FDA grants 177Lu-PSMA-617 priority review for mCRPC

The FDA has granted a priority review designation to a new drug application (NDA) for the targeted radioligand therapy 177Lu-PSMA-617 (LuPSMA) for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in the post androgen receptor pathway inhibition, post taxane-based chemotherapy setting.¹

The designation, which will expedite the regulatory review of LuPSMA in this setting, is primarily based on findings from the phase 3 VISION trial. In the study, adding LuPSMA to standard of care (SOC) led to a nearly 40% reduction in the risk of death versus SOC alone in patients with progressive PSMA-positive mCRPC.²

The findings, which were presented during the 2021 ASCO Annual Meeting, showed that at a median follow-up of 20.9 months, the addition of LuPSMA improved the median overall survival (OS) by 4 months over SOC alone (HR, 0.62). Adding the targeted radioligand therapy also led to a 5.3-month improvement in median radiographic progression-free survival (rPFS), translating to a 60% reduction in the risk of progression or death (HR, 0.40).

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a final decision on the NDA in the first half of 2022.

The open-label phase 3 VISION trial (NCT03511664) included 831 patients (1179 initially screened) with progressive PSMA-positive mCRPC who received at least 1 novel androgen axis drug (eg, enzalutamide [Xtandi] or abiraterone acetate [Zytiga]) and were previously treated with 1 to 2 taxane regimens.

PET imaging with 68Ga-PSMA-11 was used to determine PSMA positivity. Patient demographics and baseline characteristics were well balanced at baseline.

Patients were randomized in a 2:1 ratio to LuPSMA (7.4 GBq every 6 weeks x 6 cycles; n = 551) plus SOC or SOC alone (n = 280). Individual investigators determined the SOC; however, radium-223 (Xofigo) and cytotoxic chemotherapy were not allowed. The coprimary end points of the trial were OS and rPFS.

The median OS was 15.3 months in the LuPSMA arm versus 11.3 months in the SOC alone arm, translating to a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.52-0.74; P <.001).The rPFS was 8.7 versus 3.4 months, respectively (HR, 0.40; 99.2% CI, 0.29-0.57; P <.001).

There was also a statistically significant benefit favoring the LuPSMA arm for the key secondary endpoints of objective response rate (ORR), disease control rate (DCR), and time to first symptomatic skeletal event (SSE). The ORRs and DCRs were 29.8% versus 1.7% and 89.0% versus 66.7%, respectively. The median time to first SSE was 11.5 months in the LuPSMA group compared with 6.8 months in the control arm (HR, 0.50).

The safety analysis included 529 patients in the LuPSMA cohort and 205 patients in the control group. The investigators considered LuPSMA treatment to be well tolerated. The most common adverse events (AEs) across all grades occurring in the LuPSMA arm were fatigue (49.1% vs 29.3% in the control arm), bone marrow suppression (47.4% vs 17.6%, respectively), dry mouth (39.3% vs 1%), nausea/vomiting (39.3% vs 17.1%), kidney effects (8.7% vs 5.9%), second primary malignancies (2.1% vs 1%), and intracranial bleeding (1.3% vs 1.5%).

High-grade treatment-emergent AEs occurred in 52.7% of patients receiving LuPSMA compared with 38% of patients treated with SOC alone. The most common grade 3-5 AEs reported in the LuPSMA arm were bone marrow suppression (23.4% vs 6.8% in the control arm), fatigue (7% vs 2.4%, respectively), kidney effects (3.4% vs 2.9%), and nausea/vomiting (1.5% vs 0.5%).

References

1. FDA grants Priority Review for investigational targeted radioligand therapy 177Lu-PSMA-617 for patients with metastatic castration-resistant prostate cancer (mCRPC). Published online September 30, 2021. Accessed September 30, 2021. https://bit.ly/3il5JPS.

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 39, 2021 (suppl 15; abstr LBA4).