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Rashid Sayyid: Hello, everyone. This is Rashid Sayyid. I'm a urologic oncology fellow at the University of Toronto and along with Zach Klaassen, Associate Professor and Program Director of the Medical College of Georgia, we'll be discussing the latest publication from VISION that specifically looks at health-related quality of life and pain outcomes with Lu-PSMA-617+ Standard of Care versus Standard of Care alone in patients with mCRPC. This paper was recently published in The Lancet Oncology. Just to give a brief overview and a refresher of the overall study design, VISION included patients with MCRPC who had progressed on prior ARPI, meaning the antigen receptor pathway inhibitors such as abiraterone, enzalutamide, and one or two taxane regimens such as docetaxel and cabazitaxel, and all patients had a life expectancy of at least six months and had a PSMA-positive scan on PET/CT with 68 Ga-PSMA-11.

Once patients were deemed eligible, they were randomized two-to-one to protocol-permitted standard of care plus the lutetium, given every six weeks for four cycles, up to six total. Or protocol-permitted standard of care alone. And the clinical efficacy results of the co-primary endpoints imaging-based, progression-free survival and overall survival have previously been published. And as we can see here in the Kaplan-Meier curve, patients who received lutetium plus standard of care, versus standard of care alone, had significant improvements in imaging-based, progression-free survival. And this was also reflected in an overall survival benefit, as we see here, with the median overall survival improved from 11.3 months to 15.3 months. So about a four-month overall survival benefit.

Also, we want to point out that the previous publication has touched upon the patient-reported outcomes and health-related quality of life outcomes. And as we can see in the upper panel here, we have the FACT-P total score, which is the functional assessment of cancer therapy prostate. And again, we see a benefit for Lu-PSMA addition similarly with the BPI-SF pain intensity which evaluates the pain scores, again an improvement addition with lutetium.

So you ask, "Why are they publishing another paper looking at this?" Well, this was a composite endpoint that included not only whether you had any changes in your FACT-P score or your pain score, but also accounted for a composite endpoint of clinical progression or death.

That brings me to the study objective. And that was to report the non-composite health-related quality of life and pain outcomes. Also with longer follow up, also looking at new results on symptomatic skeletal events. They also want to look at hematologic and renal adverse events. And why are those two specifically relevant? We know that lutetium gets filtered through the kidneys and also the proximal tubular epithelial cells have a PSMA protein on their cell surfaces. So again, they're higher risk of lutetium-related toxicity. And also we know that cytopenias are one of the potential side effects of using the lutetium in this setting. Again, they want to touch on updated safety profile and adverse events outcomes.

We went over this briefly before, but again, our VISION is a multicenter, open-label, phase three trials across 84 centers, progressive mCRPC treated with an ARPI and one or two taxanes, and all patients had at least one PSMA positive lesion on baseline CT, MRI, or bone scan and no PSMA-negative lesions. Randomized two-to-one to lutetium plus standard of care or standard of care. And what was standard of care in this setting? What was allowed was ARPIs, example abiraterone, enzalutamide. Bisphosphonates, radiotherapy, denosumab, glucocorticoids, hydration, and analgesics. Specifically cytotoxic chemo, systemic radio isotopes like Ra-223, immunotherapy, and investigational drugs were not allowed.

Let's talk a bit more about the patient-reported outcomes, or PRO instruments, that were used. The first one is FACT-P, or the Functional Assessment of Cancer Therapy-Prostate. And this includes the general one, the Functional Assessment of Cancer Therapy-General plus the prostate cancer subscale that evaluates prostate-specific outcomes. And the score range between zero and 156, with a higher score being better in this setting. And there's different domains with these questionnaires, but the ones that were meaningful for this study, meaning the trial outcome index, was a composite of the physical and functional wellbeing and the prostate cancer subscales as well. And a clinically-meaningful worsening in the outcome was defined as a 10-point decrease from baseline for the purposes of this study.

Next we have the BPI-SF, or the Brief Pain Inventory-Short Form, which assesses pain intensity and interference with daily activities ranging from zero to 10, meaning no interference, zero to complete interference, 10. In this setting we want a lower score, as opposed to FACT-P where we want a higher score ideally. And the trial outcome here was time to worsening in the worst pain intensity, specifically, with a study event defined as a two point or a 30% increase in score.

And the third instrument that they looked at was the five-level European Quality of Life Five-Dimension scale. And this assesses a preference-based health utility score, with the score ranging between negative 0.594 to one, meaning perfect utility. And the study event was defined as either score decrease of at least 0.1 or a stable score for the purpose of this study.

And these instruments were completed virtually or in person at baseline, meaning before/at randomization, the first day of each cycle, and at the end of treatment as well. And the hematologic and clinical chemistry variables were assessed every week during cycle one, then every two weeks cycles two to six, and then post cycle six every 12 weeks, and again at the end of treatment.

How did they analyze this data? Again, we need to account for the fact that these measurements are repeated in the same individuals over time, so we need to adopt statistical measures that count for this and control for this repeated measurements. For this reason, they used the linear mixed effects models to analyze the treatment arm differences in changes in these outcomes from baseline. Also, they looked at time-to-event outcomes. Naturally they used Kaplan-Meier curves and Cox regression models. And they used a two-sided p-value of 0.05, which is standard in these trials, but it's important to highlight that there is no adjustment for multiplicity, which may mean that the odds of a false positive finding or type one error may be higher with this study. And at this point, I'll turn it over to Zach to go over the results and discussion for this paper.

