FDA approves expanded label for 177Lu-PSMA-617 in mCRPC

The FDA has approved an expanded indication for ¹⁷⁷Lu-PSMA-617 (lutetium Lu 177 vipivotide tetraxetan; Pluvicto) to include use in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with an androgen receptor pathway inhibitor (ARPI) therapy and are considered appropriate to delay taxane-based chemotherapy.¹

In March 2022, ¹⁷⁷Lu-PSMA-617 received initial approval for use in the treatment of adult patients with mCRPC who have received prior treatment with an ARPI and taxane-based chemotherapy.

“The earlier indication for Pluvicto could really change our treatment paradigms for patients with mCRPC. It offers a targeted therapy that better delays disease progression compared to a second ARPI,” said Michael Morris, MD, Prostate Cancer Section Head of GU Oncology at Memorial Sloan Kettering Cancer Center, in the news release.¹ “This approval is a significant step forward and should open the doorway to a therapy that has clear clinical advantages for the patient with mCRPC who has progressed on 1 ARPI and has not received chemotherapy.”

The approval is supported by positive data from the phase 3 PSMAfore trial (NCT04689828), which showed that ¹⁷⁷Lu-PSMA-617 prolonged radiographic progression-free survival (rPFS) compared with a change in ARPI in patients with PSMA-positive mCRPC who had progressed on a previous ARPI.³

Specifically, the median rPFS was 11.6 months (95% CI, 9.30–14.19) among patients who received ¹⁷⁷Lu-PSMA-617 vs 5.6 months (95% CI, 4.21–5.95) among patients who received a change in ARPI, translating to a 59% reduction in the risk of radiographic progression or death (HR, 0.41; 95% CI, 0.29, 0.56; P < .0001).

The overall survival (OS) analysis also favored ¹⁷⁷Lu-PSMA-617, but did not show statistical significance (HR, 0.91; 95% CI, 0.72-1.14).

According to Novartis, “The OS analysis was confounded by the high rate of patients who crossed over from the control arm to Pluvicto (60.3%). When adjusted for crossover, the OS hazard ratio was 0.59 (95% CI: 0.38, 0.91) with the inverse probability of censoring weighting (IPCW) method.”

The safety profile for ¹⁷⁷Lu-PSMA-617 was also favorable, with the most frequently reported all-grade adverse events (AEs) being grade 1-2. Grade 3-5 AEs occurred in 36% of patients in the ¹⁷⁷Lu-PSMA-617 arm vs 48% of patients in the change in ARPI arm.

In total, the open-label, phase 3 PSMAfore study included 468 patients with PSMA-positive mCRPC who had not received treatment with a taxane-based regimen. Those included in the study had tumors that had progressed on a second-generation ARPI (either abiraterone, enzalutamide, darolutamide or apalutamide).

Patients were randomly assigned 1:1 to receive ¹⁷⁷Lu-PSMA-617 (n = 234) or a change in ARPI (n = 234). Those in the change in ARPI cohort were able to cross over to receive ¹⁷⁷Lu-PSMA-617 after experiencing radiographic progression as confirmed by blinded independent central review.

“The clinical development of PSMA-targeting radioligand therapy has provided important insights into the treatment of metastatic castration-resistant prostate cancer,” concluded Oliver Sartor, MD, Chair of Genitourinary Cancer Disease Group and Director of Radiopharmaceutical Clinical Trials at Mayo Clinic, in the news release.¹ “The trial data demonstrated a clear clinical benefit in delaying disease progression in eligible patients, offering an additional therapeutic approach in this setting.”

REFERENCES

1. FDA approves Novartis radioligand therapy Pluvicto for earlier use before chemotherapy in PSMA-positive metastatic castration-resistant prostate cancer. News release. Novartis Pharma AG. Published online and accessed March 28, 2025. https://www.novartis.com/news/media-releases/fda-approves-novartis-radioligand-therapy-pluvicto-earlier-use-chemotherapy-psma-positive-metastatic-castration-resistant-prostate-cancer

2. 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 March 28, 2025. https://www.novartis.com/news/media-releases/novartis-pluvictotm-approved-fda-first-targeted-radioligand-therapy-treatment-progressive-psma-positive-metastatic-castration-resistant-prostate-cancer

3. Morris MJ, Castellano D, Herrmann K, et al. ¹⁷⁷Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-1239. doi:10.1016/S0140-6736(24)01653-2