A Phase 2/3, Randomized, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of FPI-2265 (225Ac-PSMA-I&T) in Patients With PSMA-Positive Metastatic Castration-Resistant Prostate Cancer (mCRPC), Previously Treated With 177Lu-PSMA Radioligand Therapy (RLT)

This is an open-label, randomized, multicenter study of FPI-2265 (225Ac-PSMA-I\&T). Patient population is adult participants with PSMA positive mCRPC who have had previous treatment with with 177Lu-PSMA-617 or another 177Lu-PSMA radioconjugate (RC). The purpose of the study is to determine the safety and tolerability, and recommended dose and regiment of FPI-2265.

More details:

This is an open-label, randomized, multicenter study of FPI-2265 (225Ac-PSMA-I\&T). The purpose of the dose optimization segment (Phase 2) is to determine the recommended FPI-2265 dose and regimen. Conclusions from Phase 2 will be based on safety, tolerability, and anti-tumor activity. Screening Period: At screening, participants will be assessed for eligibility and undergo a positron emission tomography (PET)/computed tomography (CT) scan to evaluate PSMA positivity. Only participants with PSMA positive cancer and confirmed eligibility criteria will be randomized. Participants randomized will enter the treatment period and receive investigational doses of FPI2265 according to the dose level and schedule as specified per proposed dose arm. Part A participants will enroll 1:1:1 at three dose level/schedules, to arms 1, 2 or 3 Part B participants will enroll after completion of part A, in a 1:1 randomization scheme to arms 6 or 7. Once Part A is fully enrolled and participants have been followed for at least 12 weeks, data from Arm 1 and 2 will be analyzed to assess the the feasibility of enrolling participants to arms 4 and 5. All participants will be monitored and assessed for efficacy response, disease progression and adverse events. Supportive care will be allowed in all arms at the discretion of the investigator and includes available care for the eligible participant according to best institutional practice for mCRPC treatment, including androgen deprivation therapy (ADT). Follow-up after end of treatment visit will proceed for 5 years. 5 participants will be enrolled into a dosimetry substudy (open at select sites only). Dosimetry substudy participants will be administered one dose at of FPI2265 and proceed with dosimetric assessments will be taken at a number of timepoints after dose administration.

Overview

FPI-2265 (225Ac-PSMA-I&T) is a small‑molecule radioligand therapy that targets prostate‑specific membrane antigen (PSMA) and delivers the alpha‑emitting radionuclide actinium‑225 to PSMA‑expressing tumor cells. It is being developed for metastatic castration‑resistant prostate cancer (mCRPC). As of April–May 2024, interim phase 2 results from the investigator‑initiated TATCIST trial were presented at AACR 2024, and a company‑sponsored registrational Phase 2/3 program (AlphaBreak; NCT06402331) began dosing. In March 2024, Fusion Pharmaceuticals (the original sponsor) agreed to be acquired by AstraZeneca, highlighting external interest in the program. (citedrive.com, prnewswire.com, reuters.com)

Mechanism of action

• Target: PSMA, a type II transmembrane glycoprotein overexpressed in most prostate cancers, with ligand binding followed by internalization into tumor cells. PSMA‑targeted small molecules such as PSMA‑I&T use a Glu‑ureido binding motif and chelator to carry therapeutic isotopes. (pmc.ncbi.nlm.nih.gov, frontiersin.org)
• Payload: Actinium‑225 is an alpha‑emitter (t1/2 ~9.9 days) whose decay chain releases multiple high‑LET alpha particles over micrometer ranges, causing dense DNA double‑strand breaks with limited off‑target penetration. (ejnmmipharmchem.springeropen.com, ncbi.nlm.nih.gov, pmc.ncbi.nlm.nih.gov)
• Ligand background: PSMA‑I&T has been validated as a theranostic scaffold in prior clinical imaging/therapy studies (with β‑emitting 177Lu), supporting its use when labeled with 225Ac. (jnm.snmjournals.org)

Efficacy

Clinical evidence specific to FPI‑2265 comes primarily from the Phase 2 TATCIST trial (investigator‑initiated; interim AACR 2024 poster):

• Population: Progressive mCRPC; heavily pretreated (median 4 prior lines); included patients with and without prior 177Lu‑PSMA therapy. As of the March 1, 2024 cutoff, 35 treated; 25 had ≥12 weeks’ follow‑up; 20 evaluable for PSA response. (prnewswire.com)
• Primary efficacy readouts reported:
• PSA50 (≥50% decline by week 12) in 10/20 (50%) overall; 61% in lutetium‑naïve and 42% in prior‑lutetium patients. In an exploratory subset with baseline PSMA SUVmean >6 (n=13), PSA50 occurred in 69%. (prnewswire.com, pipelinereview.com)
• Additional secondary endpoints (maximum PSA decline, RECIST v1.1 responses, and PCWG3 bone progression) were described as showing “meaningful improvement,” but numeric ORR/rPFS were not provided in the interim public materials. (prnewswire.com)

The ongoing Phase 2/3 AlphaBreak trial (NCT06402331) is evaluating alternative dosing schedules versus the previously used 100 kBq/kg every 8 weeks; Phase 2 (dose optimization) is followed by a Phase 3 global registration portion powered for rPFS. (ichgcp.net, biospace.com)

