Enzalutamide Plus LuPSMA Offers Enhanced PSA-PFS in mCRPC

Enzalutamide and lutetium-177-prostate-specific membrane antigen-617 (LuPSMA) have both demonstrated the ability to boost overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinical and clinical data have suggested synergy between LuPSMA and androgen receptor pathway inhibitors (ARPI) for mCRPC.

At the European Society for Medical Oncology Congress 2023, Dr. Louise Emmett and colleagues discussed the ENZA-p trial, which sought to determine if a combination of the 2 drugs would provide efficacy as a first-line treatment for poor-risk mCRPC.

The trial involved 162 patients with mCRPC who had not been previously treated with chemotherapy or ARPI (prior abiraterone and/or docetaxel for hormone-sensitive disease were allowed), had ⁶⁸Ga-PSMA-positive disease on positron emission tomography (PET), and had at least 2 risk factors associated with early progression on enzalutamide.

Each patient was randomized 1:1 into 2 treatment arms; one arm received enzalutamide 160 mg daily and the other received the same treatment with the addition of adaptive dosing LuPSMA 7.5 GBq on days 15 and 57, with 2 extra doses of LuPSMA if persistent PSMA-positive disease was found on interim ⁶⁸Ga-PSMA PET (day 92).

The primary end point was PSA progression-free survival (PSA-PFA). Secondary end points included radiological PSA (rPFS), PSA50% and PSA90% response rates (PSA50RR, PSA90RR), adverse events (AEs), and OS.

The median age of the patient group was 71 years (range, 45-96 years). Prior docetaxel and abiraterone had been administered to 54% and 13% of patients, respectively. The imaging screen failure rate was 18% (40/220). A total of 16% (13) of patients received 2 to 3 doses of LuPSMA, while 81% (67) received 4 doses. The median follow-up was 20 months (interquartile range, 18-21).

PSA-PFS was longer in the enzalutamide-plus-LuPSMA arm versus enzalutamide alone (median, 13.0 vs 7.8 months; hazard ratio, 0.43; 95% CI, 0.29-0.63; P<.001). PSA50RR and PSA90RR were higher with enzalutamide plus LuPSMA versus enzalutamide alone: 93% (77/83) versus 68% (54/79; P<.001) and 78% (65/83) versus 37% (29/79; P<.001), respectively.

The analysis of rPFS is ongoing. Serious adverse events were reported in 33% (27/81) of patients assigned enzalutamide plus LuPSMA versus 35% (28/79) on enzalutamide alone.

Adding an adaptive dose (2-4 doses) of LuPSMA to enzalutamide was found to provide anticancer activity and improve PSA-PFS, PSA50RR, and PSA90RR in patients with poor-risk mCRPC.