177Lu-PSMA-617 improves rPFS vs ARPI switch in taxane-naïve mCRPC patients

The prostate-specific membrane antigen (PSMA)–targeted radioligand, lutetium-177 (¹⁷⁷Lu)–PSMA-617, improves radiographic progression-free survival (rPFS) vs androgen receptor pathway inhibitor (ARPI) switch and has a favourable safety profile in taxane-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on one prior second-generation ARPI, results of the phase III PSMAfore trial have shown.

The trial included 468 patients with ≥1 PSMA-positive lesion and no exclusionary PSMA-negative lesions on ⁶⁸Ga-PSMA-11 PET-CT who were candidates for ARPI switch and had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were randomized 1:1 to receive open-label ¹⁷⁷Lu-PSMA-617 (7.4 GBq Q6W, 6 cycles; n=234; median age, 71 years; prior abiraterone or enzalutamide, 91.1 percent) or ARPI switch (abiraterone or enzalutamide; n=234; median age, 72 years; prior abiraterone or enzalutamide, 91.5 percent). Crossover to ¹⁷⁷Lu-PSMA-617 treatment was allowed upon radiographic progression. [Sartor O, et al, ESMO 2023, abstract LBA13]

“The primary endpoint of rPFS was met,” said investigator Professor Oliver Sartor of Department of Medical Oncology and Radiology, Mayo Clinic, Rochester, Minnesota, US.

At a median follow-up of 7.3 months, a 59 percent reduction in risk of the primary endpoint was shown with ¹⁷⁷Lu-PSMA-617 vs ARPI switch (hazard ratio [HR], 0.41; 95 percent confidence interval [CI], 0.29–0.56; p<0.0001).

“In the second interim analysis after a median follow-up of 15.9 months, median rPFS was 12.02 months with ¹⁷⁷Lu-PSMA-617 vs 5.59 months with ARPI switch. The HR for rPFS was 0.43 [95 percent CI, 0.33–0.54],” reported Sartor.

Overall survival (OS), a key secondary endpoint, showed a trend in favour of ¹⁷⁷Lu-PSMA-617 vs ARPI switch in prespecified crossover-adjusted analysis (median, 12.72 months vs 13.08 months; HR, 0.80; 95 percent CI, 0.48–1.33), but not in intent-to-treat (ITT) analysis (HR, 1.16; 95 percent CI, 0.83–1.64). “The 84.2 percent crossover rate, which was never seen in a phase III trial before, might have confounded the ITT analysis,” Sartor suggested. “OS data collection continues.”

Radiographic objective response rate was 50.7 percent vs 14.9 percent in the ¹⁷⁷Lu-PSMA-617 vs ARPI switch group, with complete response achieved in 21.1 percent vs 2.7 percent of patients. Median duration of response was 13.63 months vs 10.05 months.

A ≥50 percent reduction in prostate-specific antigen levels from baseline was confirmed in 57.6 percent vs 20.4 percent of patients in the ¹⁷⁷Lu-PSMA-617 vs ARPI switch group.

Time to composite health-related quality of life or pain worsening also favoured ¹⁷⁷Lu-PSMA-617 vs ARPI switch (Functional Assessment of Cancer Therapy-Prostate total score: median, 7.46 months vs 4.27 months; HR, 0.59; 95 percent CI, 0.47–0.72) (Brief Pain Inventory – Short Form pain intensity scale: median, 5.03 months vs 3.71 months; HR, 0.69; 95 percent CI, 0.56–0.85).

“¹⁷⁷Lu-PSMA-617 demonstrated a very favourable adverse event [AE] profile. Interestingly, rates of grade 3/4 AEs were lower with ¹⁷⁷Lu-PSMA-617 vs ARPI switch [33.9 percent vs 43.1 percent], as were AEs leading to dose adjustment [3.5 percent vs 15.1 percent],” pointed out Sartor. “AEs led to treatment discontinuation in 5.7 percent vs 5.2 percent of patients.”

The most common grade ≥3 AEs associated with ¹⁷⁷Lu-PSMA-617 were dry mouth (1.3 percent vs 0 percent for ¹⁷⁷Lu-PSMA-617 vs ARPI switch) and anaemia (6.2 percent vs 6 percent).

¹⁷⁷Lu-PSMA-617 delivers beta-particle radiation selectively to PSMA-positive cells and the surrounding microenvironment. Most patients with mCRPC have PSMA-positive lesions, and high PSMA expression is independently associated with poor prognosis. Based on positive results of the earlier phase III VISION trial, ¹⁷⁷Lu-PSMA-617 is included in ESMO’s updated guidelines on treatment of metastatic/relapsed prostate cancer patients pretreated with a novel ARPI and taxanes. [N Engl J Med 2021;385:1091-1103; Ann Oncol 2023;34:557-563]