At ASCO GU 2025 we presented our findings from the secondary VISION analysis evaluating the efficacy of Lutetium PSMA with or without ARPIs or androgen receptor pathway inhibitors for the treatment of metastatic castration-resistant prostate cancer.

What was the study design?

Speaking of the VISION trial, it was a phase III trial, multinational, evaluated efficacy and safety of Lutetium PSMA with standard of care versus standard of care alone in the treatment of metastatic castration-resistant prostate cancer. For that trial the eligible patients were the ones who had metastatic castration-resistant prostate cancer with at least one prior ARPI, androgen receptor pathway inhibitor, and one or two taxane-based chemotherapies. And they found that there was an improved PFS and OS for the patients who received Lutetium PSMA which led to the approval of the FDA for the treatment of patients with metastatic castrate-resistant prostate cancer.

But in this secondary analysis we specifically focussed on the patients who only received Lutetium PSMA and our key question was what would be the efficacy and safety of concurrent ARPIs with Lutetium PSMA for the treatment of these patients. So we had two arms, the ones who had Lutetium PSMA with concurrent ARPI versus the arm for the patients who received Lutetium PSMA without concurrent ARPIs.

What were the results of this study?

We retrospectively analysed the efficacy and safety profile. First of all, speaking of the patient characteristics, as the trial was not designed to look at these specific questions, although most of the characteristics were balanced between the two arms, including median age, advanced Gleason score 8-10 and metastatic site distribution, but there were some imbalances like PSA level, LDH level and more prior taxane-based chemotherapy in the patients who did not receive ARPI.

Taking that into consideration there was 5.5 month OS benefit for the patients who received concurrent ARPIs, 17.8 months for the patients who received concurrent ARPI with Lutetium PSMA versus 12.4 months for the patients who did not receive ARPI with Lutetium PSMA. However, the PSA progression free survival and radiographic progression free survival was not statistically significant. Both of these endpoints were trending towards better outcomes with concurrent ARPIs: PSA PFS 8.6 versus 7.3 and for radiographic PFS it was 10.2 versus 8.5 months in favour of concurrent ARPI with Lutetium PSMA. But neither was statistically significant.

Coming into the safety profile, which is super-important, the overall adverse event rates were similar between the two groups. There was no new safety signal in the patients who received concurrent ARPIs and it was well-tolerated, manageable, for those patients. Death due to adverse events were reported in eight patients, 2.8% of patients, with concurrent use of ARPIs and 4.5% in patients without concurrent ARPIs. However, we need to acknowledge the limitations of the study. The retrospective nature of analysis can introduce some unmeasured confounders affecting the OS results and multivariate analysis is also needed which is already performed and will be reported in our manuscript.

What is the significance of this study and what’s next?

In terms of the findings that we had in our study, it is actually explainable by the mechanism of the androgen receptor pathway inhibitor and PSMA Lutetium but blocking the androgen pathway can lead to the upregulation of PSMA on cancer cells which can lead to the improved benefit from PSMA Lutetium. Our study findings actually were aligned with the ENZA-p study that was presented at ASCO GU which showed a combination of enzalutamide and Lutetium PSMA led to improvement of PSA and radiographic progression free survivals and improved overall survival with around 8 months.

But, however, because of the confounders in our study and the retrospective nature of analysis, this study was more determined to be thought provoking and hypothesis generating for the future trials. We will be conducting randomised trials to evaluate the efficacy and safety of concurrent ARPI with Lutetium PSMA for the treatment of patients with metastatic castration-resistant prostate cancer to evaluate the findings that we had in this secondary analysis.