Interim [68Ga]Ga-prostate-specific membrane-antigen positron emission tomography/computed tomography (PSMA-PET/CT) has prognostic potential for overall survival (OS) in metastatic castrate-resistant prostate cancer (mCRPC), although evidence is limited. This ENZA-p sub-study evaluated 3-mo PSMA-total-tumor-volume (PSMA-TTV) as a prognostic biomarker for OS with enzalutamide ± [177Lu]Lu-PSMA-617.
ENZA-p is a randomized, phase 2 trial. Participants with mCRPC and risk factors for early treatment failure with enzalutamide were randomized (1:1) to enzalutamide or enzalutamide + [177Lu]Lu-PSMA-617. Participants underwent baseline and 3-mo [68Ga]Ga-PSMA-11-PET/CT, quantified to derive PSMA-TTV. We evaluated the prognostic value of PSMA-TTV change, and residual PSMA-TTV at 3-mo for OS (NCT04419402).
This sub-study included 152/162 (94%) randomized participants with a 3-mo PSMA-PET. Median OS was 27 mo (95% confidence interval [CI] 23–30). Baseline median PSMA-TTV 230 ml (interquartile range [IQR] 75–635) and 3-mo PSMA-TTV 103 ml (IQR 24–457). The median change in PSMA-TTV from baseline was –34% (IQR –76% to 16%) with 50/152 (33%) participants with increase in PSMA-TTV. Any increase versus decrease in PSMA-TTV at 3-mo was associated with shorter OS (HR 2.52, 95% CI 1.65–3.85) and decreased 2-yr survival 30% (95% CI 17–43) versus 67% (95% CI 56–75) (log-rank p < 0.0001). Residual 3-mo PSMA-TTV higher versus lower than the median (103 ml) was associated with shorter OS (HR 3.76, 95% CI 2.39–5.92) and lower 2-yr survival 34% (95% CI 23–45) versus 76% (95% CI 64–84) (log-rank p < 0.0001). This association was independent of treatment arm and prostate-specific antigen (PSA) response.
PSMA-TTV at 3 mos was prognostic for OS independent of study treatment and PSA response in ENZA-p, warranting further prospective validation of interim PSMA-PET response criteria.
The integration of prostate-specific membrane antigen positron emission tomography (PSMA-PET) into the management of advanced prostate cancer has, until recently, been largely confined to patient selection—particularly for PSMA-targeted radioligand therapy. However, the study by Emmett et al. challenges this paradigm by shifting the focus from baseline imaging toward dynamic, on-treatment biomarkers. Specifically, this pre-specified ENZA-p sub-study evaluates whether interim PSMA-PET–derived total tumour volume (PSMA-TTV) at 3 months can serve as a robust prognostic indicator for overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).
The key finding is both clinically intuitive and methodologically compelling: what happens early during treatment matters more than where the patient starts. While baseline PSMA-PET metrics have known prognostic value, they fail to fully discriminate responders from non-responders. In contrast, this study demonstrates that both residual tumour burden and increases in PSMA-TTV at 3 months strongly stratify survival outcomes, independent of treatment arm and PSA response. Patients with favourable imaging profiles achieved approximately 80% 2-year survival, compared with only 12% in the poorest-risk group—an effect size rarely observed with conventional biomarkers.
Beyond the now well-highlighted “50/50 criteria,” the study provides a broader and highly informative evaluation of multiple PSMA-PET–based response frameworks. Importantly, even a simple dichotomous approach—increase versus decrease in PSMA-TTV—was strongly prognostic. Patients with any increase in tumour volume at 3 months had more than a twofold higher risk of death and markedly worse 2-year survival (30% vs 67%), underscoring how early volumetric progression alone captures clinically meaningful biology.
Similarly, absolute residual tumour burden at 3 months emerged as one of the most powerful predictors of outcome. Patients with PSMA-TTV above the median had a nearly fourfold higher risk of death and inferior survival (34% vs 76% at 2 years). This finding reinforces a key biological message: persistent disease burden—even in the absence of overt progression—is not benign, and may reflect treatment resistance or aggressive tumour phenotype.
The study also evaluated established and emerging imaging response criteria. RECIP classification demonstrated clear prognostic separation, particularly for progressive disease, where 2-year survival dropped to below 10%. However, its performance was slightly inferior to the newly proposed volumetric models, suggesting that purely PSMA-driven quantitative approaches may better capture disease dynamics.
Equally relevant is the analysis of new lesion burden. Patients with ≥6 new lesions had substantially worse outcomes compared to those with fewer lesions (2-year survival ~14% vs ~62%), confirming that lesion emergence remains a clinically meaningful signal. Yet, this metric alone lacked the discriminatory power of volumetric approaches, again emphasising that counting lesions without accounting for total tumour burden may underestimate disease complexity.
Taken together, these results consistently point in the same direction: whether assessed as change, residual volume, categorical response, or new lesions, interim PSMA-PET captures prognostic information far beyond conventional tools. Notably, these associations remained robust after adjustment for PSA response and treatment arm, highlighting that PSMA-PET reflects disease biology independently of both systemic therapy and biochemical markers.
A particularly important clinical insight is the discordance between PSA and imaging response. A substantial proportion of patients with increasing PSMA-TTV did not demonstrate PSA progression (effect visible also in men treated with ARPIs for mHSPC in a case of conventional imaging), yet still experienced poor survival outcomes. This observation reinforces a growing recognition that PSA is an imperfect surrogate for treatment efficacy, especially in the era of ARPIs and PSMA-targeted therapies.
From a methodological standpoint, the study illustrates the limitations of traditional response paradigms. Linear measurements and bone scan–based criteria fail to account for the spatial heterogeneity and diffuse nature of metastatic prostate cancer. In contrast, PSMA-TTV enables a whole-body, volumetric, and biologically integrated assessment of disease. The prognostic impact of tumour change is not uniform across patients. The same percentage increase carries different implications depending on baseline disease burden, supporting hybrid models that integrate both absolute and relative metrics.
Biologically, PSMA-TTV may also be more robust than intensity-based measures such as SUVmean, which are influenced by heterogeneity and treatment-related modulation of PSMA expression.
Despite limitations, including the need for specialised quantification tools and validation in broader populations, the implications are substantial. Interim PSMA-PET may become a true decision-making tool, enabling early treatment adaptation.
In conclusion, this study provides compelling prospective evidence that quantitative PSMA-PET, across multiple complementary metrics, is a powerful and independent predictor of survival in mCRPC. Early, quantitative imaging of tumour burden fundamentally outperforms conventional response assessment and may redefine how we personalise therapy in advanced prostate cancer.