Metastatic Castration-Resistant Prostate Cancer: Addition of LuPSMA to Enzalutamide

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In an interim analysis of the Australian phase II ENZA-p trial reported in The Lancet Oncology, Emmett et al found that the addition of lutetium-177–labeled PSMA-617 (LuPSMA) to enzalutamide improved prostate-specific antigen (PSA) progression-free survival in the first-line treatment of patients with metastatic castration-resistant prostate cancer.

As stated by the investigators, “Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently.”

Study Details

In the multicenter open-label trial, 162 patients were randomly assigned between August 2020 and July 2022 to receive LuPSMA plus enzalutamide (n = 83) or enzalutamide alone (n = 79). Treatment consisted of enzalutamide at 160 mg daily alone or with adaptive-dosed (2 or 4 doses) LuPSMA at 7.5 GBq every 6 to 8 weeks dependent on findings on interim (week 12) PSMA positron-emission tomography–computed tomography. The primary endpoint was PSA progression-free survival.

PSA Progression-Free Survival

Median follow-up in the interim analysis was 20 months (interquartile range = 18–21 months).


  • The addition of LuPSMA to enzalutamide improved PSA progression-free survival.
  • Median PSA progression-free survival was 13.0 with the combination vs 7.8 months with enzalutamide alone.

Median PSA progression-free survival was 13.0 months (95% confidence interval [CI] = 11.0–17.0 months) in the combination group vs 7.8 months (95% CI = 4.3–11.0 months) in the enzalutamide group (hazard ratio [HR] = 0.43, 95% CI = 0.29–0.63, P < .0001).

Median clinical progression-free survival was 14.0 months (95% CI = 13.0–17.0 months) vs 9.4 months (95% CI = 5.9–12.0 months), with a hazard ratio of 0.47 (95% CI = 0.32–0.69). Median radiographic progression-free survival was 16.0 months (95% CI = 14.0–19.0 months) vs 12.0 months (95% CI = 8.8–21.0 months), with a hazard ratio of 0.68 (95% CI = 0.45–1.03).

Adverse Events

The most common adverse events of any grade were fatigue (75%), nausea (47%), and dry mouth (40%) in the combination therapy group and fatigue (70%), nausea (27%), and constipation (23%) in the enzalutamide group. Grade ≥ 3 adverse events occurred in 40% vs 41% of patients; events observed only in the combination group included anemia (4%) and decreased platelets (1%). No treatment-related grade 4 or 5 events were observed in either group.

The investigators concluded, “The addition of [LuPSMA] to enzalutamide improved PSA progression-free survival, providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide, and warrants further evaluation of the combination more broadly in metastatic prostate cancer.”

Louise Emmett, MD, of the Department of Theranostics & Nuclear Medicine, St. Vincent’s Hospital, Sydney, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Prostate Cancer Research Alliance, St. Vincent’s Clinic Foundation, Endocyte (a Novartis company), and others. For full disclosures of the study authors, visit

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