Adding 177Lu-PSMA-617 to Enzalutamide Improves Survival, QOL in mCRPC

Prostate Cancer

Adding [¹⁷⁷Lu]Lu-PSMA-617 (LuPSMA; Pluvicto) to enzalutamide (Xtandi) significantly improved overall survival (OS) and quality of life (QOL) in patients with metastatic castration-resistant prostate cancer (mCRPC) at high risk for early treatment failure on enzalutamide, according to results from the phase 2 ENZA-p trial shared at the 2025 ASCO Genitourinary Cancers Symposium and simultaneously published in The Lancet Oncology.^1,2

The addition of LuPSMA to enzalutamide reduced the risk of death by 45% vs enzalutamide alone. The median OS was 34 months (95% CI, 30-37) with the combination compared to 26 months (95% CI, 23-31) with enzalutamide alone (HR, 0.55; 95% CI, 0.36-0.84; P = .005). Of note, 38% of patients in the control arm were treated with subsequent LuPSMA off trial.

QOL was also improved with the combination vs enzalutamide alone. The median deterioration-free survival (DFS) for physical function was 10.6 months with the combination vs 3.4 months with enzalutamide alone (HR, 0.51; 95% CI, 0.36-0.72; P = .0001). The median DFS for overall heath status was 8.7 vs 3.3 months, respectively (HR, 0.47; 95% CI, 0.33-0.67; P < .0001).

The mean scores for pain until progression (difference 7.3; 95% CI, 1.6-13; P = .01) and mean score for fatigue until progression (difference 5.9; 95% CI, 1.1-11; P = .02) both showed better outcomes with the combination vs enzalutamide alone.

“Combining LuPSMA and enzalutamide significantly improves OS in men with mCRPC and risk factors for early treatment failure on enzalutamide alone. There was an 8-month OS benefit [with the combination] compared to [enzalutamide alone],” Louise Emmett, MD, FRACP, director of theranostics and nuclear medicine at St. Vincent’s Hospital in Sydney, Australia, said during a presentation of the data.

“The combination also improved both DFS and health-related quality of life indicators for pain, fatigue, physical function, and overall health and quality of life,” added Emmett.

Previously reported interim data from ENZA-p showed that adding LuPSMA to enzalutamide significantly improved prostate-specific antigen progression-free survival (PSA-PFS) and radiographic PFS (rPFS).³ The updated analysis upheld these benefits. With additional follow-up, the median PSA-PFS was 13 vs 7.8 months with the combination vs enzalutamide alone (HR, 0.40; 95% CI, 0.28-0.59; P = .000001), and the median rPFS was 17 vs 14 months, respectively (HR, 0.61; 95% CI, 0.42-0.87).

There were no new safety signals with the additional study follow-up. The rate of grade 3-5 adverse events (AEs) was 46% with the combination vs 44% with enzalutamide alone, “bearing in mind that the enzalutamide alone patients were on trial for 7.8 months, while the LuPSMA plus enzalutamide patients were on trial for 13 months,” Emmett noted.

About the ENZA-p Trial

The ENZA-p study included 162 patients with mCRPC who had a rising PSA that was at least 5 ng/mL. Patients had have 2 or more risk factors for early enzalutamide failure, could not have received prior chemotherapy for mCRPC, and had to have a positive ⁶⁸Ga PSMA PET/CT.

Patient characteristics were well balanced at baseline. In the enzalutamide plus LuPSMA arm, the median age was 71 (interquartile range [IQR], 66-76), the median PSA at enrollment was 39 ng/mL (IQR, 13-75), 52% of patients had de novo metastatic disease at diagnosis, and 53% had received early docetaxel for hormone-sensitive disease. Fourteen percent of patients had prior abiraterone acetate (Zytiga) and the median time since diagnosis was 2.2 years (range, 1.2-6.0).

In the enzalutamide alone arm, the median age was 71 (IQR, 63-76), the median PSA at enrollment was 33 ng/mL (IQR, 14-85), 58% had de novo metastatic disease at diagnosis, and 57% had received early docetaxel for hormone-sensitive disease. Overall, 11% of patients had prior abiraterone and the median time since diagnosis was 2.8 years (range, 1.5-6.4).

Patients were randomized to enzalutamide at 160 mg either alone (n = 79) or combined with 7.5 GBq LuPSMA (n = 83). Those in the combination arm received 2 doses of LuPSMA, with an additional 2 doses given to patients who continued to have PSMA-positive disease at the 92-day follow-up. Overall, 81% of patients in the combination arm received 4 doses.

Limitations and Overall Implications

Discussing some limitations to broad applicability of the ENZA-p outcomes, Emmett said, “This [study explored] first-line enzalutamide in the early mCRPC pre-chemotherapy setting and we know that, for the most part, ARPI [androgen receptor pathway inhibitor treatment] has moved to the metastatic hormone-sensitive setting.” She added that another limitation was that the study only included a “selective population of patients identified who had risk factors for early treatment failure on enzalutamide.”

She added, however, that, “The significant OS benefit observed and the QOL improvements really raises the question of whether PSMA radioligand therapy in prostate cancer should be administered more broadly in conjunction with ARPIs. This paves the way for phase 3 trials leveraging these complementary therapies across the prostate cancer space.”

References

1. Emmett L, Subramaniam S, Crumbaker M, et al. Overall survival and quality of life with [177Lu] Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in poor-risk, metastatic, castration-resistant prostate cancer in ENZA-p (ANZUP 1901). J Clin Oncol. 2025;43(suppl 5):17. doi: 10.1200/JCO.2025.43.5_suppl.17

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2. Emmett L, Subramaniam S, Crumbaker M, et al. Overall survival and quality of life with [177Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): secondary outcomes from a multicentre, open-label, randomised, phase 2 trial [published online February 13, 2025]. Lancet Oncol.

3. Emmett L, Subramaniam S, Crumbaker M, et al. Enzalutamide and 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): A randomised, phase II trial: ENZA-p (ANZUP 1901). LBA84 Enzalutamide and 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): A randomised, phase II trial: ENZA-p (ANZUP 1901). Ann Oncol. 2023;34:S1325. doi: 10.1016/j.annonc.2023.10.086