Rashid Sayyid: Hello everyone, and thank you for joining us today in this UroToday Journal Club recording. I'm Rashid Sayyid, a robotic urological oncology fellow at the University of Southern California in Los Angeles. And I'm delighted to be joined today, as always, by Zach Klaassen, associate professor and program director at Wellstar MCG Health in Augusta, Georgia.

And today, I'm delighted to discuss the most recent update of the Phase III PSMAfore trial of lutetium-PSMA-617 versus a change of androgen receptor pathway inhibitor in taxane-naive patients with mCRPC.

The results of this updated analysis were recently published in the Annals of Oncology with Dr. Karim Fizazi as the lead author. So if we take a look back at the pre-PSMAfore era, and we look at the treatment options for mCRPC patients who have progressed with an ARPI such as abiraterone or enzalutamide which are approved in this setting, we see based on the NCCN Guidelines from 2024 that the preferred regimens are three different options. We have docetaxel, which remains an option. And then for patients with a BRCA mutation, either olaparib or rucaparib.

So we really see that there are only three options with proven benefit in this setting. And what about the patients who either refuse or are unable to tolerate taxanes, as well as those that don't harbor a BRCA mutation?

If we look further down, we see the options are really limited, both in terms of the number as well as their efficacy and safety in this setting. So really, we need to do better in these patients and add an additional treatment option for these high-risk patients who really, we know, have poor outcomes.

And so, one obvious candidate is lutetium-PSMA-617. Can we move this option further up the treatment algorithm? If we look prior to 2022, we know that lutetium-PSMA-617 was approved for mCRPC patients who have progressed on an ARPI as well as a taxane. And this is based on the results of two Phase II trials in this setting, both VISION, which compared lutetium-PSMA-617 plus standard of care to standard of care alone, and we saw here a significant survival benefit. And then as well, we have TheraP which compared lutetium-PSMA-617 to cabazitaxel in this setting. And although there was no survival benefit, we really saw a significantly better PSA50 response with lutetium-PSMA-617, which may suggest that these patients may do better with further follow-up.

And so, in September 2024, we saw the first results of lutetium-PSMA-617 that were published in the Lancet with Dr. Michael Morris as the lead author, and this really changed the game for our patients.

And if we take a step back and refresh our minds with regard to the study design of PSMAfore, we know that this is a Phase III trial that included patients with progressive mCRPC after a prior second-generation ARPI, and who were candidates for a change in ARPI. And this was the control arm of abiraterone and enzalutamide.

It's important to note that these patients all had at least one PSMA-positive metastatic lesion on 68Ga-PSMA-11 PET, and importantly, had no exclusionary PSMA-negative lesions. All patients were either taxane-naive, or had received taxanes in either the neoadjuvant or adjuvant setting more than 12 months ago, and were not candidates for a PARP inhibitor with an excellent performance status of ECOG zero to one. And these eligible patients were randomized one-to-one to either lutetium-PSMA-617 that was dosed at 7.4 gigabecquerels once every six weeks for a total of six cycles. Pretty standard. Or they received an ARPI switch, either abiraterone or enzalutamide, just depending on what they received in the first-line setting.

It's important to note as part of the study design that crossover was allowed upon radiographic progression from the ARPI switch to the lutetium-PSMA-617 arm. And radiographic progression-free survival was the primary endpoint.

And as we saw in the primary report in the Lancet paper, this trial met its primary endpoint with a significant improvement in the median rPFS, with the final analysis of this outcome demonstrating 11.6 months in the lutetium-PSMA-617 arm versus 5.6 months. And this result becomes even more impressive when you consider that more than half of these patients crossed over from the ARPI switch to the lutetium-PSMA-617 arm. And this really highlights that the timing of giving this treatment is crucial in this setting. Because if patients received it either way but those who received it earlier did better, then really that's a clear signal that early treatment intensification and early switch to lutetium-PSMA-617 is important and helpful in this setting.

Less impressive results for overall survival to date, the last reported median overall survival after follow-up of 18 months with this report was 24 months in both arms. And we'll see the more updated results of this overall survival outcome later on with Zach discussing it.

And again, I want to highlight the fact that over half of patients, 57%, from the ARPI arm crossed over to receive lutetium-PSMA-617 after radiographic progression. And really, this gives us an overall perspective when we interpret these results and we frame them at the end.

And so, based on these results, the FDA in March of 2022 expanded Pluvicto's indication in the mCRPC setting, where we see that this agent is now approved for PSMA-positive mCRPC patients who have been treated with an ARPI and are considered appropriate to delay taxane-based chemotherapy. So we moved it one step further ahead in the treatment paradigm for the mCRPC setting.

