Highlight
Patients with metastatic castration‑resistant prostate cancer (mCRPC) treated with lutetium‑177 PSMA radioligand therapy ([177Lu]Lu‑PSMA) show markedly higher PSA responses and objective response rates and a robust reduction in radiographic progression risk; no statistically significant overall survival (OS) benefit was observed in the pooled randomized evidence, and grade ≥3 adverse events were not increased.
Background
Prostate cancer is a leading cause of cancer morbidity and mortality in men worldwide. A subset of patients progresses to metastatic castration‑resistant prostate cancer (mCRPC), a state characterized by disease progression despite androgen‑deprivation therapy and associated with limited survival. Prostate‑specific membrane antigen (PSMA) is highly expressed in most prostate cancers, particularly in advanced disease, and can be exploited for both imaging and targeted radionuclide therapy.
Lutetium‑177 labeled PSMA ligands (commonly lutetium‑177‑PSMA‑617 or related constructs) deliver beta radiation selectively to PSMA‑expressing tumor cells, producing DNA damage and cell kill over a short tissue range. Following encouraging single‑arm and randomized phase II/III trials, regulatory approval (e.g., FDA approval of Pluvicto in 2022) and uptake into practice have grown rapidly. However, uncertainty remains about the magnitude of clinical benefit across randomized trials, the effect on overall survival (OS), and the safety profile when pooled across heterogeneous study designs.
Study design (Belabaci et al., 2025 meta-analysis)
Belabaci and colleagues performed a systematic review and meta‑analysis of randomized controlled trials (RCTs) assessing [177Lu]Lu‑PSMA in mCRPC, following PRISMA methodology. Searches of PubMed, EMBASE, Cochrane Library and Scopus identified six RCTs enrolling 2,113 patients. The meta‑analysis used random‑effects models and reported pooled odds ratios (OR), risk ratios (RR), and hazard ratios (HR) with 95% confidence intervals (CIs) for key endpoints.
Key endpoints included:
– PSA response: proportion achieving ≥50% PSA decline (PSA50)
– Objective response rate (ORR) by RECIST or comparable criteria in measurable disease
– Radiographic progression‑free survival (rPFS)
– Overall survival (OS)
– Safety: grade ≥3 adverse events (AEs)
Control arms varied across trials (standard care, physician’s choice, chemotherapy in some comparisons), and inclusion criteria generally required PSMA PET positivity, though specific imaging thresholds and prior lines of therapy differed.
Key findings
The pooled results reported by Belabaci et al. provide a synthesized, randomized evidence perspective on [177Lu]Lu‑PSMA in mCRPC. Primary quantitative findings were:
– PSA response (≥50% decline): OR = 4.27 (95% CI 2.59–7.06; P < .00001). Patients randomized to [177Lu]Lu‑PSMA were over four times as likely to achieve PSA50 compared with controls. This is a clinically meaningful biologic signal and consistent with single‑trial observations.
– Objective response rate (ORR): RR = 2.93 (95% CI 1.62–5.30; P = .0004). In patients with measurable disease, objective tumor responses were roughly threefold more frequent with [177Lu]Lu‑PSMA.
– Radiographic progression‑free survival (rPFS): HR = 0.57 (95% CI 0.46–0.70; P < .00001). This indicates a 43% relative reduction in risk of radiographic progression or death, a robust and statistically significant effect favoring [177Lu]Lu‑PSMA across trials.
– Overall survival (OS): HR = 0.81 (95% CI 0.62–1.06; P = .13). Although the point estimate suggests a 19% relative reduction in mortality, this did not reach statistical significance in the pooled randomized dataset.
– Grade ≥3 adverse events: RR = 0.85 (95% CI 0.63–1.15; P = .32). There was no statistically significant increase in high‑grade toxicity with [177Lu]Lu‑PSMA compared with control treatments.
