Cancer-control outcomes with [¹⁷⁷Lu]Lu-PSMA Radioligand Therapy in elderly, frail or comorbid mCRPC patients

<b>Rationale:</b> [¹⁷⁷Lu]Lutetium prostate-specific membrane antigen radioligand therapy ([¹⁷⁷Lu]Lu-PSMA) is EMA-approved for certain indications in metastatic castration resistant prostate cancer (mCRPC). However, cancer-control outcomes in specific and trial-underrepresented subgroups are scant. <b>Methods:</b> We relied on the FRAMCAP database to elaborate progression-free (PFS) and overall (OS) survival in elderly (≥75 yrs), frail (ECOG status ≥1) mCRPC patients or those with cardiovascular disease (CVD) treated with [¹⁷⁷Lu]Lu-PSMA. <b>Results:</b> Of 312 [¹⁷⁷Lu]Lu-PSMA mCRPC patients, 76% were ≤75 vs. 24% >75 years. Patients >75 years received [¹⁷⁷Lu]Lu-PSMA more frequently within the first three mCRPC lines (85% vs. 62%) and harbored more frequently ECOG status ≥2 (13% vs. 4.3%, both p < 0.01). In PFS and OS analyses, no significant difference between patients aged ≤75 vs. >75 years was observed (hazard ratios [HR] 0.97 & 0.85, both p≥0.4) with median PFS of 12.7 vs. 11.7 and OS of 15.1 vs. 19.8 months. In ECOG-stratified analyses, no PFS difference was observed, with significantly better OS for ECOG 0 vs. ≥1 (HR 1.69, p < 0.01), but not after further multivariable adjustment. In CVD-stratified analyses, PFS failed to provide significant differences between CVD vs. no CVD (HR: 1.44, p = 0.051). However, in OS analyses, significant worse OS for CVD mCRPC [¹⁷⁷Lu]Lu-PSMA patients was observed (HR: 1.93, p < 0.01). After multivariable adjustment, CVD was an independent predictor for worse PFS and OS (both p < 0.01). <b>Conclusions:</b> Real-world evidence suggests equally effective cancer-control outcomes in elderly and frail mCRPC patients treated with [¹⁷⁷Lu]Lu-PSMA. However, patients with CVD are of higher risk for shorter PFS and OS.