Adding 177Lu-PSMA-617 to enzalutamide extends OS in mCRPC

The combination of ¹⁷⁷Lu-PSMA-617 (Pluvicto) plus enzalutamide (Xtandi) significantly improved overall survival (OS) compared with enzalutamide alone in patients with poor-risk metastatic castration-resistant prostate cancer (mCRPC), according to updated data from the phase 2 ENZA-p trial (NCT04419402).

According to the authors, these findings warrant phase 3 investigation.

The data were presented at the 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco, California,¹ and concurrently published in Lancet Oncology.²

Data on the trial’s primary end point, progression-free survival (PFS), were previously reported. Overall, the median prostate-specific antigen (PSA) PFS was 13 months in the combination arm vs 7.8 months in the monotherapy arm. The radiographic PFS (rPFS) was also extended with the combination, with a median of 17 months with ¹⁷⁷Lu-PSMA-617 plus enzalutamide vs 14 months with enzalutamide alone.

The updated data encompassed the trial’s key secondary end points, including OS, deterioration-free survival, and health-related quality of life.

At a median follow-up of 34 months, the median OS was 34 months (95% CI, 30-37) with ¹⁷⁷Lu-PSMA-617 plus enzalutamide compared with 26 months (95% CI, 23-31) with enzalutamide alone (HR, 0.55; 95% CI, 0.36-0.84; P = .0053).

Presenting author Louise Emmett, MD, FRACP, MBChB, of St Vincent’s Hospital in Australia, noted during the presentation, “This is despite the fact that 38% of patients on the enzalutamide alone arm went on to receive ¹⁷⁷Lu-PSMA-617 as subsequent treatment off protocol.”

Further, 12-month deterioration-free survival, assessed through both physical function and overall health, was improved in the combination arm. The median deterioration-free survival regarding physical function was 10.64 months (95% CI, 7.66-12.42) with ¹⁷⁷Lu-PSMA-617 plus enzalutamide vs 3.42 months (95% CI, 3.19-7.89) with enzalutamide alone (HR, 0.51; 95% CI, 0.36-0.72; P = .0001). Regarding overall health status, the median deterioration-free survival was 8.71 months (95% CI, 6.41-11.56) in the combination arm vs 3.32 months (95% CI, 3.09-5.26) in the monotherapy arm (HR, 0.47; 95% CI, 0.33-0.67; P < .0001).

Regarding health-related quality of life, the combination regimen also conferred benefits in fatigue (difference, 5.9; 95% CI, 1.1-10.7; P = .016) and pain scores (difference, 7.3; 95% CI, 1.6-12.9; P = .012) until progression.

Grade 3 to 5 adverse events (AEs) were reported in 46% of patients in the combination arm vs 44% of patients in the monotherapy arm. There were a total of 4 grade 5 AEs reported in the ¹⁷⁷Lu-PSMA-617 plus enzalutamide arm and 1 grade 5 AE reported in the enzalutamide monotherapy arm. Self-rated xerostomia was reported among 74% of patients in the combination arm vs 57% of patients in the monotherapy arm (P = .039).

In total, the ENZA-p trial enrolled 162 patients with mCRPC who were randomly assigned 1:1 to receive 160 mg enzalutamide with (n = 83) or without (n = 79) ¹⁷⁷Lu-PSMA-617. ¹⁷⁷Lu-PSMA-617 was administered at 7.5 GBq in 2 to 4 doses.

Emmett explained, “The experimental arm had ¹⁷⁷Lu-PSMA-617 administered in an adaptive dosing regimen. That means that all patients on the experimental arm received the first 2 doses of ¹⁷⁷Lu-PSMA-617, and then an interim PSMA-PET at week 12. If there was no residual disease on the PSMA-PET, no further lutetium was administered. If any disease was identified on the PSMA-PET, they received a further 2 doses. So, 81% of patients received 4 doses, and 11% of patients received 2 doses.”

The median age of participants was 71 years in both cohorts. At baseline, the median PSA was 39 ng/dL in the treatment arm vs 33 ng/dL in the active control arm. Overall, 61% of patients in the combination arm and 59% of patients in the monotherapy arm had greater than 20 PSMA-avid metastases. De novo metastatic disease at baseline was reported among 52% of patients in the combination arm vs 58% of patients in the monotherapy arm. Additionally, 53% of patients in the combination arm and 57% of patients in the monotherapy arm had received docetaxel for hormone-sensitive disease.

Overall, the authors concluded, “Our findings warrant phase 3 evaluation of adaptive-dosed ¹⁷⁷Lu-PSMA-617 in combination with androgen receptor pathway inhibitors in people with metastatic prostate cancer.”

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) Abstract 17. doi:10.1200/JCO.2025.43.5_suppl.17

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. Lancet Oncol. 2025 Feb 12:S1470-2045(25)00009-9. doi:10.1016/S1470-2045(25)00009-9