Fractionated 225Ac–J591 shows early activity, preserved QOL in mCRPC

A fractionated, dose-dense regimen of the prostate-specific membrane antigen (PSMA)-targeted alpha-emitter actinium-225 (²²⁵Ac)-J591 demonstrated encouraging antitumor activity with manageable toxicity in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC), according to phase 1 (NCT04886986) findings presented at the 2026 AACR Annual Meeting in San Deigo, California.¹

Investigators reported that a multiple-cycle every-6-week dosing schedule was not advanced because hematologic adverse events delayed retreatment.

How the study was conducted

For the study, investigators enrolled 60 patients with progressive mCRPC. Eligible patients had an ECOG performance status of 0 to 2, adequate organ function, and prior exposure to ARPI therapy and chemotherapy unless medically unfit or declining chemotherapy. Patients were treated in 2 parallel cohorts: a fractionated regimen administered on days 1 and 15, or a multiple-cycle regimen given every 6 weeks for up to 4 cycles.

The primary objectives were dose-limiting toxicity and recommended phase 2 dose (RP2D). Secondary expansion assessments included prostate-specific antigen (PSA) response, progression-free survival (PFS), overall survival (OS), imaging correlatives, and patient-reported outcomes.

The RP2D was identified as 60 kBq/kg × 2 doses. In that cohort, 68% of patients achieved a PSA decline of at least 50%, compared with 28% in the multiple-cycle arm, according to data presented at the 2026 ASCO GU Cancers Symposium.²

The fractionated regimen emerged as the preferred schedule. Across the fractionated cohort, the median PFS was 5.2 months and the median OS was 15.4 months, with outcomes reportedly improved at the RP2D. Investigators also reported statistically favorable PSA response (P = .005, PFS (P = .009), and OS (P = .003) for fractionated vs multiple-cycle dosing.

Related: FDA clears IND for 225Ac-J591 in advanced prostate cancer

The treated population reflected advanced disease burden: the median age was approximately 73 years, 88% had bone metastases, 61% had nodal disease, and roughly one-quarter had visceral metastases. Prior treatment exposure was extensive, including at least 2 prior ARPIs in 60% of patients, chemotherapy in approximately 70%, prior radium-223 in about 12%, and prior ¹⁷⁷Lu-PSMA in 20%.¹

Safety findings were dominated by hematologic toxicity. Grade 3 or 4 thrombocytopenia occurred in 26% of patients, while grade 3 or 4 neutropenia and anemia each occurred in 16.7%. Lower-frequency grade 3 events included fatigue (4.8%), AST elevation (4.8%), and pain (2.4%). The inability to maintain planned retreatment intervals in the multiple-cycle arm because of thrombocytopenia suggests schedule optimization may be as important as dose selection for alpha-emitting radiopharmaceuticals.

Health-related quality of life (HRQoL) analyses were also reported. In the multiple-cycle arm, the median FACT-P scores declined from 106 to 74 by day 85, with worsening physical and functional well-being. By contrast, the fractionated cohort showed stable to numerically improved FACT-P scores, rising from 116 to 123 (P = .2), while FACT-RNT scores remained stable without meaningful deterioration across timepoints or dose levels.

Next steps

The next test of this strategy is the ongoing phase 2 CONVERGE-01 trial (NCT06549465), evaluating Ac-225 rosopatamab tetraxetan (CONV01-α) in patients with mCRPC with and without prior ¹⁷⁷Lu-PSMA exposure.

In part 1, investigators will enroll an initial cohort receiving indium-111 (In-111)-rosopatamab tetraxetan to characterize biodistribution to target organs and metastatic lesions. Patients are then assigned based on prior radioligand exposure. Part 2 (dose optimization) will include ¹⁷⁷Lu-PSMA–naïve patients randomly assigned to a single fractionated cycle of Ac-225 rosopatamab tetraxetan at 45 or 60 kBq/kg administered on days 1 and 15. Part 3 (dose escalation) will enroll patients previously treated with ¹⁷⁷Lu-PSMA radioligand therapy and evaluate 45, 55, or 60 kBq/kg in the same fractionated schedule, with dose-limiting toxicities used to define the RP2D and potential expansion at the selected dose.

Study assessments will include laboratory monitoring, ECGs, imaging, and serial clinical evaluations. The investigators are enrolling participants through clinical trials sites across the US.

Results from the CONVERGE-01 trial will be presented at the 2026 American Society of Clinical Oncology Annual Meeting.⁴

REFERENCES

1. Tagawa ST, Thomas C, Corzo VM, et al. Fractionated (dose dense) and multiple dose PSMA-targeted alpha emitter 225Ac-J591 for advanced prostate cancer: Final primary and secondary outcomes. Presented at: 2026 American Association for Cancer Research Annual Meeting. April 17-22, 2026. San Diego, California. Abstract CT305

2. Okobi TJ, Arham AB, Thomas C, et al. Patient-reported outcomes (PRO) from a dose-escalation and expansion trial of fractionated and multiple-cycle PSMA-targeted alpha radionuclide 225Ac-J591. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 26-28, 2026; San Francisco, CA. Abstract 208

3. Study Evaluating Dosimetry, Randomized Dose Optimization, Dose Escalation and Efficacy of Ac-225 Rosopatamab Tetraxetan in Participants With PSMA PET-Positive Castration-Resistant Prostate Cancer (CRPC). ClinicalTrials.gov. Last updated August 24, 2025. Accessed April 23, 2026. https://clinicaltrials.gov/study/NCT06549465

4. Convergent Therapeutics to present phase 2 data for CONV01-α in Lu-PSMA pretreated metastatic castration-resistant prostate cancer patients at the 2026 ASCO Annual Meeting. News release. Convergent Therapeutics. April 21, 2026. Accessed April 23, 2026. https://www.businesswire.com/news/home/20260421247374/en/Convergent-Therapeutics-to-Present-Phase-2-Data-for-CONV01--in-Lu-PSMA-pretreated-Metastatic-Castration-Resistant-Prostate-Cancer-Patients-at-the-2026-ASCO-Annual-Meeting