Zach Klaassen: Thanks so much for that great introduction, Rashid. This is the trial profile, as we've seen before in the original VISION publication. This is 1,179 patients assessed for eligibility. Ultimately, 1,003 received a Ga-PSMA PET scan. 831 were enrolled, including 551 assigned to lutetium plus standard of care arm and 280 assigned to the standard of care arm. If we look at the very bottom of this figure, we see that 140 patients in the lutetium arm entered long-term follow-up, compared to 50 in the standard of care arm that entered long-term follow-up.

The next several slides will look at Kaplan-Meier curves assessing the instruments and the outcomes that Rashid highlighted in the introduction. This is time to worsening of 10 points or more in the FACT-P score, clinical disease progression or death. And the color scheme will be the similar for all of these slides, looking at lutetium in blue, standard of care in red. And we can see for this outcome the median was 5.7 months for lutetium compared to 2.2 months for standard of care, with a hazard ratio favoring Lu-PSMA of 0.54, 95% confidence interval of 0.45 to 0.66.

This is time to worsening of 10 points or more in the FACT-P score. Lutetium median 9.7 months compared to 2.4 months standard of care, where hazard ratio favoring Lu-PSMA of 0.46 95% confidence interval of 0.35 to 0.61.

This looks at time to worsening of at least 30% or at least two points in the BPI-SF scale, clinical disease progression or death. With a median of 6.9 months for lutetium arm can compared to 2.6 months in the standard of care arm with a sign significant hazard ratio of 0.52.

This is time to increase of at least two points in the BPI-SF scale, with a median of 14.3 months for lutetium. Only 2.9 months for standard of care and a hazard ratio favoring lutetium PSMA of 0.45, 95% confidence interval of 0.33 to 0.60.

This looks at time to worsening in EQ-ED-5L utility score and this is time to any decrease in utility score relative to baseline or no change in score from baseline. The median for lutetium was one month, compared to 0.5 months in standard of care. Significant hazard ratio favoring lutetium arm of 0.65, 95% confidence interval of 0.54 to 0.78.

And finally, this is time to a decrease in score of at least 0.10 points from baseline using the EQ-ED-5L utility score. And the lutetium arm had a meeting of 0.9 months, the standard of care 0.4 months, another significant hazard ratio for Lu-PSMA of 0.49 and a 95% confidence interval of 0.40 to 0.62.

This table looks at the analysis of time to worsening in months of patient-reported outcome score. We're going to focus on the pre-specified analysis on the left, which are quite similar to the post-hoc analyses on the right. And you can see it be between the FACT-P, the BPI-SF, and the EQ-5D-5L. All of these outcomes favor lutetium statistical significance compared to standard of care. And the two highlighted ones are the most impressive and most clinically relevant in terms of FACT-P total score with a hazard ratio of favoring lutetium and PSMA of 0.54 and a 95% confidence interval of 0.45 to 0.66. And the BPI-SF pain intensity score, again favoring lutetium and PSMA with a hazard ratio of 0.52 and a 95% confidence interval of 0.42 to 0.63.

This is types of symptomatic skeletal event and reasons for censoring. If we look at the top here, we see that in terms of number of events, 66% of patients had an event in lutetium arm compared to 70%. And the rest of these events are all quite similar between the two groups. However, there's a numerical difference in spinal cord compression, which is one of the most devastating adverse events for symptomatic skeletal-related events. And this was only five patients or 1% of the lutetium arm compared to 11 patients or 6% of the standard of care arm.

This table looks at overall and post-hoc subgroup analysis of time to first symptomatic skeletal event and death. At the bottom right, this is overall cohort. The symptomatic skeletal event favored the Lu-PSMA plus standard of care versus standard of care alone with a hazard ratio of 0.50 and 95% confidence interval of 0.40 to 0.62. In these rows above the overall at the bottom here, we see this is specifically for those that receive bone targeting agents and below that for those that did not receive bone targeting agents. And we can see essentially the exact same hazard ratio for each and almost the exact same hazard ratio compared to the overall. So this is improving time to first symptomatic skeletal event regardless of whether they had bone targeting agents or no bone targeting agents.

The next three slides will look at laboratory measures over time. This is for hemoglobin and we can see lutetium in blue, standard of care in red. And really no difference between these two arms for hemoglobin levels throughout the trial. We see for platelets maybe a numerical decrease for Lu-PSMA but not clinically significant, so relatively stable compared to the standard of care arm throughout the trial. And for creatinine, we see relative stability in these two arms over the course of the trial for kidney function levels.

The addition of Lu-PSMA-617 to standard of care delayed time to worsening in health-related quality of life and pain in patients with mCRPC in the VISION trial. Worsening was delayed across all patient reported outcomes, subscales, and domains, with the greatest difference in median time to event in BPI-SF pain intensity and FACT-P score.

Pain among patients with CRPC can be attributed largely to bone metastases, lumbosacral invasion, and nerve root compression. In VISION, as we mentioned in the results, the median time to first symptomatic skeletal event or death was delayed in the Lu-PSMA group versus control. And spinal cord compression, which is the most deleterious symptomatic skeletal event, was numerically less frequent among those patients receiving lutetium. Adverse events in the myelosuppression and renal effects groupings were more frequent during treatment with lutetium plus, standard of care alone, but these were mainly low-grade events.

In conclusion, treatment with Lu-PSMA-617 plus standard of care delayed radiographic progression-free survival and extended overall survival in patients with mCRPC and was associated with a longer period without deterioration in pain reported health-related quality of life and pain than seen with standard of care alone. Low rates of hematological and renal toxicity were observed with Lu-PSMA-617. And finally, these findings strengthened the rationale for use of Lu-PSMA-617 as a treatment option in patients with mCRPC who received previous androgen receptor pathway inhibitor and taxane treatment.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club of the recently published Health-Related Quality of Life Outcomes in the VISION Phase 3 Trial.