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Christopher  Wallis: Hello, and thank you for joining us for this UroToday Journal Club.  Today, we are discussing the recent publication of the VISION trial, looking at Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. This is a really interesting and potentially groundbreaking study that I am happy to present and share with you. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and with me is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. As many will know, the VISION trial was initially presented at ASCO's Annual Virtual Meeting in June 2021 and has now subsequently been published in The New England Journal of Medicine.

The mCRPC disease space is moving relatively quickly. And as you can see in the last 10 or 15 years, we have seen the approval of many treatment approaches. However, in spite of all these new treatment options, mCRPC remains a generally fatal and certainly incurable disease. So, new treatment approaches are warranted and badly needed. And one approach is to look at the targeting of our treatments specifically to tumor cells. So, one way to do this is through the use of PSMA, which is a transmembrane zinc metalloprotease. The PSMA is heavily over-expressed in prostate cancer cells and can be targeted for both diagnostic imaging purposes as well as a therapeutic target. So, 177-lutetium-PSMA is a beta-emitter, which provides selective irradiation of PSMA-positive cells and the surrounding microenvironment with relatively limited penetration bearing adjacent normal tissues.

One of the first prospective studies examining the use of lutetium in mCRPC was the LuPSMA trial, which was a single-arm, single-center phase two study looking at PSA responses. And as you can see in these plots on the right-hand side of the curve, a relatively high proportion of patients had at least a 50% response rate. And this led to the design of the phase two TheraP trial, which provided a randomized comparison of lutetium versus cabazitaxel on patients who had progressed following docetaxel. And as you can see here, again, we see a relatively high response rate to lutetium PSMA and a much higher portion of patients who have a PSA reduction of at least 50% with 66% in the lutetium arm compared to 37% in the cabazitaxel arm. And while this was not the primary endpoint of the study, TheraP also demonstrated improvements in progression-free survival for patients who had lutetium.

And so these formed the basis of phase three of the VISION trial. And so this included patients who had mCRPC who received at least one androgen receptor pathway inhibitor, that's abiraterone, enzalutamide, or the equivalent, as well as one or two taxane-based regimes. And at the time of accrual, the authors and investigators, and patients had to assign a standard of care treatment that would be deemed most appropriate for these patients in the fourth or fifth line setting. This excluded cytotoxic chemotherapies, immunotherapy, radium, or other investigational drugs.

We will walk through the remainder of the aspects of this trial design in the coming slides. So, again, to highlight, this is patients with mCRPC with at least one metastatic lesion on conventional imaging, disease progression on multiple lines of prior therapy. And notably, there were inclusion criteria based on imaging findings. And so this, unlike TheraP, which used both PSMA and FDG PET, this trial only used PSMA based inclusion. And so this required at least one PSMA positive metastasis and no PSMA negative lesions. PSMA positivity was designed as an SUV activity in the lesion, which was greater than uptake in the liver without specific SUV thresholds and PSMA negative lesions were defined as those with uptake less than or equal to that of the liver in lesions of various sizes, depending on their location.

This is an open-label, randomized phase three trial. Again, all patients received a protocol-permitted standard of care without a standard comparator, and patients were then randomized in a two-to-one fashion to receive the addition of lutetium to the standard of care versus standard of care alone. Lutetium was given at 200 microcurie IV every six weeks for four cycles with a further two cycles allowed. So, many patients received six cycles of therapy.

The two alternate primary endpoints were imaging-based progression-free survival defined as the time from randomization to independent central review determined disease progression or death, as well as overall survival. There are a number of secondary endpoints, including objective response rate, disease control rate, time to first symptomatic skeletal event or death, safety, health-related quality of life, pain, as well as biomarker outcomes including PSA response.

In terms of assessment, you can see the study schema here, but importantly, axial imaging using conventional imaging with CT or MRI, as well as bone scan were performed every eight weeks for the first 24, and then every 12 weeks thereafter.  As you can see in the schematic performance status, patient-reported quality of life, physical examination, and laboratory investigations were performed associated with each cycle and then every 12 weeks thereafter.

Efficacy outcomes were assessed in the intention to treat population. And so as a result of issues with the accrual and retention, overall survival was assessed in all patients. Whereas imaging-based progression-free survival was only assessed in patients who were accrued after trial education was expanded to minimize withdrawal from the control arm.

The study was designed with an overall alpha of 0.025, which was deemed a one-sided approach. And as you can see in this table from the supplement of this manuscript, there were a variety of approaches taken for type one error control on the basis of findings for each of the alternate primary endpoints. And so in general, in terms of radiographic progression-free survival, the study would have 84% power for a hazard ratio of 0.67 with an alpha of 0.004 once 364 events were observed. In terms of overall survival, there's a 90% power for a hazard ratio of 0.73 with an alpha of 0.025 once 508 events were observed.

So, the primary and key secondary endpoints were assessed using the log-rank test with stratification according to randomization factors. Other secondary endpoints were assessed using the chi-squared test from the Cox proportional hazards models. One-sided p-values, which were part of the study design were converted to two-sided for publication and there was an adjustment for multiple testing given the numerous secondary endpoints.

At this point in time, I am now going to hand it over to Zach to walk us through the important results from VISION.

Zachary Klaassen: Thanks, Chris. So, this figure to the right is the screening randomization and follow-up for the patients. And it's a bit of a busy figure, but we will walk through it, sequentially. Ultimately there were 1,179 patients that were assessed for eligibility. 1,003 patients underwent a Gallium PSMA PET scan and subsequently, 831 underwent randomization. This included 551 patients randomized to receive lutetium PSMA and 280 patients that were assigned to receive standard of care alone. So, moving to the bottom of this figure, 250 patients completed the lutetium PSMA regimen, five were continuing the standard of care regimen therapy and subsequently, 140 in the lutetium PSMA arm entered long-term follow-up, whereas 50 in the standard of care arm entered long-term follow-up. This is table one for this paper, looking at the characteristics of patients at baseline, according to the analysis set. So, looking at the far right, which is all patients who underwent randomization, the median age was just over 70 years, ECOG performance status of zero to one was the majority of patients at around 92%.

