Salvage Radioligand Therapy with Repeated Cycles of (177)Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer with Diffuse Bone Marrow Involvement

SIMPLE SUMMARY: Metastatic castration-resistant prostate cancer (mCRPC) with extensive spread to the bone marrow is an incurable stage of disease associated with a poor prognosis and a high risk of impaired blood cell formation. Therapeutic options prolonging survival are limited and may result in significant bone marrow toxicity. The concept of radioligand therapy (RLT) in mCRPC is marked by the targeted delivery of radionuclides, such as beta particle emitting (177)Lutetium ((177)Lu) to the prostate-specific membrane antigen (PSMA), a transmembrane protein frequently present on prostate cancer cells. RLT has yielded promising anti-tumoral activity and excellent tolerability in patients with mCRPC as shown by multiple retrospective series and a growing number of prospective trials. The presented study aims to investigate the role of RLT in mCRPC patients with metastases diffusely involving the bone marrow. Special emphasis is laid on identifying early indicators for a favorable treatment response and potential risk factors for adverse outcomes. The impact of RLT-specific variables, including administered treatment activity, cumulative activity and whole-body absorbed dose is assessed individually. ABSTRACT: Advanced stage metastatic prostate cancer with extensive bone marrow involvement is associated with a high risk of therapy-induced myelotoxicity and unfavorable outcomes. The role of salvage radioligand therapy (RLT) with (177)Lu-PSMA-617 in this subset of patients remains to be further elucidated. Forty-five patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and diffuse bone marrow involvement were treated with repeated cycles of RLT after having exhausted standard treatment options. A mean treatment activity of 7.4 ± 1.4 GBq (177)Lu-PSMA-617 was administered in a median of four treatment cycles (IQR 2-6) and the mean cumulative activity was 32.6 ± 20.1 GBq. After two RLT cycles, ≥50% PSA decline was observed in 25/45 (56%) patients and imaging-based partial remission (PR) was observed in 18/45 (40%) patients. Median imaging-based progression-free survival (PFS) was 6.4 mo (95% CI, 3.0–9.8) and the median overall survival (OS) was 10.2 months (95% CI, 7.2–12.8). The biochemical response translated into a significantly prolonged PFS (12.9 vs. 2.8 mo, p < 0.001) and OS (13.5 vs. 6.7 mo, p < 0.001). Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18–8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000–1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade ≥ 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively. Cumulative treatment activity and absorbed whole-body dose were not correlated with new onset grade ≥ 3 hematotoxicity (p = 0.91, p = 0.69). No event of grade ≥ 3 chronic kidney disease was observed during RLT or the follow-up. Last line RLT with (177)Lu-PSMA-617 in mCRPC patients with diffuse bone marrow involvement may thus contribute to prolonged disease control at an acceptable safety profile.