177Lu-PSMA-617 prolongs rPFS in taxane-naïve mCRPC, benefit greater with prior abiraterone vs enzalutamide

An exploratory post-hoc analysis of the phase 3 PSMAfore trial (NCT04689828) showed that lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) extended radiographic progression-free survival (rPFS) compared with a change in androgen receptor pathway inhibitor (ARPI), regardless of initial ARPI received (abiraterone acetate [Zytiga] or enzalutamide [Xtandi]), in patients with taxane-naïve, PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).¹ However, it was determined that outcome improvements did favor prior treatment with abiraterone vs enzalutamide in both study arms.

“These data support the consideration of lutetium Lu 177 vipivotide tetraxetan as a new standard treatment approach for this highly prevalent patient population of taxane-naive mCRPC,” said presenting author Xiao X. Wei, MD.

Among patients who had received prerandomization abiraterone, the median rPFS was 12.62 months (95% CI, 9.56-17.15) in those who received lutetium Lu 177 vipivotide tetraxetan on the study (n = 119) vs 5.78 months (95% CI, 4.93-6.44) in those who received a change in ARPI on the study (n = 130; HR, 0.47; 95% CI, 0.33-0.66). Among patients who had received prerandomization enzalutamide, the median rPFS was 12.02 months (95% CI, 7.00-17.05) in the lutetium Lu 177 vipivotide tetraxetan arm (n = 94) vs 4.34 months (95% CI, 3.88-5.78) in the ARPI change arm (n = 84; HR, 0.35; 95% CI, 0.24-0.52).

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

The open-label PSMAfore trial enrolled adult patients with confirmed progressive mCRPC with at least 1 PSMA-positive metastatic lesion on [68Ga]Ga-PSMA-11 PET/CT and no exclusionary PSMA-negative lesions. Patients needed to have progressed once on a prior second-generation ARPI and be candidates for a change in ARPI. Patients also needed to be taxane naive, except for those who had received a neoadjuvant or adjuvant taxane more than 12 months before trial enrollment. Additionally, patients could not be candidates for PARP inhibitors and needed to have an ECOG performance status (PS) of 0 or 1.

Patients were randomly assigned 1:1 to receive either lutetium Lu 177 vipivotide tetraxetan at 7.4 GBq (200 mCi) ± 10% once every 6 weeks for 6 cycles, or an ARPI change to either abiraterone or enzalutamide. Crossover from the ARPI arm to the lutetium Lu 177 vipivotide tetraxetan arm was permitted upon radiographic progression per blinded independent central review (BICR). Patients were stratified by prior ARPI setting (hormone-sensitive vs castration-resistant) and Brief Pain Inventory-Short Form worst pain intensity score (0-3 vs > 3).

The primary end point was rPFS by BICR per Prostate Cancer Clinical Trials Working Group 3/RECIST v1.1 criteria. OS served as the key secondary end point. Other secondary end points included time to second rPFS, PFS, time to second PFS, confirmed prostate-specific antigen (PSA) decrease of at least 50% (PSA50), time to symptomatic skeletal events, time to soft tissue progression, time to chemotherapy, health-related quality of life, safety, and tolerability. Exploratory end points included overall response rate (ORR), disease control rate, duration of response, time to PSA progression, time to pain progression, and biomarker associations.

At the second interim analysis of PSMAfore, which had a data cutoff of June 21, 2023, the median rPFS was 12.02 months (95% CI, 9.30-14.42) with lutetium Lu 177 vipivotide tetraxetan (n = 234) vs 5.59 months (95% CI, 4.17-5.95) with ARPI change (n = 234; HR, 0.43; 95% CI, 0.33-0.54).2 PSA50 was observed in 57.6% of evaluable patients in the lutetium Lu 177 vipivotide tetraxetan arm (n = 213) vs 20.4% of evaluable patients in the ARPI change arm (n = 221). Furthermore, the ORR was 50.7% (95% CI, 38.6%-62.8%) with lutetium Lu 177 vipivotide tetraxetan vs 14.9% (95% CI, 7.7%-25.0%) with ARPI change. Best soft tissue responses per RECIST v1.1 of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and unknown were observed in 21.1%, 29.6%, 31.0%, 15.5%, and 2.8% of patients in the lutetium Lu 177 vipivotide tetraxetan arm, respectively, and 2.7%, 12.2%, 45.9%, 32.4%, and 6.8% of patients in the ARPI change arm, respectively.

At the second interim OS analysis, an exploratory post-hoc analysis was also conducted to evaluate efficacy outcomes based on which prerandomization ARPI treatment patients had received.1

Among patients in the lutetium Lu 177 vipivotide tetraxetan and ARPI change arms, respectively, 50.9% and 55.6% had received prior abiraterone, 40.2% and 35.9% had received prior enzalutamide, 6.0% and 6.4% had received prior apalutamide (Erleada), and 3.0% and 3.0% had received prior darolutamide (Nubeqa). Of the patients in the ARPI change arm who received on-study abiraterone (n = 100), 83, 10, and 7 had received prior enzalutamide, apalutamide, and darolutamide, respectively. Of the patients in the ARPI change arm who received on-study enzalutamide (n = 132), 127 and 5 received prior abiraterone and apalutamide, respectively. Two patients in the ARPI change arm did not receive an on-study ARPI, 1 each of whom had received prior abiraterone and enzalutamide.

