Novel PSMA targeting alpha-emitting radioligand [211At]PSAt-3-Ga inhibits tumor growth and increases survival in a preclinical model of human xenograft prostate cancer

Prostate cancer is one of the most common cancers in men with more than one million new cases diagnosed annually [1, 2]. Prostate cancer diagnosed at a localized stage of disease may be treated by several approaches including surgery and external beam radiation therapy, or surveilled if not requiring immediate treatment [3]. Nonetheless, many patients progress to metastatic disease, at which point androgen deprivation therapy (ADT) in combination with chemotherapy is employed [4, 5]. Despite initial disease control, selection pressure for castration resistant cancer cells often lead to castration resistant prostate cancer (CRPC) and progression [6]. Metastatic CRPC (mCRPC) remains challenging to treat and has a poor prognosis with a median survival of 2–3 years [7]. Despite continued progress, better treatment options for metastasized disease are warranted to improve patient outcome. For this, targeted radioligand therapy (RLT) is gaining prominence in the treatment of mCRPC. As such, the beta-emitter [177Lu]Lu-PSMA-617 gained FDA approval in 2022 based on convincing therapeutic efficacy in patients with mCRPC [8]. This treatment is administered after verifying PSMA expression in malignant tumors by PET imaging and thus deliver localized beta radiation therapy at site of disease. Furthermore, the treatment has shown clinical benefit in taxane-naïve patients [9]. Recently, analogous approaches using alpha emitters have been suggested as a means to improve efficacy, and actinium-225 (225Ac) has shown encouraging effect in patients progressing on [177Lu]Lu-PSMA-617 [10, 11]. Alpha particles boast many fold higher linear energy transfer relative to beta particles, as well as a markedly shorter maximum range in tissue [12]. As such, these characteristics are considered favorable for targeting disseminated disease with limited off-target toxicity and high dose deposition in targeted cells [13, 14]. Of these, astatine-211 (211At) is deemed especially suitable due to a decay chain containing only one alpha emission (225Ac has four) omitting recoiling daughters [15] as well as a short half-life (7.2 h) suitable for peptide labelling while reducing waste management concerns [15]. We have previously published encouraging biodistribution data of a novel radioligand for prostate cancer treatment, [211At]PSAt3-Ga (Fig. 1), a structural derivative of PSMA-617, labelled with the alpha emitter 211At [16]. We demonstrated high tumor retention, acceptable kidney retention, and a low degree of deastatination was evident. Other studies investigating novel [211At]-labeled compounds have evaluated doses ranging from 0.32 to 3.7 MBq [17, 18]. In this brief communication, we hypothesize that a moderate dose of 0.5 MBq [211At]PSAt3-Ga is sufficient to inhibit tumor growth and increase survival in a xenografted mouse model of human prostate cancer with low systemic toxicity.