Promising Phase 3 Trial Results for [177Lu]Lu-PSMA-617 in Taxane-Naive Patients With mCRPC

The PSMAfore trial, a phase 3 study of [¹⁷⁷Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC), has revealed promising results. The findings, set to be presented at the 2024 Society of Nuclear Medicine and Molecular Imaging Annual Meeting by Oliver Sartor, MD, of the Mayo Clinic in Rochester, Minnesota, highlight significant improvements in several clinical outcomes compared with current androgen receptor pathway inhibitors (ARPI).

Previous research, particularly the VISION trial, established that [¹⁷⁷Lu]Lu-PSMA-617 can extend radiographic progression-free survival (rPFS) and overall survival (OS) in patients with mCRPC who have already undergone ARPI and taxane therapy. The PSMAfore trial aimed to investigate the efficacy of this radioligand therapy in patients who have not yet received taxane chemotherapy, thereby exploring its potential as an earlier line of treatment.

The trial included 468 eligible adults with mCRPC who were candidates for ARPI change after 1 progression on prior ARPI. Participants were required to have at least 1 prostate-specific membrane antigen (PSMA)-positive lesion without exclusionary PSMA-negative lesions, confirmed by [⁶⁸Ga]Ga-PSMA-11 positron emission tomography/computed tomography. Those eligible for PARP inhibitors or with recent systemic radiotherapy, immunotherapy, or chemotherapy were excluded.

Patients were randomized 1:1 to receive either [¹⁷⁷Lu]Lu-PSMA-617 (7.4 GBq every 6 weeks for 6 cycles) or an ARPI change (abiraterone or enzalutamide). Those in the ARPI change group could cross over to receive [¹⁷⁷Lu]Lu-PSMA-617 upon centrally reviewed radiographic progressive disease (rPD).

The primary end point was rPFS, with OS as the key secondary end point. Additional secondary end points included PSA50 response (a ≥50% decline in prostate-specific antigen [PSA] levels), health-related quality of life (Functional Assessment of Cancer Therapy – Prostate [FACT-P] questionnaire), and safety. Exploratory end points included time to PSA progression and objective response rate (ORR). Statistical methods involved the log-rank test for time-to-event end points, stratified Cox proportional hazards models for hazard ratios (HRs) and confidence intervals (CIs), and the Kaplan-Meier method for median estimates.

A total of 468 patients were randomized equally between the 2 groups. The primary analysis, conducted over a median study duration of 7.3 months, showed a median rPFS of 9.30 months for the [¹⁷⁷Lu]Lu-PSMA-617 group compared with 5.55 months for the ARPI change group (HR, 0.41; 95% CI, 0.29-0.56; P<.0001). These results were consistent in an exploratory analysis at the second interim OS analysis.

At the second interim analysis, with a study duration of 15.9 months and 45.1% of target deaths, 123 of 146 (84.2%) patients from the ARPI change group had crossed over to receive [¹⁷⁷Lu]Lu-PSMA-617 after rPD. Although there was a positive trend favoring [¹⁷⁷Lu]Lu-PSMA-617 in the crossover-adjusted analysis, the unadjusted OS analysis did not show a significant difference.

The [¹⁷⁷Lu]Lu-PSMA-617 group demonstrated significant benefits over the ARPI change group in several key areas. The FACT-P total score showed a longer median time to worsening (7.46 months vs 4.27 months; HR, 0.59; 95% CI, 0.47-0.72). The ORR and PSA50 response rate were higher in the [¹⁷⁷Lu]Lu-PSMA-617 group at 50.7% versus 14.9% for ORR and 57.6% versus 20.4% for PSA50 response rate. The median time to PSA progression was also longer in the [¹⁷⁷Lu]Lu-PSMA-617 group (10.55 months vs 4.24 months; HR, 0.37; 95% CI, 0.29-0.48).

The safety profile of [¹⁷⁷Lu]Lu-PSMA-617 was manageable, with a lower incidence of grade ≥3 adverse events (AEs) compared with the ARPI change group (34% vs 44%), fewer serious AEs (20% vs 28%), and a similar rate of treatment discontinuation due to AEs (5.7% vs 5.2%). The most common treatment-emergent AEs in the [¹⁷⁷Lu]Lu-PSMA-617 group included dry mouth and myelosuppression, with myelosuppression being the most frequent grade ≥3 AE in both groups.

The PSMAfore trial results indicate that [¹⁷⁷Lu]Lu-PSMA-617 significantly prolongs rPFS, delays PSA progression, and improves ORR and PSA50 response rate in taxane-naive patients with mCRPC, all while maintaining a manageable safety profile. These findings support the potential of [¹⁷⁷Lu]Lu-PSMA-617 as an effective earlier line of treatment for mCRPC.