The most common site of disease was bone at 91%, which also included lymph nodes at around 50%. Looking at the median PSA range, 77.5 in the lutetium arm and 74.6 in the standard of care arm. Moving down to patients with a previous prostatectomy, just over 40% for both arms. Looking at the previous androgen-receptor pathway inhibitor therapy, most commonly was one regimen at 54.1% in the lutetium arm and 45.7% in the standard of care arm. And finally looking at previous taxane therapy, one regimen, 59% in the lutetium arm and 55.7% in the standard of care arm. Two regimens, 39.9% in the lutetium arm and 43.6% in the standard of care arm. As you can see at the bottom of this figure, the majority of patients had previously received docetaxel and around 38% had previously received cabazitaxel.

So, looking at the first of the primary efficacy outcomes, which was imaging-based progression-free survival, you can see lutetium in blue and standard of care in red. And early and distinct splitting of this curve with a median progression-free survival of 8.7 months in the lutetium arm and 3.4 months in the standard of care arm with a hazard ratio favoring lutetium of 0.40 and a 99.2% confidence interval of 0.29 to 0.57.

This is the subgroup analysis for progression-free survival. To the left of the hazard ratio of one favors lutetium, and to the right favors standard of care. And just a general summary here, you can see that the majority of these subgroups did favor the lutetium arm with the confidence intervals crossing one for African-Americans or Asian population, however, these were small sample sizes. Moving to the second of the primary efficacy outcomes was overall survival, again, an early and wide splitting of the curves favoring lutetium with median overall survival in the lutetium arm of 15.3 months and in the standard of care arm alone, 11.3 months with a hazard ratio for death favoring lutetium of 0.62 and a 95% confidence interval of 0.5 to 0.74.

Again, the subgroup analysis for overall survival, broadly speaking, favoring lutetium PSMA for all of these subgroups. Curiously, you can see at the liver metastasis patients, small subgroup, but also not completely benefiting these patients, perhaps. And, again, with a small subgroup based on race, not a significant benefit for African-Americans or Asians at this point. Looking at the key secondary outcome, which was time to the first symptomatic skeletal event. Again, favoring lutetium PSMA with a median time to SSE of 11.5 months for lutetium PSMA and 6.8 months for standard of care alone, with a hazard ratio favoring lutetium PSMA of 0.50 and a 95% confidence interval of 0.40 to 0.62. This is an additional secondary endpoint looking at PSA response with lutetium PSMA on the left in blue and standard of care on the right in red. And you can see some drastic differences here looking at a confirmed decrease with PSA of more than 50%, 46% in the lutetium PSMA arm compared to only 7.1% in the standard of care arm. And looking at the confirmed decrease of more than 80%, 33.0% in the lutetium arm, and 2.0% in the standard of care alone arm.

These two figures look at the top-line health-related quality of life and pain outcomes. The top Kaplan-Meier curve looks at FACT-P total score, favoring lutetium PSMA with a hazard ratio of 0.54 and a 95% confidence interval of 0.45 to 0.66. And below this is the pain outcomes assessed by the BPI-sf pain intensity score also favoring lutetium PSMA with a hazard ratio of 0.52 and a 95% confidence interval of 0.43 to 0.63.

This table looks at the adverse events and you can see here, this is broken down by all grades and grades greater than or equal to three. And you can see any adverse event greater than or equal to three, the lutetium arm was 52.7% compared to 38% for the standard of care arm. Important grade group greater than or equal to three adverse events included anemia at 12.9% in the lutetium arm compared to 4.9% in the standard of care arm, as well as the thrombocytopenia at 7.9% in the lutetium arm compared to 1% in the standard of care arm and lymphopenia at 7.8% in the lutetium arm and 0.5% in the standard of care arm. Looking at the bottom of this table some important points here, adverse events that led to a reduction in lutetium PSMA dose was 1.9%. Adverse events that led to the interruption of lutetium PSMA were 7.9%. And the adverse events that led to the discontinuation of lutetium PSMA at 7%.

So, several important discussion points from the VISION trial and they note that treatment with lutetium PSMA prolonged overall survival in a population of patients with disease that was refracted to androgen-receptor pathway inhibitors as well as taxane chemotherapy. As I noted previously, almost all the patients had received prior docetaxel and 38% had already received cabazitaxel. As Chris noted, this trial did not compare lutetium PSMA with another specific treatment as was done with the phase two TheraP trial, whereas in VISION, they investigated the use of lutetium PSMA as an addition to the existing standard of care. And the rationale for excluding some of these treatment options, such as Radium 223, was that the safety profile of these therapies had not been established in combination with lutetium PSMA. A possible advantage of the imaging criteria used in VISION was to allow patients with PSMA-positive mCRPC to receive life-extending therapy on the basis of only one PET scan plus conventional imaging.

So, in conclusion, in this trial, the VISION trial, looked at the addition of lutetium PSMA to the standard of care and how it significantly extended survival among patients with mCRPC and progressive disease who had received previous treatment with one or more androgen-receptor pathway inhibitors and one or two taxanes.

Finally, treatment with lutetium PSMA was associated with toxic effects that were mainly of grade three or lower, and this therapy also extended the time to SSEs, prolonged the time to worsening health-related quality of life and pain, and delayed biochemical progression.

Thank you very much. We hope you enjoyed this UroToday Journal Club discussing the recently published VISION trial in The New England Journal of Medicine.