Context from broader 225Ac‑PSMA literature (not specific to FPI‑2265) indicates activity of 225Ac‑PSMA RLTs in mCRPC with frequent PSA declines and xerostomia as the main toxicity, but heterogeneity across products and study designs warrants caution in cross‑comparison. (pubmed.ncbi.nlm.nih.gov)

Safety

From the TATCIST interim AACR 2024 report:

• Overall tolerability: Predominantly Grade 1–2 treatment‑related adverse events (TRAEs). Most common were xerostomia, thrombocytopenia, anemia, fatigue, and dry eye. Xerostomia was mainly Grade 1–2 (no discontinuations due to xerostomia). (prnewswire.com)
• Serious events: One treatment‑related death (cerebral hemorrhage) was reported in a “superscan” patient; 3/25 discontinued due to TRAEs (two were superscan patients). (prnewswire.com)

Safety characterization and recommended dosing are being further evaluated in the AlphaBreak Phase 2 dose‑optimization (arms include 50 kBq/kg q4w, 75 kBq/kg q6w, and 100 kBq/kg q8w). (biospace.com)

Mechanistically, alpha emitters produce high‑LET DNA damage with short path length; while this underlies potent tumor cell killing, salivary gland uptake of PSMA ligands likely contributes to xerostomia seen across PSMA‑directed alpha therapies. (pmc.ncbi.nlm.nih.gov)

Key trials

• TATCIST (NCT05219500): Phase 2, FPI‑2265 100 kBq/kg q8w up to four doses, with protocolized dose modifications based on response/tolerability; status “active, not recruiting” as of February 2025. (ichgcp.net)
• AlphaBreak (NCT06402331): Phase 2/3 randomized, open‑label post‑177Lu‑PSMA setting; Phase 2 dose optimization ongoing; Phase 3 planned to start in 2025 with ~550 patients and rPFS primary endpoint. (ichgcp.net, prnewswire.com)

Further reading

• AACR 2024 interim clinical trial poster (CT224) for TATCIST (FPI‑2265): Preliminary efficacy and safety in mCRPC. (citedrive.com)
• Background on PSMA‑I&T scaffold and PSMA biology: Journal of Nuclear Medicine 2015 (PSMA‑I&T) and reviews of PSMA theranostics. (jnm.snmjournals.org, pmc.ncbi.nlm.nih.gov)
• Physics/biology of 225Ac alpha therapy: EJNMMI Radiopharmacy and Chemistry 2024 review; additional mechanistic overviews. (ejnmmipharmchem.springeropen.com, pmc.ncbi.nlm.nih.gov)
• AlphaBreak trial registration details (NCT06402331) and design updates. (ichgcp.net, biospace.com)
• Reuters coverage of AstraZeneca’s acquisition of Fusion Pharmaceuticals (portfolio includes FPI‑2265). (reuters.com)

Notes and limitations: As of the publicly presented AACR 2024 interim, detailed radiographic response rates, rPFS, and OS for FPI‑2265 have not been reported in peer‑reviewed form. Ongoing Phase 2/3 data will better define efficacy, safety, and optimal dosing. (prnewswire.com, ichgcp.net)

Last updated: Sep 2025

Key Inclusion Criteria:

* Phase 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

* Diagnosis of adenocarcinoma of prostate proven by histopathology.

* Must have had prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum/plasma testosterone

* Progressive mCRPC at time of study entry.

* Must have been previously treated with lutetium-PSMA therapy (lutetium-177 vipivotide tetraxetan or other lutetium-177-PSMA RLT). Treatment must have been completed \>6 weeks prior to the first dose of study drug.

* Participants with known BRCA mutations should have received FDA-approved therapies such as PARP inhibitors, per Investigator discretion.

* Positive PSMA PET/CT scan

* Adequate organ function

* For participants who have partners of childbearing potential: Partner and/or participant must not be planning to conceive and must use a method of birth control with adequate barrier protection deemed acceptable by the Principal Investigator during the study treatment and for six months after last study drug administration.

Key Exclusion Criteria:

* Participants who received more than two prior lines of cytotoxic chemotherapy for CRPC.

* Phase 2: participants who progress prior to administration of the 3rd cycle of prior treatment with 177Lu-PSMA therapy

* All prior treatment-related adverse events must have resolved to Grade ≤1 (CTCAE v5.0). Alopecia and stable persistent Grade 2 peripheral neuropathy may be allowed at the discretion of the Investigator.

* Participants with known, unresolved, urinary tract obstruction are excluded.

* Administration of any systemic cytotoxic or investigational therapy ≤30 days of the first dose of study treatment or five half-lives, whichever is shorter. Completion of large-field external beam radiotherapy ≤four weeks of the first dose of study treatment.

* Participants with a history of central nervous system (CNS) metastases are excluded except those who have received therapy

* Participants with any liver metastases will be excluded from the Phase 2 segment of the study.

* Participants with skeletal metastases presented as a superscan on a ⁹⁹ᵐTc bone scan.

* Previous or concurrent cancer that is distinct from the cancer under investigation in primary site or histology, except treated cutaneous basal cell carcinoma or squamous cell carcinoma and superficial bladder tumors. Any cancer curatively treated \>two years prior to the first dose of treatment is permitted.

* Concurrent serious (as determined by the investigator) medical conditions

* Major surgery ≤30 days prior to the first dose of study treatment.