Lutetium-177-labeled prostate-specific membrane antigen radioligand therapy (¹⁷⁷Lu-PSMA-RLT) emerged as a novel treatment for metastatic castration-resistant prostate cancer (mCRPC) following FDA approval in 2022. Its role in metastatic hormone-sensitive prostate cancer (mHSPC) is under active investigation. This systematic review synthesizes evidence on the efficacy, safety, and combinatorial strategies involving ¹⁷⁷Lu-PSMA-RLT in mHSPC. PubMed, Embase, ClinicalTrials.gov, and WHO ICTRP were searched for studies (2010-2025) evaluating ¹⁷⁷Lu-PSMA in mHSPC. Eligible sources included randomized trials, observational studies, and relevant conference abstracts. Data on study design, population, treatment regimen, PSA response (≥50% decline), progression-free survival (PFS), and toxicity were extracted and synthesized in accordance with PRISMA guidelines. Fourteen studies met inclusion, in which ¹⁷⁷Lu-PSMA-RLT was administered as monotherapy or in combination with ADT, chemotherapy, stereotactic body radiation therapy (SBRT), or tandem α-emitters therapy. PSA50 rates ranged from 44% to 100%, with the highest responses in treatment-naïve de novo populations. Median PFS ranged from 9.5 months in high-volume cohorts to 23.3 months in low-volume settings and 31.0 months in combination regimens. Randomized trials (LUNAR, UpFrontPSMA, CONSOLIDATE, and interim PSMAddition) demonstrated improved PSA/PFS responses compared with their respective control arms. Toxicity was generally low, mostly xerostomia and fatigue; grade ≥III adverse events were infrequent. Dosimetry studies confirmed safe renal and marrow exposure. Early evidence indicates ¹⁷⁷Lu-PSMA-RLT is feasible with preliminary signals of efficacy in select patients with mHSPC, particularly in treatment-naïve de novo populations, and when used in combination strategies. Current studies face limitations of small sample sizes, heterogeneous protocols, and short follow-up durations.
Urologic oncology. 2026 Jul 18 [Epub ahead of print]
Joseph McGrath, Robert Willis, Sudharshanan Balaji, Yudai Ishiyama, Hunter Sceats, Mark Bandyk, K C Balaji
Department of Urology, University of Florida - Jacksonville, Jacksonville, FL., Alabama College of Osteopathic Medicine, Dothan, AL., Department of Urology, Government Kilpauk Medical College, Chennai, India., Department of Urology, University of Florida - Jacksonville, Jacksonville, FL. Electronic address: .