Phil noted in his introduction. And it's also notable given the poor prognosis of de novo high-volume metastatic hormone-sensitive prostate cancer for the patients that are receiving ADT plus docetaxel. And this is roughly a median overall survival of four years and a five-year OS rate of 23%.

Some of the discussion around this trial has been on the control arm, and so certainly, as we saw in this trial, it was ADT plus docetaxel. At the time of the trial, which was roughly around 2020, this was a reasonable control arm. At that point, triplet therapy had not been approved. So maybe looking at this several years later, perhaps the control arm wasn't as strong as it could have been. But at the time of trial design and trial enrollment, this was a reasonable control arm.

Of course, we do await the results of the Phase 3 PSMAddition Randomized Controlled Trial. This says, "Completed accrual." This is comparing an ARPI plus six cycles of lutetium-177 PSMA-617, versus an ARPI in metastatic hormone-sensitive prostate cancer. And this will include all comers for metastatic hormone-sensitive disease, whether it be low or high-volume, de novo or metachronous. Whereas for the UpFrontPSMA, this was only high-volume de novo patients.

So several important take-home messages. First, UpFrontPSMA is the first randomized study in patients with high-volume metastatic hormone-sensitive prostate cancer to show a benefit from the addition of lutetium-177 PSMA-617 to standard-of-care treatment. Lutetium-177 PSMA-617, followed by docetaxel, improved antitumor activity in patients with de novo high-volume disease compared to docetaxel alone, without an increase in toxic effects. And finally, these data suggest that lutetium-177 PSMA-617 could potentially have a role in the therapeutic management of metastatic hormone-sensitive disease.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of the UpFrontPSMA trial recently presented at ESMO 2024 and published in Lancet Oncology.