Clinical interpretation: The meta‑analysis confirms meaningful anti‑tumor activity and improved disease control (rPFS) with [177Lu]Lu‑PSMA in randomized settings, with a favorable short‑term safety profile. However, a definitive OS benefit has not been demonstrated by the pooled RCT data to date.
Context with notable randomized trials
These pooled results are biologically and clinically concordant with landmark randomized studies. For example, the phase III VISION trial (Sartor et al., NEJM 2021) reported improved rPFS and OS with [177Lu]Lu‑PSMA‑617 plus standard care compared with standard care alone. The randomized phase II TheraP trial (Hofman et al., Lancet Oncology 2021) compared [177Lu]Lu‑PSMA‑617 with cabazitaxel in patients previously treated with docetaxel and androgen‑receptor signaling inhibitors, showing superior PSA response and improved progression‑free outcomes. Differences in populations, comparators, follow‑up duration, and subsequent therapies contribute to heterogeneity across trials and explain why pooled OS remains non‑significant in the meta‑analysis.
Safety and tolerability
The pooled analysis found no increase in grade ≥3 AEs with [177Lu]Lu‑PSMA. Common toxicities reported across trials include fatigue, nausea, mild to moderate hematologic suppression (anemia, thrombocytopenia, neutropenia), and xerostomia (salivary gland dysfunction). Long‑term renal effects have not been prominent in randomized data but require continued surveillance. The absence of increased high‑grade toxicity in pooled RCTs is reassuring, though individual trial AE profiles and patient comorbidities should guide clinical decisions.
Expert commentary and methodological considerations
Several points warrant emphasis when interpreting the meta‑analysis and applying findings to practice:
– OS signal diluted by trial factors: Overall survival can be difficult to demonstrate in modern mCRPC trials because of cross‑over to active therapy, availability of multiple subsequent lines of life‑prolonging treatments, and variable follow‑up. Some trials permitted post‑progression crossover to PSMA therapy or included control arms with active agents, which attenuates differences in OS.
– Heterogeneity of trials: The included RCTs differed in patient selection (prior therapies, performance status), PSMA PET positivity criteria, dosing schedules, radioligand constructs (PSMA‑617 vs other ligands), and control regimens. While random‑effects pooling accounts statistically for between‑study variance, clinical heterogeneity remains and should guide application to individual patients.
– Power and event rates: Several trials were powered for radiographic endpoints or PSA response rather than OS. The pooled sample size improves statistical power but may still be insufficient to detect modest OS differences or may require longer follow‑up to reveal survival advantages.
– Biomarker and imaging selection: Benefit is largely limited to PSMA PET‑positive disease. Standardized thresholds for PSMA PET positivity and complementary FDG PET to exclude discordant high‑FDG/low‑PSMA lesions are important for optimal patient selection.
– Quality of life and patient‑reported outcomes: While tumor‑centric endpoints are improved, the impact on symptoms, quality of life (QoL), and functional status require more consistent reporting across trials. Several RCTs have shown QoL preservation or improvement, but pooled QoL data remain limited.
Clinical implications and future directions
For clinicians managing mCRPC, the meta‑analysis supports integrating [177Lu]Lu‑PSMA therapy as an effective option to achieve disease control in PSMA‑positive patients, particularly after progression on androgen‑receptor pathway inhibitors and taxanes (the common indication studied). The favorable safety profile reinforces its suitability for patients intolerant of or refractory to cytotoxic chemotherapy.
Key areas for ongoing research and clinical optimization include:
– Defining optimal sequencing: head‑to‑head and combination trials testing [177Lu]Lu‑PSMA earlier in the disease course, in combination with androgen‑receptor pathway inhibitors, chemotherapy, PARP inhibitors, or immunotherapy.
– Personalizing dose and dosimetry: patient‑level dosimetry may allow dose escalation to maximize tumoricidal effect while protecting normal tissues.
