In a substudy of the Australian phase II ENZA-p trial reported in The Lancet Oncology, Emmett et al found that baseline prostate-specific membrane antigen (PSMA)–positron-emission tomography (PET) total tumor volume (TTV) was prognostic for overall survival and predictive for a beneficial effect on overall survival in patients receiving enzalutamide plus lutetium-177–labeled PSMA-617 (LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). The mean standardized uptake value (SUV) was not associated with outcomes.
The primary analysis of the trial showed that adding LuPSMA to enzalutamide as first-line therapy improved overall survival in patients with mCRPC.
Study Details
In the open-label multicenter trial, 162 patients were randomly assigned between August 2020 and July 2022 to receive enzalutamide plus LuPSMA (n = 83) or enzalutamide alone (n = 79). Patients had no prior treatment with docetaxel or an androgen receptor pathway inhibitor (abiraterone permitted) for metastatic disease and had gallium Ga-68–PSMA-11 PET/CT–positive disease.
The current substudy included 160 patients, with 81 in the enzalutamide-plus-LuPSMA group and 79 in the enzalutamide-alone group. PSMA TTV and mean SUVs were derived and correlated with overall survival and prostate-specific antigen (PSA) progression-free survival. Thresholds used for analysis were mean SUV highest quartile (Q4 vs Q1–3) and PSMA TTV median at baseline.
Key Findings
Baseline median mean SUV was 7.7 (interquartile range [IQR] = 6.5–9.8), and median PSMA TTV was 234 mL (IQR = 76–687 mL). Median follow-up at final data cutoff (end of July 2024) was 34 months (IQR = 29–39 months). Death had occurred in 43 patients in the enzalutamide-plus-LuPSMA group and in 53 patients in the enzalutamide-alone group.
In the enzalutamide-alone group, median overall survival was 39 months (95% confidence interval [CI] = 31 months to not estimable) among patients with a PSMA TTV below the median value vs 20 months (95% CI = 13–24 months) among those with values above the median (hazard ratio [HR] = 0.23, 95% CI = 0.13–0.42, P < .0001). In the enzalutamide-plus-LuPSMA group, median overall survival was 35 months (95% CI = 32–37 months) among patients with values below the median value vs 28 months (95% CI = 26–34 months) among those with values above the median (HR = 0.66, 95% CI = 0.36–1.21, P = .18).
In the enzalutamide-alone group, median overall survival was 29 months (95% CI = 17–39 months) for patients with a mean SUV Q4 vs 25 months (95% CI = 21–31 months) among those with a mean SUV Q1–3 (HR = 0.84, 95% CI = 0.44–1.60, P = .59). In the enzalutamide-plus-LuPSMA group, median overall survival was 32 months (95% CI = 21 months to not estimable) for patients with a mean SUV Q4 vs 34 months (95% CI = 27–35 months) among those with a mean SUV Q1–3 (HR = 0.80, 95% CI = 0.38–1.68, P = .56).
In the enzalutamide-alone group, the median PSA progression-free survival was 5.0 months (95% CI = 3.0–9.9 months) for patients with a mean SUV Q4 vs 7.8 months (95% CI = 4.0–11.0 months) among those with a mean SUV Q1–3 (HR = 1.17, 95% CI = 0.69–2.01). In the enzalutamide-plus-LuPSMA group, the median PSA progression-free survival was 15 months (95% CI = 7 months to not estimable) for patients with a mean SUV Q4 vs 13 months (95% CI = 10–17 months) among those with a mean SUV Q1–3 (HR = 0.69, 95% CI = 0.38–1.25).
The investigators concluded: “Baseline PSMA TTV is prognostic for overall survival and predictive for a beneficial effect on overall survival with the addition of [LuPSMA] to enzalutamide as first-line treatment for high-risk [mCRPC]. By contrast, PSMA [mean SUV] was not prognostic for PSA progression-free survival or overall survival when [LuPSMA] was administered with enzalutamide.”
Louise Emmett, MD, of the Department of Theranostics and Nuclear Medicine, St. Vincent’s Hospital, Sydney, is the corresponding author of The Lancet Oncology article.
Disclosure: The study was funded by The Prostate Cancer Research Alliance Initiative (Movember and Australian Federal Government), Prostate Cancer Foundation Challenge Award, Endocyte (a Novartis company), Astellas, and others. For full disclosures of all study authors, visit thelancet.com.
