177Lu-PSMA-617 extends rPFS in taxane-naïve mCRPC better than abiraterone and enzalutamide/enzalutamide

Exploratory post hoc analysis ofthe phase 3 PSMAfore trial (NCT04689828) showed that compared with changes in androgen receptor pathway inhibitors (ARPIs), regardless of the initial ARPI received, e.g. Ho (abiraterone acetate [Zytiga] or enzalutamide/enzalutamide), lutetium Lu177 in patients with taxane-negative, PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) Vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) prolonged radiation progression-free survival (rFS).

PSMA is a transmembrane glycoprotein with carboxypeptidase activity that is highly expressed in prostate cancer, including metastatic lesions. Its normal expression is relatively restricted and mainly appears in salivary and lacrimal glands. PSMA is the target of PET imaging. Lu 177vipivotide tetraxetan is a targeted radioligand therapy for patients with PSMA-positive mCRPC.

The PSMAfore open-label trial enrolled adult patients diagnosed with progressive mCRPC who had at least 1 PSMA-positive metastatic lesion on [68Ga]Ga-PSMA-11 PET/CT and no exclusionary PSMA-negative lesions. Patients need to have progressed on a previous second-generation ARPI and be candidates for ARPI change. Patients were required to have received a taxane for the first time except those who had received neoadjuvant or adjuvant taxane therapy more than 12 months before trial enrollment. Additionally, patients are not candidates for PARP inhibitors and require an ECOG performance status (PS) of 0 or 1.

Patients were randomly assigned in a 1:1 ratio to receive 7.4GBq (200mCi) of 10% lutetium Lu177 vipivotide tetraxetan every 6 weeks for 6 cycles, or abiraterone or enzalutamide ARPI change. Crossover from the ARPI arm to lutetium Lu177 vipivotide tetraxetan was allowed based on imaging progression by blinded independent central review (BICR). Patients were stratified according to previous ARPI setting (hormone-sensitive vs castration-resistant) and Brief Pain Scale-Brief Worst Pain Intensity Score (0-3 vs >3).

According to the Prostate Cancer Clinical Trials Working Group3/RECIST v1.1 standard, the primary endpoint is BICR rPFS. Operating system is a key secondary endpoint. Other secondary endpoints include time to second rPFS, PFS, time to second PFS, confirmed prostate-specific antigen (PSA) decline of at least 50% (PSA 50), time to skeletal symptoms, time to soft tissue progression, time to chemotherapy, health-related quality of life, safety and tolerability. Exploratory endpoints included overall response rate (ORR), disease control rate, duration of response, time to PSA progression, time to pain progression, and biomarker correlations.

In the second interim analysis of PSMAfore, the median rPFS for Lu 177 vipivotide tetraxetan was 12.02 months (95% CI, 9.30-14.42), while the ARPI changed (HR, 0.43; 95% CI, 0.33-0.54). PSA 50 was observed in 57.6% of evaluable patients in the Lu177 vipivotide tetraxetan group and in 20.4% of evaluable patients in the ARPI change group. In addition, the ORR of lutetium Lu177 vipivotide tetraxetan was 50.7% (95% CI, 38.6%-62.8%), while the ARPI-altered ORR was 14.9% (95% CI, 7.7%-25.0%). Complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and unknown optimal soft tissue response rates according to RECIST v1.1 were observed in 21.1%, 29.6%, 31.0%, 15.5%, and 2.8% of patients in the Lu177 vipivotide tetraxetan arm, respectively, at ARPI It was observed in 2.7%, 12.2%, 45.9%, 32.4% and 6.8% of patients in the change group.

In the second interim analysis of OS, an exploratory post hoc analysis was also conducted to evaluate the efficacy outcomes of patients treated with ARPI before randomization. These data support lutetium Lu177 vipivotide tetraxetan as a new standard of care for this highly prevalent taxane-naive mCRPC patient population.