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Prostate Cancer Treatment and Research / Prostate Cancer Diagnosis and Treatment · Journal article
European Radiology Experimental · August 18, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a first-in-human, open-label study of the novel alpha-emitter 225Ac-PSMA-CY313 in 16 heavily pretreated mCRPC patients. The agent showed a manageable safety profile with predominantly grade-1 xerostomia (75% of patients), mild-to-moderate hematologic toxicities, a PSA50 response rate of 37.5%, and radiographic response of 31.3%; the authors acknowledge that efficacy and comparative safety conclusions require validation in larger prospective trials.
Prospective, open-label, single-arm first-in-human study. Heavily pretreated patients with progressive metastatic castration-resistant prostate cancer refractory to standard therapies. Intervention: 225Ac-PSMA-CY313 200 μCi intravenously every 8 weeks. n = 16.
Xerostomia occurred in 75% of patients, predominantly grade 1 (68.8%), with one grade 2 case; no grade 4 toxicities or treatment-related deaths PSA50 response was 37.5% (95% CI: 15.2%–64.6%) with median PSA change of 18.1% (range: −143.0% to 100.0%) Radiographic response was 31.3% (95% CI: 11.0–58.7%); disease control rate (partial response + stable disease) was 62.5% (95% CI: 35.4–84.8%)
Source does not report follow-up duration, progression-free survival, overall survival, or long-term toxicity data Xerostomia occurred in 75% of patients, predominantly grade 1 (68.8%), with one grade 2 case; no grade 4 toxicities or treatment-related deaths
This preliminary finding suggests 225Ac-PSMA-CY313 may offer a favorable safety-efficacy profile as a next-generation PSMA-targeted alpha therapy for advanced mCRPC patients with limited options; however, the open-label, single-arm design with small sample size means these results require confirmation in controlled, larger prospective trials before clinical recommendations can be made.
First-in-human, open-label, single-arm study of 16 heavily pretreated patients with surrogate and radiographic endpoints; demonstrates feasibility and signal but requires larger prospective validation before clinical impact can be determined.
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This preliminary finding suggests 225Ac-PSMA-CY313 may offer a favorable safety-efficacy profile as a next-generation PSMA-targeted alpha therapy for advanced mCRPC patients with limited options; however, the open-label, single-arm design with small sample size means these results require confirmation in controlled, larger prospective trials before clinical recommendations can be made.
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Abstract 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 225 Ac exhibits superior cytotoxicity compared with beta-emitting radiopharmaceuticals; however, dose-limiting xerostomia from salivary gland accumulation restricts clinical application. 225 Ac-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 225 Ac-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 225 Ac-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, 225 Ac-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 225 Ac-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 225 Ac-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.
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