ENZA-p Trial: Enzalutamide With [177Lu]Lu-PSMA-617 Improves OS in mCRPC

The ENZA-p trial analyzed the activity and safety of enzalutamide with [¹⁷⁷Lu]Lu-PSMA-617 (a radiopharmaceutical containing prostate-specific membrane antigen) versus enzalutamide alone as a first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). New data have elaborated on the study’s findings along with additional follow-up information.

ENZA-p was a phase 2 trial conducted at 15 hospitals in Australia. A total of 162 patients with mCRPC received treatment in the study: each patient had no history of treatment with docetaxel or androgen receptor pathway inhibitors (ARPIs) and had [⁶⁸Ga]Ga PSMA-PET-CT–positive disease, an Eastern Cooperative Oncology Group performance status of 0-2, and at least 2 risk factors for early progression during treatment with enzalutamide.

A total of 79 patients received oral enzalutamide 160 mg daily alone, and 83 patients received the same treatment in combination with 2 or 4 adaptive doses of intravenous [¹⁷⁷Lu]Lu-PSMA-617 at 7.5 GBq every 6 to 8 weeks. Prostate-specific antigen progression-free survival (PSA PFS) was the primary end point, and overall survival (OS) and health-related quality of life (HRQOL) were secondary end points.

After a median follow-up of 34 months (interquartile range, 29-39): 53 (67%) patients in the enzalutamide group and 43 (52%) in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group had died. Overall survival was found to be longer in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group than in the enzalutamide monotherapy group (median, 34 months [95% CI, 30-37] vs 26 months [95% CI, 23-31]; hazard ratio [HR], 0.55 [95% CI, 0·36-0·84]; log-rank P=0.0053).

Health-related quality of life was rated by 154 patients (95%). Deterioration-free survival at 12 months and stratified log-rank P values favored enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 in both physical function (median, 10.64 months [95% CI, 7.66-12.42] vs 3.42 months [95% CI, 3.19-7.89]; HR, 0.51 [95% CI, 0.36-0.72]; log-rank P<0.0001) and overall health and QOL (8.71 months [95% CI, 6.41-11.56] vs 3.32 months [95% CI, 3.09-5.26]; HR, 0.47 [95% CI, 0.33-0.67]; log-rank P=0.0001).

Mean scores for pain until progression favored enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 over enzalutamide alone (difference, 7.3 [95% CI, 1.6-12.9]; P=0.012). Mean scores for fatigue until progression favored enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 over enzalutamide alone (difference, 5.9 [95% CI, 1.1-10.7]; P=0.016). Grade 3-5 adverse events occurred in 35 patients (44%) in the enzalutamide monotherapy group and 37 of 81 patients (46%) in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group. No deaths were attributed to study treatment in either group.

This analysis of the trial demonstrated that the combination of enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 improved OS and HRQOL, along with PSA PFS. These findings warrant the phase 3 evaluation of adaptive-dose [¹⁷⁷Lu]Lu-PSMA-617 in combination with ARPIs in patients with mCRPC.