New alpha-emitting radiopharmaceutical therapy achieves strong responses in advanced prostate cancer

A new alpha-emitting radiopharmaceutical therapy (RPT) for advanced prostate cancer was well tolerated, with no dose-limiting toxicities observed, and showed encouraging signs of antitumor activity, according to a phase 1 trial published in The Journal of Nuclear Medicine's Late-Breaking Fast Track. Among patients treated with ²¹²Pb-ADVC001, 80 percent experienced a decline in prostate-specific antigen (PSA) levels of at least 50 percent, and the overall response rate was 100 percent. The findings support further clinical development of ²¹²Pb-ADVC001 to address the significant unmet needs in metastatic prostate cancer.

Prostate-specific membrane antigen (PSMA)–targeted RPT is an established treatment for metastatic androgen pathway modulation-resistant prostate cancer (mAPM-R, formerly metastatic castration-resistant prostate cancer). Although ¹⁷⁷Lu-PSMA-617, a beta-emitting RPT, has shown improved overall and radiographic progression-free survival in pivotal trials, approximately one-third of patients are resistant to ¹⁷⁷Lu-PSMA, and most responders progress during, or soon after treatment.

"Current RPTs use fixed dosing regimens that do not account for variability in tumor response," said the study authors. "These limitations highlight the need for novel treatment strategies that may enhance patient outcomes using more potent payloads and optimization of dose and schedule."

Alpha-emitting RPTs have emerged as a new treatment approach: unlike beta emitters such as ¹⁷⁷Lu, which release lower-energy particles that travel up to a couple of millimeters, alpha emitters release high-energy particles that travel only a few cell widths, delivering concentrated radiation to cancer cells while sparing surrounding healthy tissue. The TheraPb phase 1 trial, a first-in-human study, evaluated both escalating doses and dosing frequency of the alpha-targeting RPT ²¹²Pb-ADVC001.

The study included 22 participants with progressive mAPM-R previously treated with an androgen-receptor pathway inhibitor and taxane chemotherapy. Escalating doses of 60–200 MBq of ²¹²Pb-ADVC001 were administered at prespecified intervals every six, four, two, or one week for up to six doses across seven dose-schedule cohorts. Researchers examined dose-limiting toxicities and adverse events to recommend doses for a phase 2 trial. They also evaluated PSA response, radiographic progression-free survival, and overall response rate.

No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. The most common treatment-related adverse events were dry mouth and nausea, and no serious adverse events occurred. Given these findings, the study committee selected 160 and 200 MBq as the recommended doses for phase 2 of TheraPb. In this early-phase study, 80 percent of participants had a PSA decline of 50 percent or more and the median radiographic progression-free survival was 11.2 months. The overall response rate was 100 percent. 

"Flexibility in dosing, together with the overall safety profile of ²¹²Pb-ADVC001, further provides a rationale for evaluating combination strategies with other anti-cancer agents to maximize clinical outcomes," stated the authors.

JNM's Late-Breaking Fast Track is a highly selective, accelerated publication pathway reserved for high-impact, time-sensitive data of exceptional interest to the nuclear medicine and molecular imaging community. The track welcomes high-signal, practice-changing phase 2/3 clinical trials, as well as highly innovative, first-in-human phase 1 trials demonstrating profound scientific novelty and clinical urgency.