Article Summary
Lutetium-177 PSMA-617, a radioligand therapy approved for advanced prostate cancer, shows early promise in treating earlier-stage metastatic hormone-sensitive prostate cancer, potentially allowing patients to reduce lifelong hormone therapy while delaying disease progression with mild side effects.
- PSA50 response rates (at least 50% PSA reduction) ranged from 44% to 100% across studies, with the strongest responses in treatment-naive patients
- Improved progression-free survival: Lu-177 PSMA-617 combined with docetaxel and ADT achieved 31.0 months versus 20.2 months with standard therapy alone
- Safety profile: Toxicity was predominantly mild with fatigue, dry mouth, and low-grade blood cell reductions; grade III or higher adverse events were infrequent
- Multiple treatment combinations: Therapy was evaluated as monotherapy or combined with hormone therapy, chemotherapy, radiation, or other agents
- FDA approval: Lu-177 PSMA-617 (Pluvicto) received FDA approval in 2022 for advanced castration-resistant prostate cancer and is now being studied in earlier disease stages
Lutetium-177 (Lu-177) prostate-specific membrane antigen (PSMA)-617 shows early signs of benefit in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to a recent review.
A team led by urologist KC Balaji, MD, of the University of Florida in Jacksonville, synthesized evidence in the medical literature on the efficacy, safety, and combinatorial strategies involving Lu-177 PSMA-617 and found the radioligand therapy (RLT) could potentially reduce reliance on lifelong hormone suppression while delaying patient progression to castration resistance.
“Given the morbidity of lifelong androgen suppression, the potential ability of RLT to provide durable disease control while mitigating systemic side effects represents an exciting and important therapeutic opportunity,” the group wrote. The study was published July 18 in Urologic Oncology: Seminars and Original Investigations.
New therapies for metastatic prostate cancer have historically evolved through a pattern in which systemic agents are first established in the post-chemotherapy castration-resistant setting before advancing to earlier stages in the disease course, the authors explained. Docetaxel and androgen receptor pathway inhibitors (ARPIs) followed this trajectory, for instance, as well as poly (ADP-ribose) polymerase PARP inhibitors, they noted.
Lu-177-PSMA-617 (Pluvicto, Novartis) received U.S. Food and Drug Administration (FDA) approval in 2022 for metastatic castration-resistant prostate cancer (mCRPC), a later stage of disease in which the cancer has stopped responding to hormone therapy. mHSPC represents an earlier stage, in which the cancer still responds to hormone-based treatment and there are an increasing number of clinical studies investigating its use in this setting.
To pool the evidence so far, the researchers searched PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform for studies published or registered between 2010 and 2025. They found 14 studies that met their inclusion criteria and extracted and synthesized data on study design, population, treatment regimen, prostate-specific antigen (PSA) response, and progression-free survival (PFS).
Among the 14 studies, four were randomized trials: three phase II trials and one phase III. Six studies were prospective or retrospective single-arm or pilot cohorts, and four were dosimetry-focused studies. Lu-177-PSMA-617 was evaluated as monotherapy or combined with androgen deprivation therapy (ADT), chemotherapy, stereotactic body radiation therapy (SBRT), or tandem alpha-emitter therapy.
According to the findings, PSA50 response rates (the number of patients with at least a 50% drop in PSA) ranged from 44% to 100% across studies, with the strongest responses in treatment-naive, de novo patients. In an exploratory pooled analysis of six studies (n = 117), the PSA50 rate was 62.7%.
Toxicity was generally mild, with fatigue, xerostomia, and low-grade cytopenias most common, the researchers reported. Grade III or higher adverse events were infrequent, and dosimetry studies confirmed radiation exposure to the kidneys and bone marrow stayed within safe thresholds.
Four randomized trials reported improved outcomes with Lu-177-PSMA-617-based regimens compared with their control arms:
UpFrontPSMA: Lu-177-PSMA-617 plus docetaxel and ADT improved biochemical PFS to 31.0 months versus 20.2 months with docetaxel and ADT alone (p = 0.039).
CONSOLIDATE: Lu-177-PSMA-617 consolidation therapy improved radiographic PFS to 18.0 months (95% CI, 9–27) versus 9.0 months (95% CI, 4–14) with ADT alone.
LUNAR: Neoadjuvant Lu-177-PSMA-617 plus SBRT improved PFS to 17.6 months versus 7.4 months with SBRT alone (HR 0.37, p < 0.0001).
PSMAddition (interim): Adding Lu-177-PSMA-617 to ADT plus an ARPI improved radiographic PFS (HR 0.72, p = 0.002) versus ADT plus ARPI alone.
“Early clinical evidence suggests that Lu-177 PSMA radioligand therapy is a feasible strategy with predominantly low-grade AEs and demonstrates encouraging signals of antitumor activity for select patients with mHSPC,” the group wrote.
Ultimately, definitive phase III data are required to determine how Lu-177 PSMA-617 RLT compares with established mHSPC therapies and to define the optimal patient population, treatment partners, and sequencing strategy, the researchers concluded.
Read the full study here.
