Dosing begins in study of PSMA-targeted therapy in mCRPC

The first patient has been dosed in the phase 2 portion of the AlphaBreak trial (NCT06402331), evaluating FPI-2265 (²²⁵Ac-PSMA I&T) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have been previously treated with ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA) radiotherapy, according to a news release from Fusion Pharmaceuticals, the developer of the therapy.¹

The phase 2 portion of the AlphaBreak study is planning to enroll approximately 60 patients by the end of 2024.

"Despite recent advances in the field, we see many patients with mCRPC still in need of additional treatment options, especially after progressing on lutetium-based radiotherapy. It is encouraging to see the promising clinical activity and good safety profile demonstrated by FPI-2265. The initiation of the AlphaBreak trial brings us a step closer to addressing the gap for patients and providing this needed treatment option," said trial investigator and CEO of XCancer Luke Nordquist, MD, FACP, in the news release.¹

FPI-2265 is an actinium-225 based PSMA targeting radioconjugate. The phase 2/3, open-label, randomized, multicenter AlphaBreak trial is evaluating the safety and efficacy of the therapy in patients with mCRPC who have been previously treated with ¹⁷⁷Lu-PSMA radiotherapy.

The phase 2 portion of the study is designed to determine whether there are any added safety or efficacy benefits of 2 alternative dosing regimens compared with the previously studied regimen of 100 kBq/kg every 8 weeks, which was explored in the phase 2 TATCIST trial (NCT05219500). Patients in the AlphaBreak study will be randomly assigned 1:1:1 to receive either 9 doses of 50 kBq/kg of FPI-2265 every 4 weeks (arm 1), 6 doses of 75 kBq/kg of FPI-2265 every 6 weeks (arm 2), or to 4 doses of 100 kBq/kg of FPI-2265 every 8 weeks.

The co-primary outcome measures for the study are the frequency, duration, and severity of treatment-emergent adverse events and the frequency and proportion of patients with a decline in prostate-specific antigen levels by at least 50% (PSA50).²

In total, the phase 2 portion of the AlphaBreak study is planning to enroll approximately 60 patients by the end of 2024. Pending analysis of the phase 2 data and an end of phase 2 meeting with the FDA, Fusion Pharmaceuticals plans to initiate a phase 3 global registration study of the AlphaBreak trial in 2025. The phase 3 study would enroll approximately 550 patients.

Data on FPI-2265

Fusion Pharmaceuticals presented interim efficacy and safety data on FPI-2265 from the phase 2 TATCIST study at the 2024 American Association for Cancer Research (AACR) Annual Meeting, which was held April 5-10 in San Diego, California.³

Overall, the study included heavily pretreated patients with progressive mCRPC, including patients who had received prior lutetium-based radioconjugates.

The analysis, conducted at a data cutoff of March 1, 2024, included 35 patients who had received at least 1 dose of FPI-2265, with 25 patients having at least 12 weeks of follow-up.

Data showed that 50% of patients included in the efficacy analysis (n = 20) achieved a PSA50 response, regardless of prior lutetium treatment. When broken up by lutetium status, PSA50 was achieved in 61% of lutetium-naïve participants and 42% of lutetium-treated patients. In an exploratory subset analysis of 13 patients who had a baseline PSMA mean standardized uptake value of greater then 6, 69% of patients achieved a PSA50 response.

There were also meaningful improvements noted regarding the study’s secondary end points, which included maximum percentage of PSA decline, reviewer-assessed response rates based on RECIST v1.1 criteria, and the rate of disease progression in bone per PCWG3 criteria.

FPI-2265 was also generally well-tolerated, with treatment-related adverse events (TRAEs) being predominantly grade 1 or 2. Discontinuation due to TRAEs occurred in 3 out of 25 patients included in the safety analysis.

Long-term follow-up for the TATCIST trial remains ongoing.

Chief Medical Officer Dmitri Bobilev, MD, concluded in the news release on the AlphaBreak study,¹ "Actinium-based PSMA targeting RCs have demonstrated compelling safety and clinical activity, which is supported by Fusion's encouraging data from the Phase 2 TATCIST trial reported recently at the AACR Annual Meeting. We believe FPI-2265 represents an important potential new treatment option for patients with mCRPC, and with the initiation of the AlphaBreak trial we are pleased to move forward.”

References

1. Fusion Pharmaceuticals announces first patient dosed in the phase 2 portion of the AlphaBreak trial evaluating FPI-2265 in metastatic castration-resistant prostate cancer. News release. Fusion Pharmaceuticals. May 9, 2024. Accessed May 10, 2024. https://ir.fusionpharma.com/2024-05-09-Fusion-Pharmaceuticals-Announces-First-Patient-Dosed-in-the-Phase-2-Portion-of-the-AlphaBreak-Trial-Evaluating-FPI-2265-in-Metastatic-Castration-Resistant-Prostate-Cancer

2. FPI-2265 (225Ac-PSMA-I&T) for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) (AlphaBreak). ClinicalTrials.gov. Last updated May 8, 2024. Accessed May 10, 2024. https://clinicaltrials.gov/study/NCT06402331

3. Fusion Pharmaceuticals announces presentation of interim data from the phase 2 TATCIST clinical trial evaluating FPI-2265 at the AACR Annual Meeting 2024. News release. Fusion Pharmaceuticals. April 9, 2024. Accessed May 10, 2024. https://ir.fusionpharma.com/2024-04-09-Fusion-Pharmaceuticals-Announces-Presentation-of-Interim-Data-from-the-Phase-2-TATCIST-Clinical-Trial-Evaluating-FPI-2265-at-the-AACR-Annual-Meeting-2024