Safety and Efficacy of (177)Lutetium-PSMA-617 Radioligand Therapy Shortly after Failing (223)Radium-Dichloride

SIMPLE SUMMARY: The alpha emitter (223)Radium-dichloride ((223)Ra) and the beta emitter (177)Lutetium ((177)Lu) targeting the prostate-specific membrane antigen (PSMA) are sequentially used for therapy of advanced bone-metastatic castration-resistant prostate cancer. Despite routine performance in patients who had received (223)Ra, it is not clear whether disease sites refractory to alpha radiation can be effectively treated with (177)Lu-PSMA-617. Secondly, it remains to be elucidated if therapy with (177)Lu-PSMA-617 can be safely performed shortly after (223)Ra, bearing in mind the myelotoxic potential of both treatments. The aim of our retrospective study was to evaluate safety and efficacy of (177)Lu-PSMA-617 within less than 8 weeks after failing (223)Ra. Radioligand therapy with (177)Lu-PSMA-617 shortly after failing (223)Ra is effective and can result in long-standing disease control even in patients with disseminated or diffuse bone involvement. Patients with oligo- and multifocal bone metastases show significantly longer overall survival with lower risk of significant hematotoxicity compared to patients with disseminated/diffuse involvement. ABSTRACT: Bone-seeking (223)Radium-dichloride ((223)Ra) is an established treatment prolonging survival and reducing morbidity in selected patients with metastatic castration-resistant prostate cancer (mCRPC) with skeletal involvement. Radioligand therapy with (177)Lutetium-PSMA-617 ((177)Lu-PSMA-617) has been increasingly implemented in patients with mCRPC failing conventional treatment options. In this study, the safety and efficacy of (177)Lu-PSMA-617 in patients with progressive bone involvement under treatment with (223)Ra was assessed. Twenty-eight men (median age 73 years, range 63–89 years) with progressive mCRPC, who started (177)Lu-PSMA-617 within 8 weeks after the last (223)Ra administration, received a median of 4 (IQR 3–6) and a total of 120 cycles of (223)Ra and a median of 4 (IQR 2–7) cycles (177)Lu-PSMA-617 with a mean treatment activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA response (≥50% PSA decline 12 weeks after the first (177)Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients. Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6–14) months and median overall survival (OS) was 18 (95% CI, 14–22) months. Patients with low bone tumor burden (2–20 lesions) had a significantly longer OS (28 vs. 14 months, p < 0.045) compared to patients with a high tumor burden (>20 lesions). Grade ≥ 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively. In progressive bone-metastatic mCRPC patients, prompt initiation of (177)Lu-PSMA-617 after failing (223)Ra is effective with an acceptable toxicity profile.