Evaluation of the safety and efficacy of 225Ac-PSMA-CY313 in metastatic castration-resistant prostate cancer: preliminary results.

OBJECTIVE: Metastatic castration-resistant prostate cancer (mCRPC) remains associated with poor long-term outcomes, and survival under current treatment is modest. Prostate-specific membrane antigen (PSMA)-targeted alpha therapy using 225Ac exhibits superior cytotoxicity compared with beta-emitting radiopharmaceuticals; however, dose-limiting xerostomia from salivary gland accumulation restricts clinical application. 225Ac-PSMA-CY313 is a next-generation radioligand designed to reduce off-target salivary uptake while maintaining tumor-targeting efficacy. We evaluated the safety and preliminary efficacy of 225Ac-PSMA-CY313 in heavily pretreated mCRPC patients. MATERIALS AND METHODS: This prospective, open-label, single-arm study enrolled 16 patients with progressive mCRPC refractory to standard therapies. Patients received 225Ac-PSMA-CY313 (200 μCi intravenously every 8 weeks). The primary endpoint was treatment-related toxicity per NCI-CTCAE v5.0. Secondary endpoints included ≥ 50% PSA decline (PSA50) and radiographic response per RECIST 1.1/PCWG3. RESULTS: Xerostomia occurred in 75% of patients, predominantly grade-1 (68.8%), with one grade-2 case. Hematologic toxicities were mild-to-moderate: anemia 68.8% (grade 3: 6.3%), leukopenia 25.0% (all grade 1-2). No grade 4 toxicities or treatment-related deaths occurred. Significant laboratory changes included hemoglobin decrease (117.7 ± 19.2 versus 105.0 ± 19.7 g/L, p = 0 .012). PSA50 response was 37.5% (95% confidence interval [CI]: 15.2%-64.6%), with a median PSA change of 18.1% (range: -143.0% to 100.0%). Radiographic response was 31.3% (95% CI: 11.0-58.7%), and the disease control (partial response + stable disease) rate was 62.5% (95% CI: 35.4-84.8%). CONCLUSION: In this first-in-human study of 16 patients, 225Ac-PSMA-CY313 showed a manageable safety profile with predominantly low-grade xerostomia, a PSA50 response of 37.5%, and an image-based response of 31.3%. Conclusions regarding efficacy and comparative safety require validation in larger prospective trials. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2400083275, Registered 19 April 2024. https://www.chictr.org.cn . KEY POINTS: Question What are the safety and efficacy outcomes of the novel alpha-emitting radiopharmaceutical 225Ac-PSMA-CY313 in advanced mCRPC? Findings This first-in-human study demonstrates that ²²⁵Ac-PSMA-CY313 produces high PSA response rates with predominantly mild to moderate reversible adverse events. Relevance statement 225Ac-PSMA-CY313 showed promise as a next-generation PSMA-targeted α-therapy with a favorable safety-efficacy profile for advanced prostate cancer patients with limited therapeutic options, supporting its further clinical development.