PSMAddition shows rPFS benefit for 177Lu-PSMA-617 triplet in PSMA-positive mHSPC

Adding 177Lu-PSMA-617 to ADT plus an ARPI improved radiographic progression-free survival in patients with PSMA-positive metastatic hormone-sensitive prostate cancer. Results from the phase 3 PSMAddition study also showed that health-related quality of life and pain were largely maintained with the triplet regimen compared with ADT plus ARPI alone during a median follow-up of 23.6 months.

PSMAddition was designed to test whether adding 177Lu-PSMA-617 to ADT plus an ARPI could prolong rPFS and overall survival in patients with PSMA-positive disease identified on gallium-68 PSMA positron emission tomography. The primary efficacy analysis demonstrated a statistically significant rPFS improvement with the triplet regimen, with a hazard ratio of 0.72 (95% CI, 0.58-0.90; P = .002).

The study enrolled patients with untreated or minimally treated PSMA-positive mHSPC confirmed by gallium-68 PSMA PET imaging and an ECOG performance status of 0, 1, or 2. Participants were randomly assigned in a 1:1 ratio to receive ADT plus an ARPI, or ADT plus an ARPI with up to 6 cycles, maximum 36 weeks, of 177Lu-PSMA-617. The primary end point was rPFS, and key secondary end points included overall survival, health-related quality of life, pain, and time to first symptomatic skeletal event.

Patient-reported outcomes were assessed with the Functional Assessment of Cancer Therapy–Prostate total score, EuroQol 5-Dimension 5-Level utility score, and Brief Pain Inventory–Short Form. Assessments were conducted every 6 weeks through week 36, then every 12 weeks, then 24 and 48 weeks after end of treatment.

In the 177Lu-PSMA-617 plus ADT and ARPI arm, 511 patients (89.3%) had a baseline FACT-P total score available, 512 (89.5%) had an EQ-5D-5L utility score, and 509 (89.0%) had a BPI-SF worst pain intensity score. In the ADT plus ARPI arm, baseline completion rates were 483 patients (84.4%) for the FACT-P total score, 487 (85.1%) for the EQ-5D-5L utility score, and 481 (84.1%) for the BPI-SF worst pain intensity score.

Time-to-event end points were prespecified and defined as the time from randomization to the first occurrence of clinically meaningful worsening during treatment. For pain outcomes assessed by the BPI-SF, worsening was defined as a 30% or greater increase or an increase of at least 2 points from baseline in pain intensity, pain interference, or worst pain intensity. Symptomatic skeletal events were defined as a new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, the requirement for radiotherapy to treat bone pain, clinical disease progression, or death.

Composite analyses of time to worsening in health-related quality of life and pain showed hazard ratios greater than 1.0 but less than 1.2 across instruments, with all confidence intervals overlapping 1.0, indicating no statistically significant differences between treatment arms. Time to first symptomatic skeletal event, with or without death included in the composite end point, was comparable between arms.