TOPLINE:

In men with metastatic castration-resistant prostate cancer, prostate-specific membrane antigen (PSMA)-total tumor volume (TTV) on PET imaging was prognostic for overall survival with enzalutamide monotherapy and predictive of a survival benefit from adding lutetium-177 (¹⁷⁷Lu)-PSMA-617. 

METHODOLOGY:

• Studies have shown that quantitative PSMA-PET parameters such as whole-body standardized uptake value (SUV)mean and TTV have prognostic value for ¹⁷⁷Lu-PSMA-617 monotherapy in patients with metastatic castration-resistant prostate cancer. However, their prognostic and predictive value for enzalutamide plus Lu-PSMA-617 combination therapy and enzalutamide monotherapy remain unclear.
• To investigate this, researchers conducted a substudy of the phase 2 Enza-p trial involving 160 participants with progressive metastatic castration-resistant prostate cancer who had not previously received docetaxel or androgen receptor pathway inhibitors.
• Participants were randomly assigned to receive either 160 mg/d enzalutamide alone (n = 79) or 160 mg/d enzalutamide plus adaptive-dosed ¹⁷⁷Lu-PSMA-617 7.5 GBq (n = 81) administered 2 and 8 weeks after enzalutamide treatment initiation, with up to two additional doses at weeks 16 and 24 based on PSMA-PET findings at week 12.
• The researchers performed baseline gallium-68-PSMA-11 PET-CT in all participants and quantified PSMA-TTVs and whole-body SUVmeans.
• The primary endpoint was overall survival, and the secondary endpoint was prostate-specific antigen (PSA) progression-free survival. The tertiary endpoint was to determine the association between SUVmean and PSMA-TTV with clinical outcomes overall and by treatment received. The median follow-up duration was 34 months.

TAKEAWAY:

• In the enzalutamide-only group, median overall survival was 39 months for patients with PSMA-TTV less than the median compared with 20 months for those with PSMA-TTV exceeding it (hazard ratio [HR], 0.23; P < .0001). In the combination group, survival duration was 35 months vs 28 months, respectively (HR, 0.66; P = .18). The test for interaction between PSMA-TTV and treatment group was significant (P = .0078).
• After adjustment for clinical prognostic factors, PSMA-TTV remained independently prognostic for overall survival with enzalutamide monotherapy (HR, 0.33) but not with combination therapy (HR, 0.66). PSMA-TTV was, however, predictive of a survival benefit with combination therapy: Among patients with a PSMA-TTV greater than the median, adding Lu-PSMA-617 to enzalutamide increased median overall survival from 20 months to 28 months. When PSMA-TTV was less than the median, there was no overall survival advantage (median 39 months vs 35 months).
• The median PSA progression-free survival was longer with combination therapy than with enzalutamide monotherapy across the PSMA-TTV subgroups: 11 months vs 3 months in the more-than-median PSMA-TTV group and 15 months vs 11 months in the less-than-median PSMA-TTV group (PSMA-TTV and treatment group: P for interaction = .017).
• In contrast to previous studies of Lu-PSMA-617 monotherapy, PSMA SUVmean (highest quartile vs lower three quartiles) was not associated with median overall survival in the monotherapy or combination groups, nor was PSA progression-free survival.

IN PRACTICE:

“Baseline [PSMA-TTV] is prognostic for overall survival and predictive of a beneficial effect on overall survival with the addition of ¹⁷⁷Lu-PSMA-617 to enzalutamide in metastatic castration-resistant prostate cancer,” the authors wrote. “The prognostic value of [PSMA-TTV] for enzalutamide identified in this study suggests an additional potential role of [PSMA]-PET in metastatic prostate cancer above and beyond its current use in defining suitability for ¹⁷⁷Lu -PSMA-617 therapy.”

SOURCE:

The study, led by Louise Emmett, MD, St. Vincent’s Hospital in Sydney, Australia, was published online in The Lancet Oncology.

LIMITATIONS:

PSMA-PET quantification required labor-intensive semiautomated software not in routine use. The study enrolled a high-risk metastatic castration-resistant prostate cancer subgroup, limiting generalizability. Screening excluded patients with low-PSMA-expression, potentially underrepresenting them.

DISCLOSURES:

The ENZA-p trial was supported by the Prostate Cancer Research Alliance initiative, Prostate Cancer Foundation Challenge Award, St. Vincent’s Clinic Foundation, GenesisCare, Roy Morgan, Endocyte (a Novartis company), and Astellas. Several authors reported receiving research grants or consulting fees from and having other ties with various sources. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.