– Comparing beta vs alpha emitters: alpha‑particle emitters (e.g., actinium‑225 PSMA) show high potency but different toxicity profiles; comparative studies are needed.
– Standardizing PSMA PET criteria and developing predictive biomarkers of response beyond PET uptake, such as circulating tumor DNA or PSMA expression quantification.
– Health economics and access: assessing cost‑effectiveness and addressing infrastructure needs for widespread delivery of radioligand therapy.
Limitations of the meta-analysis
Limitations include trial heterogeneity (selection criteria, control arms, PSMA ligand used, dosing), variability in follow‑up durations, and potential publication or reporting bias. The pooled OS estimate was underpowered to exclude a clinically meaningful survival benefit, and patient‑level data were not available to explore subgroups or adjust for post‑progression therapies.
Conclusion
The pooled randomized evidence synthesized by Belabaci et al. (2025) demonstrates that [177Lu]Lu‑PSMA provides substantial anti‑tumor activity in mCRPC, producing higher PSA responses and objective responses and reducing the risk of radiographic progression with no increase in high‑grade toxicity. While a clear OS advantage was not demonstrated in the pooled analysis, the totality of randomized data—including trials showing OS benefit in some settings—supports the role of [177Lu]Lu‑PSMA as an important treatment option for PSMA PET–positive mCRPC. Further randomized research with longer follow‑up, standardized selection criteria, and trials testing earlier use and combination strategies will clarify its optimal place in the treatment sequence.
Funding and clinicaltrials.gov
The meta‑analysis cited: Belabaci Z, Sleiay M, Abdelshafi A, Otmani Z, Moubarak ES, Amer F. Safety and Efficacy of Lutetium‑177 PSMA Therapy for Metastatic Castration‑Resistant Prostate Cancer: A Systematic Review and Meta‑Analysis of Randomized Controlled Trials. Clin Genitourin Cancer. 2025 Oct;23(5):102398. doi: 10.1016/j.clgc.2025.102398.
For ongoing and future trials of PSMA‑targeted radioligand therapies, search ClinicalTrials.gov using terms such as “lutetium-177 PSMA” or “PSMA radioligand therapy” to view actively recruiting randomized trials and phase 3 studies exploring sequencing and combination strategies.
References
1. Belabaci Z, Sleiay M, Abdelshafi A, Otmani Z, Moubarak ES, Amer F. Safety and Efficacy of Lutetium‑177 PSMA Therapy for Metastatic Castration‑Resistant Prostate Cancer: A Systematic Review and Meta‑Analysis of Randomized Controlled Trials. Clin Genitourin Cancer. 2025 Oct;23(5):102398. doi: 10.1016/j.clgc.2025.102398. PMID: 40737767.
2. Sartor O, de Bono J, Chi KN, et al. Lutetium‑177‑PSMA‑617 for Metastatic Castration‑Resistant Prostate Cancer. N Engl J Med. 2021;385(12):1091–1103. doi:10.1056/NEJMoa2107322.
3. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu‑PSMA‑617 versus cabazitaxel in patients with metastatic castration‑resistant prostate cancer (TheraP): a randomised, open‑label, phase 2 trial. Lancet Oncology. 2021;22(6):849–859. doi:10.1016/S1470-2045(21)00169-0.
4. U.S. Food and Drug Administration. FDA Approves Pluvicto (lutetium Lu 177 vipivotide tetraxetan) for Metastatic Castration‑Resistant Prostate Cancer. March 23, 2022. Accessed via https://www.fda.gov/ (press release).
5. Hicks RJ, Hofman MS, et al. Practical guidance for implementation of PSMA‑targeted radioligand therapy in metastatic prostate cancer: multidisciplinary considerations. (Selected society statements and review summaries). Eur J Nucl Med Mol Imaging and SNMMI guidance documents, ongoing literature.
(Readers are encouraged to consult the primary studies and guideline statements for detailed inclusion criteria, dosing regimens, and trial‑specific outcomes.)
