The PSMAfore protocol was FDA approved on March 28, 2025, moving the option of using [177Lu]-PSMA-617 front-forward in early progressive metastatic castration-resistant prostate cancer (mCRPC). Currently, metastatic castration-resistant PC is treated with Lupron alone (or a similar drug such as Orgovyx, Degarelix or Zoladex) combined with an androgen receptor pathway inhibitor (ARPI) such as Enzalutamide, Apalutamide or Darolutamide; or Zytiga, an androgen biosynthesis inhibitor).
The PSMAfore protocol studied a comparison of 177Lu (Pluvicto) to an alternative second-line ARPI after progression on initial hormone suppression. Earlier studies have found chemotherapy more effective than a second-line ARPI, but chemotherapy might not be chosen due to greater toxicity or patient preference. The rationale for the protocol was to address the relative ineffectiveness of second-line hormone suppression after progression on an initial hormone suppressor.
Enrollment required at least one PET/CT positive lesion, but no PET negative lesions imaged only on CT. In advanced metastatic disease 23-30% of patients lose the PSMA target or have transformed to neuroendocrine type lesions that lack PSMA expression. These lesions would not be expected to respond to Pluvicto. Eligibility excluded men in whom chemotherapy could appropriately be delayed. The study excluded men who were candidates for PARP inhibition, with i.e., Olaparib, which in practice, might appropriately be prescribed following progression on the first hormone therapy.
The baseline median PSA of the men in the study was 14.9 – 18.4; ng/mL. Metastases to bone occurred in ~87% and in lymph nodes, ~32%. The median time to radiographic progression for Pluvicto was ~11 months vs ~4 months for the second-line ARPI. Pluvicto was administered every 6 weeks for 6 cycles.
The Findings: The results favored Pluvicto. It was 59% better than the second-line ARPI with a median radiographic progression-free survival of ~12 months vs ~6 months for the second-line ARPI. In this study Pluvicto was much better tolerated than the second-line ARPI with fewer dose reductions and less hematologic toxicity, and it afforded the option of delaying chemotherapy. Dry month remained an uncomfortable development occurring in ~58% of men for Pluvicto vs 2.2 % for the second-line ARPI. Because 177Lu can cause bone marrow toxicity it might be better avoided in men with a heavy bone marrow burden of metastatic cancer.
New Developments: Pluvicto is only the beginning of radioligand developments for prostate cancer: Under study are two varieties of Actinium-225 radioligands, one targeting the PSMA protein and another targeting an as yet undisclosed different antigen also expressed on nearly all prostate cancer cells.
- “Study of 225-Ac-PSMA-617 in men with PSMA-positive Prostate Cancer” (NCT04597411) is currently open in many locations for men with progressive metastatic cancer. This is an international dose-escalation study in men with PSMA-positive cancer ‘’with or without prior [177Lu]Lu-PSMA-617 Radioligand Therapy (Pluvicto).” Eligibility excludes men with lesions negative on PSMA PET/CT (who would not be expected to respond) except for PET-negative osseous lesions.
The Actinium-225 ligand attaches to the internal portion of the 750 amino acid PSMA chain, radiating the cell internally, causing irreparable lethal double-strand DNA breaks. It has been found to be effective in the face of resistance to Pluvicto as reported by Feuerecker et al.,(Eur Urol. 2021) in which 17/26 heavily pre-treated patients progressing after Pluvicto, hormone suppression and chemotherapy. This study reported a PSA decline of > 50%, a median PSA progression-free survival of 3.5 months and an overall survival of 7.7 months.
Actinium-225 emits potent alpha particles (nuclei of helium atoms), which travel only a few cell widths, delivering forceful and lethal impact on DNA in the local region. Like Radium-223, (Xofigo), another alpha emitter, it is most effective in small metastatic lesions, and because of its short trajectory, minimizes off-target marrow damage. This short transit is different from 177Lu which radiates electrons (beta radiation) that travel farther, passing through many cells, but causing indirect, potentially reservable, double-strand DNA breaks. (Discussed in Dadgar, Theranostics. 2025).
Since the start of the Actinium protocol, a comprehensive review of targeted Ac-225 alpha therapy was published in January 2025, by Besiroglu (The Prostate) reviewing16 studies based on 1102 patients. Sixty-three percent showed a >50% PSA decline. The pooled mean OS and PFS were ~13 months and ~11 months, respectively. As before, 84% experienced dry mouth; hematologic toxicities were minimal.
- The most recent Actinium-225 formulation is ATNM-400 which combines Ac-225 with a monoclonal antibody targeting an undisclosed non-PSMA receptor highly expressed on cancer cells whose expression persists after prior exposure to Pluvicto. After linking to the receptor, ATNM-400 is rapidly internalized emitting powerful short-range lethal alpha particles whose short trajectory results in fewer off-target toxicities. This data was presented on April 28th at the Am Assn for Cancer Research, Abst 578.
BOTTOM LINE: With the expected increased early use of Pluvicto as in the PSMAfore protocol there likely will be men who failed to respond or relapsed after successful Pluvicto therapy who will be candidates for therapy with 225-Ac-PSMA-617 or the Actinium ATNM-400 regimen.