Phase 1 Findings Support PSMA-PET–Guided Patient Selection for Radio-ADC in mCRPC

Phase 1 Findings Support PSMA-PET–Guided Patient Selection for Radio-ADC in mCRPC

Prostate-specific membrane antigen (PSMA)-PET imaging was shown to support identification of patients for a trial of the radio antibody-drug conjugate (rADC) lutetium-177 (177Lu) rosopatamab tetraxetan (TLX591-Tx) in combination with the standard of care (SOC) for metastatic castration-resistant prostate cancer (mCRPC), according to results published in Cancers.¹

The findings from the phase 1 ProstACT SELECT trial (NCT04786847) confirm the utility of ⁶⁸Ga-PSMA-11 PET imaging (Illuccix) for selecting patients for TLX591-Tx therapy using a theranostic approach and also highlight the agent's manageable safety and differentiated pharmacologic profile from existing radioligand therapy approaches.

“The results provide compelling evidence that the PSMA-PET imaging agent and TLX591-Tx are targeting the same disease sites, supporting the ongoing ProstACT Global trial for mCRPC, where there remains significant unmet need for additional treatment options,” Nat Lenzo, MD, of St John of God Hospital Murdoch in Australia, principal investigator on ProstACT SELECT, stated in a news release.²

TLX591-Tx is a PSMA-targeting rADC that uses a monoclonal antibody-based approach, distinct from small-molecule PSMA-targeted radioligand therapies such as lutetium Lu 177 vipivotide tetraxetan (Pluvicto). The larger size of monoclonal antibodies leads to slower systemic clearance and prolonged circulation time, potentially limiting exposure in tissues such as the salivary glands, renal tubules, and small intestine, and thereby reducing off-target radiation exposure relative to small-molecule radioligand therapies.

Trial Design

ProstACT SELECT was a multicenter, single-arm, open-label trial with 2 sequential cohorts, designed primarily to evaluate safety, tolerability, biodistribution, and organ radiation dosimetry of TLX591-Tx in combination with investigator-determined SOC in patients with PSMA-expressing mCRPC with disease progression despite prior treatment with an androgen receptor pathway inhibitor (ARPI), such as enzalutamide (Xtandi) or abiraterone (Zytiga).

Cohort 1 (n = 5) received a subtherapeutic imaging dose of TLX591-Tx (1 GBq [27 mCi]) followed 14 days later by 1 therapeutic dose (2.8 GBq [76 mCi]); cohort 2 (n = 25) received 2 therapeutic doses 14 days apart. Baseline ⁶⁸Ga-PSMA-11 PET was used to confirm eligibility and was compared qualitatively with serial single-photon emission computed tomography (SPECT)/CT performed at 5 timepoints after the first dose. Of 38 patients screened, 30 were enrolled and received at least 1 dose of TLX591-Tx; median age was 72.5 years.

Safety and Dosimetry Findings

No new safety signals were observed. Of 212 total treatment-emergent adverse events (TEAEs) reported across 30 patients, 125 (59.0%) were considered treatment-related, occurring in 25 patients (83.3%). Fatigue was the most common treatment-related nonhematologic TEAE (60.0% of patients). Hematologic TEAEs considered treatment-related included thrombocytopenia in 56.0% of cohort 2 patients and neutropenia in 36.0%; grade 4 thrombocytopenia, lymphopenia, and neutropenia occurred in 20.0%, 4.0%, and 4.0% of cohort 2 patients, respectively, with all grade 4 events resolving and only 1 patient requiring platelet transfusion. Grade 1 xerostomia occurred in 20.0% of cohort 2 patients, all transient. Two patient deaths occurred during the trial, both deemed unrelated to TLX591-Tx.

Radiation exposure was within safety limits. The highest mean absorbed organ doses were observed in the liver (2.44 ± 0.56 Gy/GBq), the primary clearance organ, with substantially lower exposure to the salivary glands (0.07 ± 0.03 Gy/GBq) and kidneys (0.64 ± 0.17 Gy/GBq) in cohort 2. Tumor-associated activity was retained through the final protocol-specified imaging timepoint of 312 hours (13 days) after administration, with an estimated lesion biological half-life of 326 hours. Tumor targeting observed on TLX591-Tx SPECT/CT was qualitatively consistent with uptake on baseline ⁶⁸Ga-PSMA-11 PET.

Early Efficacy Signals

Among 16 evaluable patients in the protocol-defined efficacy population, the median radiographic progression-free survival (rPFS) was 8.8 months (95% CI, 4.0-11.3); 1 patient achieved a partial response, and 13 had stable disease. Among 23 patients who received both therapeutic doses, 47.8% experienced any prostate-specific antigen (PSA) decline from baseline, with 26.1% achieving a 30% or greater decline and 13.0% achieving a 50% or greater decline.

Investigator and Company Perspective

The study authors noted that interpretation is limited by the trial's small sample size, single-arm design, and limited long-term follow-up, and that efficacy findings should be considered exploratory. TLX591-Tx has not received marketing authorization in any jurisdiction and is currently being evaluated further in the phase 3 ProstACT Global trial (NCT06520345), which recently received positive feedback from the FDA to proceed with its prospective randomized portion.

REFERENCES

1. Lenzo N, O’Byrne K, Ngai S, et al. Theranostic potential of 177Lu-TLX591 with best standard-of-care and ⁶⁸Ga-PSMA-11 PET for patients with metastatic castration-resistant prostate cancer: results from the phase 1 ProstACT SELECT trial. Cancers. 2026;18(14):2331. doi:10.3390/cancers18142331

2. TLX591-Tx ProstACT SELECT Study Published in Cancers Journal. News release. Telix Pharmaceuticals. July 22, 2026. Accessed July 22, 2026. https://tinyurl.com/4h7v9d8t