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

Background/Objectives: Lutetium (177Lu) TLX591 (177Lu-TLX591) is a radio antibody–drug conjugate (rADC) that utilizes a novel monoclonal antibody-based approach for treatment of patients with prostate-specific membrane antigen (PSMA)-expressing metastatic castration-resistant prostate cancer (mCRPC). ProstACT SELECT (NCT04786847) was a multicenter, single-arm, open-label Phase 1 trial evaluating patient selection for 177Lu-TLX591 therapy using 68Ga-PSMA-11 PSMA positron emission tomography (PET) in a heterogenous sample of patients with mCRPC. Primary and key secondary objectives were to evaluate safety and tolerability, biodistribution, and organ radiation dosimetry of 177Lu-TLX591 in combination with the best standard of care (SOC) for patients with PSMA-expressing mCRPC who progressed despite prior treatment with an androgen receptor pathway inhibitor. Methods: Thirty patients received 177Lu-TLX591 intravenously in combination with investigator-determined SOC. Cohort 1 (n = 5) received an imaging dose of 177Lu-TLX591 (1 GBq [27 mCi]), followed 14 days later by one therapeutic dose (2.8 GBq [76 mCi]). Cohort 2 received two therapeutic doses of 177Lu-TLX591, 14 days apart. Baseline 68Ga-PSMA-11 PET was performed to confirm eligibility and was qualitatively compared with serial 177Lu-TLX591 single-photon emission computed tomography (SPECT)/CT, which was performed at five timepoints following the first 177Lu-TLX591 administration and also used to evaluate organ radiation dosimetry. Safety assessments included monitoring for treatment-emergent adverse events and collection of laboratory samples at specified timepoints used for biomarker analyses. Results: Tumor targeting observed on 177Lu-TLX591 SPECT/CT imaging was qualitatively consistent with uptake observed on 68Ga-PSMA-11 PET imaging. No new safety signals were observed. Radiation exposure was within safety limits, with the highest absorbed dose to liver (clearance organ; 2.44 ± 0.56 Gy/GBq) and with lower exposure to salivary glands (0.07 ± 0.03 Gy/GBq) and kidneys (0.64 ± 0.17 Gy/GBq). Activity was retained in tumor lesions through to the final protocol-specified imaging timepoint (312 h) following administration. Conclusions: In this Phase 1, single-arm study, 68Ga-PSMA-11 PET supported patient selection for 177Lu-TLX591 therapy. In a heterogenous population representative of a real-world setting, 177Lu-TLX591 therapy in combination with SOC demonstrated a manageable and predictable safety profile, durable retention, and low salivary gland radiation exposure. Further evaluation in larger, randomized studies is warranted.