Longer exposure to ¹⁷⁷Lu-PSMA-617 (Pluvicto) plus standard of care (SoC) was not associated with a higher toxicity risk in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC), according to a follow-up safety analysis of data from the phase 3 VISION trial (NCT03511664).1

Overall, the data showed a similar incidence of treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) between cycles 1-4 and cycles 5-6 of treatment, regardless of grade or severity. There were no additional safety signals reported for those patients who received more than 4 cycles of ¹⁷⁷Lu-PSMA-617.

Previously published data from the VISION trial showed a higher incidence of any-grade or grade 3 or higher TEAEs among patients who received ¹⁷⁷Lu-PSMA-617 plus SoC vs SoC alone.2 In the current safety analysis, the investigators conducted an exposure-adjusted analysis to account for the effect of an extended safety observation period in the treatment arm.

After these adjustments, data still showed a greater incidence for dry eyes, dry mouth, and myelosuppression for patients in the combination arm vs those receiving SoC alone. The incidence of any-grade fatigue and gastrointestinal events was also shown to be 2 to 3 times higher among those in the combination arm, though the difference decreased when accounting for exposure duration. The authors also noted that musculoskeletal, renal, liver events, and dyspnoea were higher among patients receiving SoC alone vs those receiving ¹⁷⁷Lu-PSMA-617 plus SoC after accounting for exposure.

“This analysis was undertaken to get a deeper understanding of the safety profile of Lu-PSMA-617. One issue of adverse event reporting in the VISION trial was that the overall treatment exposure in the Lu-PSMA-617 arm was 3 times longer than in the control arm because of the substantially prolonged time until radiographic progression was reached," said lead author Kim N. Chi, MD, in correspondence with Urology Times®. Chi is the chief medical officer and vice president of BC Cancer.

Chi continued, "Adjusting for that difference in treatment exposure provides a clearer picture of what adverse events are directly related to Lu-PSMA-617, such as myelosuppression and dry mouth, versus those that are unrelated to treatment. In addition, we wanted to assess the impact of cumulative treatment beyond 4 cycles of therapy with Lu-PSMA-617, and we found in this analyses that longer exposure to treatment was not associated with a higher toxicity risk."

In total, the phase 3 VISION trial included 734 patients, of which 529 received ¹⁷⁷Lu-PSMA-617 plus SoC. Among those in the combination arm, 45% (n = 240) received 4 cycles or less of 177Lu-PSMA-617, and 55% (n = 289) received 5 to 6 cycles of ¹⁷⁷Lu-PSMA-617.

The international, open-label study included patients with PSMA-positive mCRPC who were previously treated with at least 1 ARPI and 1 or 2 taxane regimens.Patients were randomly assigned 2:1 to receive ¹⁷⁷Lu-PSMA-617 plus SoC every 6 weeks for up to 6 cycles or to SoC alone.

The primary end points for the study were overall survival and radiographic progression-free survival (rPFS). The findings, which supported the FDA approval of ¹⁷⁷Lu-PSMA-617 in March 2022, showed that the addition of ¹⁷⁷Lu-PSMA-617 to SoC led to a nearly 40% reduction in the risk of death vs SoC alone (15.3 months vs 11.3 months) in patients with PSMA-positive mCRPC. Adding the targeted radioligand therapy also led to a 5.3-month improvement in median rPFS, translating to a 60% reduction in the risk of progression or death (HR, 0.40).2,3

The authors of the current study note that additional phase 3 studies are ongoing to assess the safety profile and therapeutic benefit of ¹⁷⁷Lu-PSMA-617 in earlier stages of the treatment sequence for patients with mCRPC.

Reference

1. Chi KN, Armstrong AJ, Krause BJ, et al. Safety analyses of the phase 3 VISION trial of [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Eur Urol. 2024:S0302-2838(23)03297-9. doi:10.1016/j.eururo.2023.12.004

2. Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021 (suppl 15; abstr LBA4)

3. Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. News release. Novartis. March 23, 2022. Accessed January 18, 2024. https://www.novartis.com/news/media-releases/novartis-pluvictotm-approved-fda-first-targeted-radioligand-therapy-treatment-progressive-psma-positive-metastatic-castration-resistant-prostate-cancer