ESMO 2023: PSMAfore Phase 3 Trial of [177Lu]Lu-PSMA-617 in Taxane-Naive Patients with Metastatic Castration Resistant Prostate Cancer

( The 2023 ESMO annual meeting included a Presidential session, featuring a presentation by Dr. Oliver Sartor discussing results of PSMAfore, a phase 3 trial of 177Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC). 177Lu-PSMA-617 is a targeted radioligand therapy for PSMA-positive mCRPC with the following mechanism of action:

psma illustration

It has been previously shown that 177Lu-PSMA-617 prolongs rPFS and OS in patients with mCRPC and prior ARPI and taxane therapy based on data from the VISION trial.1 The PSMAfore trial subsequently examined 177Lu-PSMA-617 in taxane-naive patients and was presented at the ESMO 2023 annual congress.

 Eligible adults for PSMAfore had mCRPC, were candidates for ARPI change after one progression on prior ARPI, and had ≥1 PSMA positive lesions and no exclusionary PSMA negative lesions by 68Ga-PSMA-11 PET/CT. Candidates for PARP inhibition and patients with prior systemic radiotherapy (<6 months ago), immunotherapy (except sipuleucel-T), or chemotherapy (except [neo]adjuvant >12 months ago) were ineligible. Randomization was 1:1 to open-label 177Lu-PSMA-617 (7.4 GBq every 6 weeks for 6 cycles) or ARPI change (abiraterone or enzalutamide). Importantly, patients randomized to ARPI could crossover to 177Lu-PSMA-617 following centrally reviewed radiographic progression. The trial design for PSMAfore is as follows: 

177Lu-PSMA-617 flow
The primary endpoint was rPFS (PCWG3/RECIST v1.1) and key secondary endpoints included OS (both overall α=0.025, one-sided) and FACT-P outcomes, with a key exploratory endpoint being ORR and duration of response. The primary analysis was to occur at approximately 156 rPFS events and the second OS interim analysis at approximately 125 deaths. Crossover-adjusted analysis was the prespecified method for OS by rank-preserving structural failure time.

 Overall, there were 468 patients randomized. As follows is the patient disposition at the second interim OS analysis, noting that 84.2% of patients that had an rPFS event in the ARPI change subsequently went on to receive crossover 177Lu-PSMA-617:177Lu-PSMA-617 ARPI change
The baseline characteristics were generally well balanced between the two groups:
177Lu-PSMA-617 characteristics
At the primary analysis (median follow-up, 7.3 months; n = 467), the primary endpoint of rPFS was met (HR 0.41, 95% CI 0.29 to 0.56), which was similar to second interim analysis (HR 0.43, 95% CI 0.33 to 0.54)177Lu-PSMA-617 arpi change 2
The subgroup analysis for rPFS showed a general benefit favoring the 177Lu-PSMA-617 group:
177Lu-PSMA-617 rPFS
Among men with measurable disease, the objective response rate was 50.7% for 177Lu-PSMA-617 versus 14.9% for ARPI change. The median duration of response was 13.63 months (95% CI 11.56 – NE) for 177Lu-PSMA-617 versus 10.05 months (95% CI 4.63 – NE) for ARPI change. As follows is a summary of the radiographic response rates, highlighting that patients in the 177Lu-PSMA-617 arm had a complete response rate of 21.1% versus 2.7% in the ARPI change arm:177Lu-PSMA-617 patient arpi change
Patients receiving 177Lu-PSMA-617 had a confirmed PSA decrease rate >=50% in 57.6% of patients compared to 20.4% of patients in the ARPI change arm. Time to symptomatic skeletal events also favored the 177Lu-PSMA-617 arm (HR 0.35, 95% CI 0.22 to 0.57). Time to composite health related quality of life or pain worsening as summarized by the FACT-P total score (HR 0.59, 95% CI 0.47 to 0.72) and BPI-SF pain intensity scale (HR 0.69, 95% CI 0.56 to 0.85), respectively, also favored 177Lu-PSMA-617:177Lu-PSMA-617 factp
Additionally, at the second interim analysis (45.1% of target deaths), 123/146 (84.2%) patients with reviewed radiographic progression who discontinued ARPI crossed over to receive 177Lu-PSMA-617. In the pre-specified cross-over adjusted analysis, there was a trend favoring 177Lu-PSMA-617, but no statistical difference in OS between the groups:
177Lu-PSMA-617 cross adjusted
In the unadjusted, intention to treat analysis for OS, the HR was 1.16 (95% CI 0.83 to 1.64). For 177Lu-PSMA-617 vs ARPI change, the incidence of grade ≥3 adverse events was 33.9% (most commonly anemia and dry mouth) versus 43.1%, serious adverse events 20.3% vs 28.0%, and adverse events leading to discontinuation 5.7% vs 5.2%, respectively. A summary of the most common adverse events is as follows:
177Lu-PSMA-617 adverse events
Dr. Sartor concluded his presentation discussing results of PSMAfore, a phase 3 trial of 177Lu-PSMA-617 in taxane-naive patients with mCRPC with the following take-home points:

  • 177Lu-PSMA-617 prolonged rPFS vs ARPI change in taxane-naive patients with PSMA+ mCRPC
  • Secondary and exploratory endpoints, including PSA response, objective response rate, time to symptomatic skeletal events, and time to worsening in health related quality of life and pain, also favored 177Lu-PSMA-617
  • The prespecified crossover-adjusted OS trended favorably for 177Lu-PSMA-617, given that the 84.2% crossover rate may have confounded the intention to treat analysis; OS data collection is ongoing
  • 177Lu-PSMA-617 had a manageable safety profile and was well tolerated

Presented by: A. Oliver Sartor, MD, Disease Group Leader GU Cancers, Director of Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.

  1. Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
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