Phase 1 Dose-Escalation Study of the Rapid-Clearance Radioligand [177Lu]Lu-P17-087 in Metastatic Castration-Resistant Prostate Cancer: Dosimetry, Safety, and Preliminary Efficacy.

Given the rapid systemic clearance and favorable kinetic profile of the novel DOTA(GA)2-conjugated ligand [177Lu]Lu-P17-087, this phase 1 study aimed to systematically evaluate the safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of escalating therapeutic activities in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Nine patients with progressive mCRPC and high prostate-specific membrane antigen (PSMA) expression on PET/CT were enrolled. An adaptive intrapatient dose-escalation protocol was used, with administered activities categorized as low (1.1-2.3 GBq), mid (3.7-5.6 GBq), and high (∼7.4 GBq). Serial whole-body planar scintigraphy (1-96 h postinjection) and quantitative SPECT/CT (24 h postinjection) were acquired for dosimetry analysis using OLINDA/EXM. Safety was assessed per Common Terminology Criteria for Adverse Events version 5.0. Antitumor efficacy was evaluated by prostate-specific antigen (PSA) response and radiographic response using PSMA PET/CT (RECIP 1.0). Activity-associated PSA changes were summarized descriptively across administered activity levels. Results: [177Lu]Lu-P17-087 exhibited rapid pharmacokinetics (effective half-life of 0.52 h in blood). This fast-clearance profile yielded low absorbed doses to dose-limiting organs, including the kidneys (0.39 ± 0.26 Gy/GBq) and red marrow (0.07 ± 0.01 Gy/GBq). Conversely, lesions showed sustained retention, particularly in lymph node metastases (half-life, 22.9 h). The dose-escalation regimen was well tolerated; no dose-limiting toxicities or grade 3/4 hematologic adverse events were observed, even at the maximum administered activity of 7.4 GBq. Biochemical response was observed in most patients, with 8 of 9 (88.9%) demonstrating a decline in PSA levels from baseline. A 50% decline from baseline in PSA was achieved in 2 of 9 patients (22.2%). The magnitude of PSA reduction varied across administered activity levels. Conclusion: This phase 1 dose-escalation study showed rapid in vivo clearance of [177Lu]Lu-P17-087 and low early normal-organ toxicity in this small cohort. Administration of activities up to 7.4 GBq per cycle was feasible and was associated with preliminary antitumor activity. Larger studies with longer follow-up are required to define efficacy, safety, and the optimal dosing strategy.