Outcome of (177)Lu-PSMA-617 Radioligand Therapy in Chemo-Refractory Patients with Metastatic Castration-Resistant Early-Onset Prostate Cancer

SIMPLE SUMMARY: The risk of prostate cancer development, the second most commonly occurring cancer in men overall, increases strongly with age. About 10% of patients, however, are diagnosed with early-onset prostate cancer (age at diagnosis: ≤55 years). This is considered to be a distinct clinical and pathological phenotype with a poor prognosis. Generally, prostate cancer cells express high quantities of prostate-specific membrane antigen (PSMA) on their surface. Radioligand therapy is a type of treatment, which, among other available agents, uses the beta-emitting radionuclide (177)Lutetium ((177)Lu) and a PSMA-targeting ligand termed PSMA-617 for internal irradiation of metastatic prostate cancer cells. The aim of our retrospective study was to assess the efficacy and safety of radioligand therapy with (177)Lu-PSMA-617 in early-onset metastasized castration-resistant prostate cancer patients refractory to chemotherapy. Special emphasis was placed on the patients’ response to the treatment and survival. The study provides support for the expected shorter survival compared to heterogenous patient groups. ABSTRACT: The aim of this retrospective study was to assess the outcome of patients with metastasized castration-resistant early-onset prostate cancer refractory to chemotherapy receiving radioligand therapy with (177)Lutetium-PSMA-617 (LuPSMA-RLT). Twenty-five patients of ≤55 years of age at prostate cancer diagnosis, treated with a median of four (IQR 2–6) cycles (mean of 7.7 ± 1.4 GBq per cycle) every 6–8 weeks, were analyzed. Survival outcome was calculated based on the Kaplan–Meier method. The median progression-free survival (PFS) was 3.8 months (95% CI 2.3–5.3), and overall survival (OS) was 8.5 months (95% CI 6.2–10.8). An initial PSA reduction (≥ 50%) was observed in 9/25 (36%) of patients without being significantly associated with OS (p = 0.601). PSA response (PSA decline ≥50% at 12 weeks) was observed in 12/25 (48%) of patients and significantly associated with longer OS (16.0 months, 95% CI 7.4–24.6 vs. 4.0 months, 95% CI 1.1–6.9, p = 0.002). Imaging-based response using (68)Ga-PSMA-11-PET/CT after two to three cycles was seen in 11/25 (44%). Additionally, responders had a significantly longer median PFS (8.7 months, 95% CI 1.3–16.1 vs. 1.9 months, 95% CI 1.7–2.2, p < 0.001) and OS (16.0 months, 95% CI 7.6–24.4 vs. 4.0 months, 95% CI 0.9–7.1; p = 0.002). Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade ≥ 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade ≥ 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline ≥ 1) in 8/17 (47%) of patients. Compared to previous reports, radioligand therapy with (177)Lu-PSMA-617 in metastasized castration-resistant early-onset prostate cancer patients refractory to chemotherapy yields similar response rates with a comparable safety profile, but is associated with shorter survival.