Alpha-particle PRRT is being evaluated in clinical trials for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), both after disease progression on beta-particle PRRT and in patients who are PRRT naive. Early data suggest that alpha-particle PRRT is tolerable and may be an effective treatment option for patients who have previously received beta-particle PRRT.

The field of theranostics is growing, and the use of PRRT to treat SSTR-positive NETs has transformed the way we care for patients with NETs. The PRRT agent that we routinely use in clinical practice is the beta-emitting radioisotope ¹⁷⁷Lu-dotatate. An exciting area right now from a patient care and research standpoint relates to alpha-particle–emitting PRRT. Alpha particles have a potential mechanistic advantage over beta particles, with a higher linear energy transfer that may increase the likelihood of double-stranded DNA breaks that can kill cancer cells. They also have a shorter tissue range that may lower the rate of nontarget, radiation-induced adverse events.

Trials have evaluated the efficacy of alpha-emitting PRRT agents, including ²²⁵Ac-dotatate and ²¹²Pb-dotamtate, and these single-arm, prospective studies have reported very encouraging disease control rates and objective response rates. Randomized trials are now being conducted. For example, the ongoing, randomized, phase 1b/3 ACTION-1 trial is evaluating ²²⁵Ac-dotatate in the retreatment setting for patients with SSTR-positive GEP-NETs whose disease has progressed following prior ¹⁷⁷Lu-SSA therapy. The phase 1b data showed that the most common grade 3 and higher adverse events observed with ²²⁵Ac-dotatate included anemia and lymphopenia, but there were no dose-limiting toxicities and no treatment-related serious adverse events leading to drug discontinuation. The confirmed objective response rate was 29% in the phase 1b part of the trial. The phase 3 part of the trial will compare PRRT retreatment with ²²⁵Ac-dotatate vs standard-of-care treatment, including everolimus, sunitinib, or high-dose SSA therapy.

There are also trials evaluating the use of alpha-particle PRRT in the frontline setting for patients with SSTR-positive GEP-NETs who have not received treatment with PRRT. ²¹²Pb-dotamtate has been evaluated in phase 1 and 2 studies in a PRRT-naive population. In the phase 1 trial, the objective response rate was 62% for patients with GEP-NETs who had never received PRRT. The results of the phase 2 trial, which included a larger number of PRRT-naive patients, showed a response rate of 56%. This high response rate and benefit ultimately led to the US Food and Drug Administration (FDA) granting breakthrough therapy designation to ²¹²Pb-dotamtate earlier this year.

Alpha-particle–emitting agents have the potential to advance the field, especially if there is greater efficacy and improved safety. It will be interesting to see whether alpha-emitting PRRT agents are superior to beta-emitting ¹⁷⁷Lu-dotatate, and whether they may become a standard frontline therapy in the future. There is also a lot of interest in trying to understand the role of retreatment with PRRT and how this approach may compare with some of the systemic agents that are currently used to treat NETs.