And so, the study objective of this updated report was to present the final overall survival analysis of PSMAfore, both based on the intention-to-treat principle, meaning it doesn't matter what you received, it is analyzed based on what arm you were assigned to or randomized to initially. And then the crossover-adjusted OS analysis. And this specific analysis accounts for the fact that these patients who were in the ARPI switch arm switched over to receive lutetium-PSMA-617. So it accounts for that treatment effect. And we also want to discuss the updated safety outcomes, including exposure-adjusted outcomes in this setting.

At this point, I'll turn it over to Zach, who'll go over the results from this updated report of PSMAfore, as well as discuss these findings in the treatment context of this disease process, as well as give us a real-world perspective on this option for our patients.

Zachary Klaassen: Rashid, thanks so much, as always, for setting the stage for the results and discussion. This is the final overall survival analysis for PSMAfore. We see again, very similar results to what was initially presented last year. Hazard ratio 0.91, 95% confidence intervals, 0.72 to 1.14, P-value of 0.20. So no difference in overall survival in the intention-to-treat population between the lutetium-PSMA-617 arm and the ARPI change arm.

As Rashid mentioned, there was some fancy statistics done. This is crossover-adjusted overall survival by IPCW as well as RPSFT. And when we look at the IPCW-adjusted overall survival hazard ratio, they ran several models. The full model, which assumes that there are no unmeasured confounders, has a benefit favoring lutetium-PSMA-617, a hazard ratio of 0.59, and a 95% confidence interval of 0.38 to 0.91.

When we look at the RPSFT-adjusted overall survival hazard ratio, this was not statistically significant, hazard ratio of 0.84. And without getting into too many of the details of the statistical analysis, this common treatment assumption was likely not met. And this method fails to adjust for confounding in the context of overlapping ITT survival curves, which we saw on the last slide. So we see a benefit when we're doing the IPCW. We do not see a benefit with RPSFT crossover-adjusted overall survival analysis.

The next three slides, we'll look at some of the additional results that have not been reported today. The first of these is time to soft tissue progression. We see here a clear benefit for lutetium-PSMA-617 versus ARPI change. Hazard ratio is 0.34. 95% confidence interval, 0.23 to 0.51.

The second new result is the time to radiographic disease progression after crossover, otherwise known as rPFS2. The median rPFS2 was 5.42 months for the crossover to lutetium-PSMA-617.

And finally, time to chemotherapy. This was not previously reported. Again, no difference between the two arms, hazard ratio of 1.07, the 95% confidence interval is crossing one, so no difference in time to chemotherapy between the two arms in this trial. When we look at treatments received after discontinuation, the top part of this graph has lutetium-PSMA-617 and the bottom part is the ARPI change. And so when we look at the first subsequent therapy after receipt of lutetium-PSMA-617, the orange block is chemotherapy, roughly 50% of patients received chemotherapy. This was also the most common second and third-line treatment after randomized treatment. Chemotherapy, again, second and third most common for the lutetium-PSMA-617 arm.

Looking at the bottom, this is ARPI change. Not surprisingly, as Rashid mentioned, almost 60% of patients received lutetium-PSMA-617 after they received their ARPI change. And again, when we look at the second and third-line, this becomes more common for chemotherapy for both of these subsequent treatment lines of therapy.

Switching to safety, and in terms of the updated exposure-adjusted safety during randomized treatment, when we look at serious treatment-related adverse events, any grade 5.9% for lutetium-PSMA-617 compared to 3.2% for the ARPI change, compared to 5.2% for grade three plus serious adverse events for lutetium-PSMA-617 compared to 3.2% for the ARPI change arm.

Looking at treatment-related adverse events resulting in adjustment of the dose. Very similar for the grade three adverse events, 1.9% for lutetium-PSMA-617, but only 3.8% for the ARPI change. We do see many more any grade for the ARPI change arm leading to adjustment of dose, 22.1% compared to 5.2%.

When we look at leading to interruption of treatment, this certainly favored the lutetium-PSMA-617 arm, 19.6% any grade, compared to 27.8% for grade three plus, 8.5% compared to 11.3%.

And finally, looking at leading to discontinuation of treatment, 7.7% any grade for lutetium-PSMA-617 compared to 6.4% for ARPI change. And very similar, roughly 5% grade three plus for both arms when looking at leading to discontinuation of treatment. I want to point out one key specific adverse event. This is dry mouth, which we know is associated with lutetium-PSMA-617 treatment. This was 59.5% of the patients having dry mouth of any grade in the PSMAfore trial.

