At a recent major oncology conference, Professor Fred Saad from the University of Montreal Hospital Center delivered an oral presentation on the latest findings of the PANTHER study (Abstract 19). This study reported the first-in-human phase 1 dose-escalation results of a novel PSMA-targeted radioligand therapy (RLT)—Actinium-225-PSMA-trillium (225Ac-PSMA-trillium)—in patients with metastatic castration-resistant prostate cancer (mCRPC), bringing a new treatment strategy and hope to heavily pretreated patients.01 Background and Mechanism: A Novel PSMA-Targeted Radioligand Therapy
Currently, radioligand therapies (RLTs), such as Radium-223 and 177Lu-PSMA, have proven to be both safe and efficacious. Compared to traditional beta-emitters, developing PSMA-targeted agents that emit alpha particles offers significant theoretical advantages: alpha particles deliver higher linear energy transfer (LET) with a shorter tissue penetration range, thereby potently eradicating tumor cells while minimizing damage to surrounding healthy tissues. 225Ac-PSMA-trillium is a trifunctional macrocyclic compound developed based on this mechanism, designed to achieve stable chelation of Actinium-225, thereby improving both efficacy and safety.
02 Study Design and Baseline Characteristics: Focusing on Heavily Pretreated mCRPC
The dose-escalation phase of the PANTHER study enrolled mCRPC patients who had progressed on at least one androgen receptor pathway inhibitor (ARPI) and one taxane-based chemotherapy.
- Dosing Regimen: The study evaluated four ascending dose cohorts: 75, 100, 125, and 150 kBq/kg. Patients received up to four intravenous infusions at 6-week intervals. In the absence of observed dose-limiting toxicities (DLTs), backfill patients were added to individual dose levels to establish the recommended dose for the expansion phase.
- Baseline Characteristics: A total of 50 patients were included, with highly similar baseline characteristics across all dose levels. Notably, 80% of patients completed all 4 cycles of treatment, with a median of 4 cycles received, demonstrating favorable clinical compliance.
03 Safety Data: Well-Tolerated with No Dose-Limiting Toxicities Observed
Safety evaluations showed that the overall safety profile of 225Ac-PSMA-trillium was manageable.
- Toxicities: No DLTs were observed at any dose level, and there were no treatment-related deaths. Almost no patients required dose modifications until the highest dose cohort (150 kBq/kg), where 3 out of 13 patients required a dose reduction. In the overall population, only 6% of patients discontinued treatment due to adverse events (AEs).
- Specific Adverse Events: Xerostomia (dry mouth) was the most commonly reported AE, occurring in 86% of patients; however, the vast majority were Grade 1, with no Grade 3 or 4 xerostomia events observed. Following xerostomia, the most common AEs were Grade 1 fatigue, nausea, and decreased appetite.
04 Efficacy Performance: The 125 kBq/kg Cohort Demonstrates Deep Imaging and Biochemical Responses
The study demonstrated that 225Ac-PSMA-trillium induced deep biochemical responses (PSA responses) across all dose levels.
- Overall Population: The overall PSA50 (≥50% decline in PSA from baseline) response rate was 62%, and the PSA90 response rate was 40%. In the overall population, a 50% objective response rate by RECIST criteria was achieved.
- 125 kBq/kg Optimal Dose Cohort: The efficacy data in this cohort were particularly outstanding, with a PSA50 response rate of 83%, a PSA90 response rate of 67%, and an overall RECIST response rate of 71%. Based on a comprehensive assessment of safety and efficacy, the research team identified 125 kBq/kg as the recommended dose for the subsequent expansion phase.
- Imaging Correlation: PSA responses were observed across all mean PSMA SUV levels. Data showed that among patients who achieved a PSA50 response, 93% had a mean PSMA SUV greater than 10.
05 Exploratory Biomarkers and Case Sharing: Significant ctDNA Clearance and Durable Responses
In addition to standard clinical parameters, the study conducted exploratory circulating tumor DNA (ctDNA) analyses.
- ctDNA Dynamics: Declines in ctDNA were observed at all dose levels and correlated well with PSA responses. In the 125 kBq/kg dose cohort, there was an 89% decline in ctDNA, with 36% of patients achieving complete ctDNA clearance, further confirming the robust antitumor activity at this dose.
- Typical Cases: Prof. Fred Saad shared representative cases from the 125 kBq/kg cohort during the meeting. In one patient, imaging showed near-complete disappearance of visible lesions after 2 cycles of treatment, with PSA declining to almost undetectable levels; this deep, durable response was maintained for over one year.
Conclusion and Outlook
Prof. Fred Saad concluded that the phase 1 results of the PANTHER study robustly confirm the safety and remarkable antitumor activity of 225Ac-PSMA-trillium in heavily pretreated mCRPC patients. Based on the 83% PSA50 response rate and 71% overall RECIST response rate, 125 kBq/kg has been established as the recommended dose and is currently being utilized in the expansion phase of the study.
Currently, the expansion cohorts are evaluating the efficacy of this therapy in mCRPC populations, including post-chemotherapy, pre-chemotherapy, and post-177Lu-PSMA RLT settings. The phase 1 data presented not only lay the foundation for the ongoing expansion study but will also directly inform the design of future phase 3 clinical trials evaluating this agent in mCRPC, potentially bringing a more precise and highly efficacious targeted RLT option for patients with advanced prostate cancer.
