Abstract
Simple SummaryRadioligand therapy (RLT) with prostate-specific membrane antigen (PSMA)-directed agents has shown remarkable results in patients with advanced prostate cancer. Our objective was to provide data on the side effect profile of PSMA-directed RLT using the therapeutic radiotracer [177Lu]Lu-PSMA I&T. We evaluated patients with castration-resistant metastatic prostate cancer treated with at least three cycles of [177Lu]Lu-PSMA I&T. A substantial fraction of the patients already had impaired renal function and/or reduced white blood cell counts at baseline, but the degree of nephrotoxicity or hematotoxicity under RLT was low. No severe toxicities occurred under RLT.(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [177Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [177Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [99mTc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman’s rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = −0.40, p = 0.005) and the eGFR change with Gleason score (r = −0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [177Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.
Highlights
In recent years, therapeutic regimens for patients with metastatic castration-resistant prostate cancer have been expanded by novel drug developments, e.g., the nextgeneration androgen receptor signaling inhibitors abiraterone and enzalutamide [1,2], or chemotherapy with docetaxel or cabazitaxel [3,4,5]
Further advances include the introduction of prostate-specific membrane antigen (PSMA)-directed diagnostic agents and their therapeutic equivalents, which have been evaluated in prospective trials with remarkable outcomes in advanced disease [6,7,8,9,10]
In the TheraP-trial investigating [177 Lu]Lu-PSMA-617 vs. cabazitaxel, grade III/IV adverse events occurred in 33% of 98 patients in the radioligand therapy (RLT)
Summary
Therapeutic regimens for patients with metastatic castration-resistant prostate cancer (mCRPC) have been expanded by novel drug developments, e.g., the nextgeneration androgen receptor signaling inhibitors abiraterone and enzalutamide [1,2], or chemotherapy with docetaxel or cabazitaxel [3,4,5]. MCRPC patients treated with radioligand therapy (RLT) using [177 Lu]-PSMA only experienced mild side effects, with kidneys and bone marrow as organs at risk. Nephropathy was reported in only 13% of the patients with very few grade III/IV toxicities [11] Those retrospective reports have been further corroborated in a prospective setting, in particular by using [177 Lu]Lu-PSMA-617. The recently published Lu-PSMA trial reported on grade III/IV lymphopenia, thrombopenia, anemia, and neutropenia in up to 32% of the cases, whereas for the kidneys, only grade I/II events were reported in 10% of the treated patients [8]. In the TheraP-trial investigating [177 Lu]Lu-PSMA-617 vs cabazitaxel, grade III/IV adverse events occurred in 33% of 98 patients in the RLT arm. In the VISION trial, the largest prospective cohort studied to date, 52.7% of the patients showed events of ≥grade
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