This table looks at the time to onset and resolution of dry mouth, hematological AEs, and renal toxicity. When we look at the top part, this is the dry mouth statistics, 60.8% had dry mouth with lutetium-PSMA-617, compared to only 2.6% in the ARPI change. But what's important here is this resolved quite quickly. So the median time to resolution was only 1.12 months in this lutetium-PSMA-617 arm. When we look at hematologic events, again, higher for lutetium-PSMA-617, 39.2% compared to 23.2%. But again, quick resolution of these adverse events. Median 1.77 months for lutetium-PSMA-617, compared to 0.92 months for ARPI change.

And finally, looking at renal toxicity, quite low for both of these treatment arms, less than 10%. With again, quick resolution of renal toxicity, 0.71 months for lutetium-PSMA-617, compared to 0.2 months for the ARPI change.

The next couple of figures, we'll look at some of these AEs in more specific context. This looks at the proportion of patients with hematologic treatment-emergent adverse events, and those that received somewhere between one to four doses versus those that received all six doses. The take-home message here is that generally for anemia, lymphopenia, neutropenia, thrombocytopenia, leukopenia, and pancytopenia, there really was no signal of worse adverse events with the receipt of that fifth and sixth treatment. So again, the majority of these were tolerated well, whether you had one to four cycles or whether you had five to six cycles.

This is a similar looking graph. Looking at again, hematologic AEs, but looking at the number of bone metastases at baseline. So looking at the blue bars, this is lutetium-PSMA-617. The orange and yellow is ARPI change. What I'll point out here is for anemia and thrombocytopenia with increasing bone metastases we can see here, there were worse all-grade and grade three plus adverse events for lutetium-PSMA-617, for anemia and thrombocytopenia. And I think the rest of these are generally about the same with regard to number of bone metastases and specific hematologic adverse events.

So by way of discussion, in the final overall survival analysis of PSMAfore, there was no statistically significant difference in overall survival between treatment arms based on the ITT principle. What we did see though is when there was IPCW crossover-adjusted overall survival analysis, this suggested crossover confounded the overall survival analysis. As we've pointed out several times, the rate of crossover in PSMAfore was high. Over 60% of patients in the ARPI arm crossed over, and this was among 75% with confirmed radiographic progression. What's interesting is that the majority of these patients in the ARPI arm that received the investigational drug, they received it quite early in the study, at a median of just over seven months after randomization.

What's important is the overall safety profile of lutetium-PSMA-617 at the final overall survival analysis was favorable and similar to the previous analysis with no new safety signals. We saw that the overall adjusted incidence of dry mouth in the lutetium-PSMA-617 arm in PSMAfore was roughly 60%, which was higher than was previously observed in VISION at 38.8%. However, most of these events are grade one to two, they did not lead to dosage modifications, and they did resolve quickly by the time of the final overall survival analysis. As we mentioned, rates of renal toxicity were low and comparable between treatment arms.

There are several important limitations and considerations for taking into context the overall survival in the PSMAfore trial. The first is that selection bias and unmeasured variables may have further affected outcomes in the crossover group, because this was a post-randomization event, and this was likely confounded in the ITT analysis of overall survival.

Secondly, other variables such as PSMA expression may have influenced outcomes, and were not accounted for in these two correction models from this analysis.

Third, patients with known genomic alterations that conferred eligibility for other treatments, such as homologous recombination mutations that would make them eligible for PARP inhibitor therapy, these patients were excluded, and so this may have also affected the overall survival analyses.

And finally, the trial may have been underpowered to detect an overall survival difference. It was initially powered for an overall survival benefit of 80%, which may have been further reduced by the high level of crossover in PSMAfore.

What's interesting, and I think will be very important for our listeners and for us practitioners, is that all patients in active therapy or follow-up upon closure of the trial will be eligible for a further long-term follow-up study, which will provide further insights into long-term safety outcomes of patients receiving lutetium-PSMA-617.

So by way of take-home messages in the final overall survival analysis of PSMAfore, overall survival was not statistically different between lutetium-PSMA-617 and ARPI change. The safety profile was acceptable and consistent with previous reports. And taken together, given that lutetium-PSMA-617 prolonged rPFS, also prolonged time to PSA progression and time to worsening health-related quality of life, as well as pain, these results support the use of lutetium-PSMA-617 for PSMA-positive mCRPC in the pre-chemotherapy setting.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of the final OS analysis from PSMAfore.