177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial

Abstract

Background: [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of ¹⁷⁷Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer.

Methods: In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous ¹⁷⁷Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to ¹⁷⁷Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff.

Findings: Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive ¹⁷⁷Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of ¹⁷⁷Lu-PSMA-617 cycles was 6·0 (IQR 4·0-6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive ¹⁷⁷Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38-10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77-not estimable) in the ¹⁷⁷Lu-PSMA-617 group versus 5·55 months (4·04-5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29-0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24-27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30-14·19) in the ¹⁷⁷Lu-PSMA-617 group versus 5·59 months (4·21-5·95) in the ARPI change group (HR 0·49 [95% CI 0·39-0·61]). The incidence of grade 3-5 adverse events was lower in the ¹⁷⁷Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related]).

Interpretation: ¹⁷⁷Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, ¹⁷⁷Lu-PSMA-617 may be an effective treatment alternative.

Funding: Novartis.

Figure 1:. Screening, randomisation, and follow-up at the time of third interim overall survival analysis

* 37 met PSMA PET imaging criteria but were excluded because they did not meet the other eligibility criteria or for other reasons. ^† One additional patient who underwent randomisation and was assigned to ¹⁷⁷Lu-PSMA-617 is not shown because they had a protocol deviation of informed consent not signed and were excluded from all analyses. One patient was randomised after the data cut-off for the primary analysis of the primary endpoint. ^‡ Abiraterone, n=100; enzalutamide, n=132. ^§ Patients eligible to crossover to ¹⁷⁷Lu-PSMA-617 had discontinued ARPI change with radiographic disease progression by blinded independent central review as per RECIST v1·1. ARPI=androgen receptor pathway inhibitor; CT=computed tomography; PET=positron-emission tomography; PSMA=prostate-specific membrane antigen.

Figure 2:. Radiographic progression-free survival (primary efficacy endpoint), overall survival (key secondary efficacy endpoint), health-related quality of life (secondary efficacy endpoint), and patient-reported pain (exploratory efficacy endpoint)

Panel A shows the updated analysis of radiographic progression-free survival at the time of the third interim overall survival analysis. The primary analysis of radiographic progression-free survival is shown in Figure S2. Radiographic progression-free survival was defined as the time to radiographic disease progression by blinded independent central review as per the Prostate Cancer Clinical Trials Working Group 3 criteria, or death. Panel B shows the third interim intention-to-treat analysis of overall survival. Note: three patients died before receiving ¹⁷⁷Lu-PSMA-617. Panel C shows the time to worsening of 10 points or greater in FACT-P total score^,, disease progression, or death at the time of the third interim overall survival analysis. Panel D shows the time to worsening of 2 points or greater in BPI-SF pain intensity scale^,, clinical disease progression, or death at the time of the third interim overall survival analysis. Schedule of investigations is detailed in Figure S1. ARPI=androgen receptor pathway inhibitor; BPI-SF=Brief Pain Inventory-Short Form; CI=confidence interval; FACT-P=Functional Assessment of Cancer Therapy-Prostate; NE=not estimable; PSMA=prostate-specific membrane antigen.

Figure 3:. Prostate-specific antigen responses (secondary efficacy endpoint) and soft tissue responses* (exploratory efficacy endpoint)

Panel A shows PSA responses. Data are from patients with available PSA measurements at the time of the third interim overall survival analysis; increases greater than 100% are truncated to 100%. Assessments were at 3, 6, and 12 months after randomisation. Panel B shows objective response rate. Data are from a subset of patients with measurable disease at baseline at the time of the third interim overall survival analysis; objective response rate is the sum of complete soft tissue response and partial soft tissue response; duration of response is estimated using the Kaplan–Meier method in patients with objective response as the duration from first documented best overall response to documented disease progression or death. * Assessment of soft tissue response was based on RECIST v1.1 but excluded bone lesion progression. ARPI=androgen receptor pathway inhibitor; CI=confidence interval; NE=not estimable; PSA=prostate-specific antigen; PSMA=prostate-specific membrane antigen; RECIST=Response Evaluation Criteria in Solid Tumours.