Among patients in the lutetium Lu 177 vipivotide tetraxetan arm who received pre-randomization abiraterone, the median age was 70.0 years (range, 43-94), 89.1% were White, 64.7% had an ECOG PS of 0, the median PSA level was 19.4 ng/mL (range, 0-963), the median hemoglobin level was 12.8 g/dL (range, 9.1-15.5), and the median alkaline phosphate level was 104.0 U/L (range, 39-1727). In total, 1.7%, 31.1%, and 81.5% of patients had disease in the liver, lymph nodes, and bone, respectively. Among patients in this arm who received pre-randomization enzalutamide, the median age was 72.0 years (range, 57-91), 92.6% were White, 59.6% had an ECOG PS of 0, the median PSA level was 19.6 ng/mL (range, 0-1197), the median hemoglobin level was 12.6 g/dL (range, 8.8-15.1), and the median alkaline phosphate level was 102.0 U/L (range, 36-1251). In total, 4.3%, 23.4%, and 81.9% of patients had disease in the liver, lymph nodes, and bone, respectively.

Among patients in the ARPI change arm who received pre-randomization abiraterone, the median age was 72.0 years (range, 54-91), 90.0% were White, 50.8% had an ECOG PS of 0, the median PSA level was 14.0 ng/mL (range, 1-4224), the median hemoglobin level was 12.8 g/dL (range, 9.2-15.4), and the median alkaline phosphate level was 99.0 U/L (range, 28-1319). In total, 6.2%, 19.2%, and 83.8% of patients had disease in the liver, lymph nodes, and bone, respectively. Among patients in this arm who received pre-randomization enzalutamide, the median age was 73.0 years (range, 54-89), 94.0% were White, 44.0% had an ECOG PS of 0, the median PSA level was 20.7 ng/mL (range, 0-3298), the median hemoglobin level was 13.2 g/dL (range, 8.8-15.5), and the median alkaline phosphate level was 111.0 U/L (range, 34-1140). In total, 2.4%, 35.7%, and 86.9% of patients had disease in the liver, lymph nodes, and bone, respectively.

In the group of evaluable patients who received prerandomization abiraterone, 64.2% and 25.6% of the lutetium Lu 177 vipivotide tetraxetan (n = 109) and ARPI change (n = 125) arms achieved confirmed PSA50, respectively. Among the evaluable patients who received prerandomization enzalutamide, 51.7% and 12.5% of the lutetium Lu 177 vipivotide tetraxetan (n = 87) and ARPI change (n = 80) arms achieved confirmed PSA50, respectively.

Among evaluable patientswho had received prerandomization abiraterone, the ORRs were 61.1% (95% CI, 43.5%-76.9%) and 16.2% (95% CI, 6.2%-32.0%) in the lutetium Lu 177 vipivotide tetraxetan and ARPI change arms, respectively. Best soft tissue responses per RECIST v1.1 of CR, PR, SD, PD, and unknown were observed in 25.0%, 36.1%, 22.2%, and 2.8% of patients in the lutetium Lu 177 vipivotide tetraxetan arm, respectively, and 2.7%, 13.5%, 45.9%, 35.1%, and 2.7% of patients in the ARPI change arm, respectively. Among evaluable patientswho had received prerandomization enzalutamide, the ORRs were 40.0% (95% CI, 22.7%-59.4%) and 13.3% (95% CI, 3.8%-30.7%) in the lutetium Lu 177 vipivotide tetraxetan and ARPI change arms, respectively. Best soft tissue responses per RECIST v1.1 of CR, PR, SD, PD, and unknown were observed in 20.0%, 20.0%, 40.0%, 16.7%, and 3.3% of patients in the lutetium Lu 177 vipivotide tetraxetan arm, respectively, and 3.3%, 10.0%, 46.7%, 26.7%, and 13.3% of patients in the ARPI change arm, respectively.

“These data support the consideration of lutetium Lu 177 vipivotide tetraxetan as a new standard treatment approach for this highly prevalent patient population of taxane-naive mCRPC,” presenting author Xiao X. Wei, MD, MAS, deputy director of Clinical Research at the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, both in Boston, Massachusetts, concluded in the presentation.

Disclosures: Dr Wei reports consultation or advisory roles with Dendreon, MacroGenics, and Novartis; receiving institutional research funding from Bristol Myers Squibb; conducting scientific trials with Barinthus Biotherapeutics, MacroGenics, Novartis, and Poseida Therapeutics; and receiving travel support from Novartis.

References
1. Shore ND, Wei XX, Chi KN, et al. Efficacy of [177Lu]Lu-PSMA-617 versus ARPI change in taxane-naive patients with metastatic castration-resistant prostate cancer by pre-randomization ARPI (PSMAfore). J Urol. 2024;211(5S2). doi:10.1097/01.JU.0001015816.87470.c9.04
2. Sartor O, Castellano Gauna DE, Herrmann K, et al. Phase III trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Ann Oncol. 2023;34(suppl 2):S1324-S1325. doi:10.1016/j.annonc.2023.10.085