PSMAfore: Prolonged rPFS From Lu-177 PSMA-617 in Taxane-Naïve mCRPC

Results of the phase 3 PSMAfore trial—presented during a Presidential Symposium at the European Society for Medical Oncology Congress 2023—showed a clinically meaningful and statistically significant benefit in radiographic progression-free survival (rPFS) after [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) therapy in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who are taxane-naïve.

Prior research has shown that ¹⁷⁷Lu-PSMA-617 prolongs rPFS and overall survival (OS) in patients with mCRPC and prior androgen receptor pathway inhibitor (ARPI) and taxane therapy.

Alton O. Sartor, MD, of the Tulane University School of Medicine, and colleagues designed the open-label, multicenter PSMAfore trial to compare the safety and efficacy of ¹⁷⁷Lu-PSMA-617 versus a change in ARPI therapy (abiraterone or enzalutamide) in taxane-naïve patients with PSMA-positive mCRPC. Patients enrolled must have progressed only once after receiving a second-generation ARPI—any of abiraterone, enzalutamide, darolutamide, or apalutamide.

A total of 467 patients were randomized (1:1) to receive either ¹⁷⁷Lu-PSMA-617 or ARPI change, and those randomized to ARPI change could cross over to ¹⁷⁷Lu-PSMA-617 after radiographic progression.

The primary end point was rPFS, defined as the time from randomization to radiographic progression by the Prostate Cancer Clinical Trials Working Group 3-modified Response Evaluation Criteria in Solid Tumors version 1.1 or death. Among the secondary end points was OS, defined as the time from randomization until death from any cause.

After a median follow-up of 7.3 months, Dr. Sartor and colleagues reported that the primary end point of rPFS was met (hazard ratio [HR], 0.41; 95% CI, 0.29-0.56; P<.0001).

After data cutoff of 8.6 months, an updated rPFS analysis (HR, 0.43; 95% CI, 0.33%-0.54%) showed a consistent clinical benefit in patients receiving ¹⁷⁷Lu-PSMA-617 versus those with a change in ARPI. The time to radiographic progression was more than doubled (12.0 months versus 5.6 months, respectively).

Comparable rPFS was noted at the second interim analysis (median follow-up, 15.9 months), at which time 84.2% of patients with radiographic progression who discontinued ARPI crossed over. Researchers observed a positive OS trend in favor of ¹⁷⁷Lu-PSMA-617 per rank-preserving structural failure time, but not per unadjusted OS analysis.

Adverse events associated with ¹⁷⁷Lu-PSMA-617 in the trial were primarily grade 1 and 2 and included dry mouth (57.3%), asthenia (31.7%), nausea (31.3%), anemia (24.2%), and fatigue (2.9%).

“The rPFS data are impressive, and the treatment effect is comparable with what was observed in the VISION trial,” said Dr. Sartor during the presentation. “We look forward to a future where ¹⁷⁷Lu-PSMA-617 may be a viable therapy for patients in need of alternative, earlier options.”

The next interim OS analysis is expected in 2024.