ANDROMEDA Trial: Alpha vs. Beta PSMA Therapy

The ANDROMEDA phase 2 trialrepresents an advancement in managing recurrent oligometastatic prostate cancer by directly pitting alpha-emitting 225Ac-PSMA-617 against the established beta-emitting 177Lu-PSMA-617 (Pluvicto), both combined with stereotactic body radiotherapy (SBRT). This head-to-head comparison stems from the need to address limitations in current therapies for patients whose cancer returns in 1-5 detectable spots on PSMA-PET, where visible lesions are ablated by SBRT but microscopic disease often escapes, driving progression.

The rationale builds squarely on the phase 2 LUNAR trial, which demonstrated that neoadjuvant 177Lu-PSMA-617 (or the analogous 177Lu-PNT2002) plus SBRT dramatically improved progression-free survival, 17.6 months versus 7.4 months with SBRT alone (HR 0.37, 95% CI 0.22-0.61, P < .0001), in hormone-sensitive oligorecurrent cases, by targeting both imaged metastases and subclinical spread. While beta particles from 177Lu-PSMA-617 penetrate several millimeters, enabling broader coverage but with potential off-target effects, alpha particles from 225Ac-PSMA-617 pack higher linear energy transfer in a sub-millimeter range, offering superior cell-killing potency against resistant micrometastases that PSMA imaging misses.

Investigators hypothesize that a single cycle of 225Ac-PSMA-617 could outperform two cycles of 177Lu-PSMA-617 in eradicating undetectable disease, potentially extending PFS further while minimizing cumulative toxicity like xerostomia or renal strain common to repeated dosing. Administered intravenously 4-6 weeks before SBRT—timed after a confirmatory 68Ga-PSMA-11 PET—the radionuclides exploit PSMA’s overexpression on prostate cancer cells for precise delivery, sparing healthy tissue and aiming to delay or avert androgen deprivation therapy with its burdensome side effects.

By focusing on 24-month PSMA-PET-defined PFS as the primary endpoint, alongside ADT-free survival and quality-of-life metrics, the trial seeks definitive evidence on whether alpha-emission’s intensity translates to more durable control in this vulnerable window before castration resistance sets in.

Clinical trial.