A first-in-human phase 1 trial has reported encouraging safety and antitumor activity with the novel alpha-emitting radiopharmaceutical therapy (RPT) ²¹²Pb-ADVC001 in patients with advanced prostate cancer. The findings, published in The Journal of Nuclear Medicine through its Late-Breaking Fast Track, demonstrated no dose-limiting toxicities and substantial clinical responses, supporting further investigation of this targeted treatment approach.
Prostate-specific membrane antigen (PSMA)-targeted RPT has become an established treatment strategy for metastatic androgen pathway modulation-resistant prostate cancer (mAPM-R), formerly known as metastatic castration-resistant prostate cancer. Although the beta-emitting radiopharmaceutical ¹⁷⁷Lu-PSMA-617 has demonstrated improvements in overall survival and radiographic progression-free survival, treatment resistance remains a major challenge. Approximately one-third of patients exhibit resistance, while many initial responders eventually experience disease progression, highlighting the need for alternative therapeutic approaches.
Alpha-emitting radiopharmaceuticals may help address this unmet need through their distinct radiation properties. Unlike beta particles, which travel several millimeters through tissue, alpha particles deliver high-energy radiation over a much shorter distance, typically spanning only a few cell widths. Their high linear energy transfer can induce substantial DNA damage in targeted tumor cells while potentially limiting radiation exposure to surrounding healthy tissues. The investigational agent ²¹²Pb-ADVC001 uses lead-212 to deliver targeted alpha radiation to PSMA-expressing prostate cancer cells.
The first-in-human TheraPb phase 1b trial (NCT05720130) evaluated the safety, tolerability, optimal dosing, and preliminary antitumor activity of ²¹²Pb-ADVC001. The study enrolled 22 patients with progressive mAPM-R who had previously received at least one androgen-receptor pathway inhibitor and one taxane chemotherapy regimen, unless contraindicated or declined. Participants received escalating doses ranging from 60 to 200 MBq at intervals of six, four, two, or one week, with up to six administrations across seven dose-schedule cohorts. The primary objective was to determine the recommended phase 2 dose based on dose-limiting toxicities and adverse events, while secondary endpoints included prostate-specific antigen (PSA) response, overall response rate, and radiographic progression-free survival.
After a median follow-up of 14.1 months, no dose-limiting toxicities were observed, and the maximum tolerated dose was not reached, even with weekly administration. The most frequently reported treatment-related adverse events were dry mouth, occurring in 82% of participants, and nausea, reported in 64%. All reported cases of these events were grade 1 or 2, with no grade 4 or 5 treatment-related adverse events or serious treatment-related adverse events. Based on the overall safety and tolerability findings, doses of 160 and 200 MBq were selected for further evaluation in phase 2.
The preliminary efficacy findings were also encouraging. Among the 15 participants treated at the recommended phase 2 dose levels, 12 (80%) achieved a PSA decline of at least 50%. The median radiographic progression-free survival was 11.2 months. Furthermore, the overall response rate was 100%, with centrally confirmed objective responses in all five patients with measurable disease who were evaluable according to Response Evaluation Criteria in Solid Tumours (RECIST). These findings suggest substantial antitumor activity in a population with previously treated, progressive disease.
An important aspect of the TheraPb trial was its evaluation of multiple dosing intervals rather than reliance on a fixed administration schedule. This approach may help optimize treatment exposure and clinical response while maintaining acceptable tolerability. The ability to administer ²¹²Pb-ADVC001 at shorter intervals, including weekly dosing, also provides a rationale for investigating response-adapted treatment schedules and potential combinations with other anticancer agents.
The findings have supported the progression of ²¹²Pb-ADVC001 into phase 2 evaluation, with the selected doses of 160 and 200 MBq being investigated in patients with metastatic prostate cancer. The ongoing development programme includes assessment of induction, maintenance, and response-adapted dosing strategies aimed at improving the depth and durability of treatment responses.
Although these early results indicate promising therapeutic potential, the small sample size, particularly the limited number of patients evaluable for objective response, warrants cautious interpretation. Larger clinical studies are needed to confirm long-term safety and efficacy, determine optimal dosing strategies, and establish whether targeted alpha therapy can provide sustained clinical benefits for patients with advanced prostate cancer, including those who develop resistance to existing PSMA-targeted treatments.
References
- Hansen AR, Pattison DA, Goh JC, Ngai SS, Ravi Kumar AS, Gan CL, et al. TheraPb phase 1b: first-in-human dose-escalation and optimization study of 212Pb-ADVC001 in PSMA-positive metastatic androgen pathway modulation-resistant prostate cancer. J Nucl Med. 2026;67.