177Lu-PSMA-617 then 225Ac-PSMA rescue therapy

225Ac-PSMA-617 or 225Ac-PSMA-I&T alpha-particle radioligand therapy is used, mainly outside the United States where actinium-225 is more accessible (for example in Germany), as salvage treatment for metastatic castration-resistant prostate cancer that has progressed after beta-emitting 177Lu-PSMA radioligand therapy (such as Pluvicto) plus prior androgen-receptor pathway inhibitors and taxane chemotherapy. Zacherl et al. (J Nucl Med 2021) reported the first dedicated series: of 14 patients treated with 225Ac-PSMA-I&T, 11 (79%) had previously received 177Lu-PSMA; 50% achieved a PSA decline of 50% or more, with median progression-free survival of 3.1 months and median overall survival of 7.7 months.

A subsequent meta-analysis of retrospective 225Ac-PSMA-617 series (largely post-177Lu-PSMA patients) found pooled rates of 87% for any PSA decline and 66% for a PSA50 response, with pooled median overall survival of 12.5 months and progression-free survival of 9.1 months, and a molecular imaging response in 54% of patients — activity that the authors describe as clinically meaningful in a population that has exhausted other options, achieved with relatively low toxicity (xerostomia is the dominant, often dose-limiting, side effect; haematological toxicity is generally milder than with 177Lu-PSMA). A larger, more recent single-centre series (2025) similarly reported a median overall survival around 7 months in a mixed population, ranging up to 39 months in favourable cases.

Importantly, multiple groups note that patients who progressed on 177Lu-PSMA before starting 225Ac-PSMA have inferior outcomes compared with alpha-therapy-naive patients (a 2022 series found a 45% versus 50% PSA50 rate, and a 2021 Ezziddin group series used 225Ac-PSMA as an 'augmentation' added to, rather than purely after, 177Lu-PSMA cycles, reporting median PSA-progression-free survival of 9.1 months and overall survival of 14.8 months). 225Ac-PSMA remains investigational (not FDA- or EMA-approved) and randomised trials comparing it against other post-177Lu-PSMA options are still needed; it is generally reserved for salvage use in patients with adequate marrow reserve who have exhausted approved options.