Radioligand Treatment with [177Lu]Lu-PSMA I&T in the Older Patients - Safety, Efficacy, and Prognostic Factors for Survival

Introduction: The peak incidence of prostate cancer (PC) is over 75 years of age, making elderly patients a major target population for novel treatment options. We aimed to evaluate the safety and efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) using [177Lu]Lu-PSMA I&T in individuals at least 75 years of age, including predictors of overall survival (OS).

Methods: Fifty-six men (≥75 years) with metastatic castration-resistant PC (mCRPC) treated with PSMA RLT using [177Lu]Lu-PSMA I&T were identified. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 by assessing hematologic (platelets, leukocytes, hemoglobin) and renal (eGFR, creatinine) parameters. In addition, baseline liver parameters (including aspartate aminotransferase (AST) and alkaline phosphatase (AP)), lactate dehydrogenase (LDH), C-reactive protein (CRP) and Gleason score were recorded. PSA response was determined at every cycle after initiation of RLT (available for 47 patients). Metastatic spread was determined in bone, lymph nodes, liver and lung. Quantitative PET parameters including mean, peak and maximum SUV, PSMA positive tumor volume (PSMA-TV) and total PSMA lesion (TL-PSMA = PSMA-TV*SUV mean) were also determined. In 37 patients with available interim PSMA PET/CT after two cycles, changes from baseline (providing Δ) were determined and PET response was classified according to RECIP 1.0, while biochemical response according to PCWG3 criteria. Univariable Cox regression was performed, followed by multivariable and Kaplan-Meier analyses to determine the association with OS.

Results: Treated patients were diagnosed with an initial Gleason score of 8 (5-10) and presented with a median age at first cycle of 78 years (range, 75-95). A median cumulative activity of 18.2 GBq (range, 4.9-54.8 GBq) [177Lu]Lu-PSMA I&T was administered in a median of 3 (range, 1-9) cycles of RLT. No CTC grade ≥III occurred after RLT, but the following grade I/II hematologic CTCAEs were observed: anemia in 21%, followed by leukocytopenia in 17% and thrombocytopenia in 7%. eGFR decreased by 2.5%, with grade I/II CTCAE in 19% (creatinine increase 5%; creatinine CTCAE grade I/II, 14%). Median OS was 11 months, while 34/56 (60.7%) patients died. 38/47 (80.9%) showed a decrease in PSA after therapy with a median decrease of 57% (range, 0.6 - 99%), 23/38 achieved a decrease of more than 50%.In univariable analysis, the following parameters were significantly associated with OS: PSA, CRP, LDH, AST, AP, and hemoglobin (p<0.05, each). We included PSA, CRP and LDH in a multivariable Cox regression and additionally adjusted for PSMA-TV. Baseline PSA (per ng/ml, HR, 1.001 [95%CI, 1.000-1.002]; P<0.1), LDH (per U/l, HR, 1.008 [95%CI 1.002-1.013]; P<0.01) remained significant prognosticators for OS, while PSMA-TV and CRP did not. Kaplan-Meier analysis showed no significant difference in OS for patients with progressive disease (PD) according to RECIP or PCWG3 alone, but the combination of both criteria showed a significantly shorter OS (11 vs. 22 months, HR, 3.3 [95%CI 0.9-11.5]; P<0.01) in patients with PD. Patients with any PSA response after RLT showed a longer OS (21 vs. 7 months, HR, 0.3 [95%CI 0.1-1.2]; P<0.01).

Conclusions: RLT with [177Lu]Lu-PSMA I&T is safe in patients older than 75 years and showed results comparable to previous studies including also men of younger age. Initial lower PSA and LDH were associated with longer OS in these patients, while PSMA-TV was not. Patients who have a decrease in PSA after starting RLT have a significantly longer OS, highlighting the importance of biochemical response to RLT. A combination of RECIP and PCWG3 should be preferred to assess response.

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