Adding 177Lu-PSMA-617 to ADT Plus ARPI Improves Radiographic PFS in mHSPC

Results from the phase 3 PSMAddition study (NCT04720157) revealed at the 2026 ASCO Genitourinary Cancers Symposium demonstrated that adding [¹⁷⁷Lu] Lu-PSMA-617 to androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) yielded favorable radiographic progression-free survival (rPFS) among patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The presenter of these results, Michael J. Morris, MD, said that the findings prompted evaluation of patient-reported outcomes (PROs) to determine whether clinical benefit was achieved without compromising daily functioning or symptom burden.

During a median follow-up of 23.6 months (range, 17.7-42.8), longitudinal analyses demonstrated that health-related quality of life (HRQOL) and pain were largely maintained with the triplet regimen compared with ADT plus ARPI alone. Time to first symptomatic skeletal event (SSE), with or without death included in the composite end point, was comparable between arms.

“These data represent time to worsening quality of life and pain…when the patient has the decline in quality of life, the patient is censored, and even if the patient’s quality of life improves later in the study, you will not see that…We are presenting today the actual quality-of-life data longitudinally, which is much more illuminating,” Morris, prostate cancer section head in Genitourinary Oncology and Steven A. Greenberg Chair in Prostate Cancer Research, Memorial Sloan Kettering Cancer Center, said.

Understanding the background and methods associated with the PSMAddition study

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

“That does, of course, beg the question: how did patients feel and how did they function over the course of treatment on both arms, having benefited from a more durable disease control in the ¹⁷⁷Lu-PSMA-617 arm,” Morris emphasized when discussing the rationale of this research.

PSMAddition 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 (control arm), or
• ADT plus an ARPI with up to 6 cycles (maximum 36 weeks) of ¹⁷⁷Lu-PSMA-617 (triplet arm).

The primary end point was rPFS. Key secondary end points included OS, HRQOL, pain, and time to first SSE. PRO instruments consisted of Functional Assessment of Cancer Therapy–Prostate (FACT-P) total score, EuroQol 5-Dimension 5-Level (EQ-5D-5L) utility score, and Brief Pain Inventory–Short Form (BPI-SF). Patient-reported HRQOL and pain were assessed 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 (n = 572), 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 (n = 572), 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 endpoints were prespecified and defined as the time from randomization to the first occurrence of clinically meaningful worsening during treatment. Worsening in FACT-P total score was defined as a decrease of at least 10 points from baseline. For the FACT-P well-being subscales, worsening was defined as a decrease of at least 3 points from baseline. Worsening in EQ-5D-5L utility score was defined as a decrease of 0.08 points or greater from baseline.

For pain outcomes assessed by the BPI-SF, worsening was defined as a ≥30% 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 the occurrence of 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.

These definitions were applied prospectively to evaluate time to deterioration across HRQOL, pain, and skeletal morbidity endpoints in the study population.

HRQOL findings

Composite analyses of time to worsening in HRQOL 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.

For the FACT-P total score, the median time to deterioration was 11.33 months (95% CI, 8.84-14.03) in the ¹⁷⁷Lu-PSMA-617 plus ADT and ARPI arm compared with 17.12 months (95% CI, 13.80-19.91) in the ADT plus ARPI arm (HR, 1.14; 95% CI, 0.98-1.33).

For the EQ-5D-5L utility score, the median time to worsening was 11.10 months (95% CI, 8.84–14.06) with ¹⁷⁷Lu-PSMA-617 plus ADT and ARPI and 15.67 months (95% CI, 11.76–19.12) with ADT plus ARPI (HR, 1.13; 95% CI, 0.97-1.31).

Pain outcomes assessed by the BPI-SF demonstrated a median time to worsening of 11.53 months (95% CI, 8.77-14.09) in the triplet arm and 13.83 months (95% CI, 11.10-16.79) in the doublet arm (HR, 1.02; 95% CI, 0.87-1.18).

Longitudinal FACT-P total scores revealed an initial divergence between treatment arms during the period in which patients received triplet therapy, driven primarily by the FACT-P functional well-being and prostate cancer–specific subscales. This early separation suggested a transient decrement in HRQOL among patients receiving ¹⁷⁷Lu-PSMA-617 in combination with ADT plus ARPI, Morris explained.

However, this difference diminished over time. Once both groups were receiving doublet therapy alone, the curves reconverged, and overall HRQOL was similar between arms. Importantly, this pattern reflects dynamic recovery rather than persistent impairment.

In contrast, EQ-5D-5L utility scores demonstrated no meaningful longitudinal differences between treatment groups throughout the evaluable period, he emphasized.

Pain control was comparable between the triplet and doublet arms across the entire evaluable timeframe. There was no evidence of increased pain burden associated with ¹⁷⁷Lu-PSMA-617 when added to ADT plus ARPI.

Time to First SSE

Time to first symptomatic skeletal event (SSE) or death was comparable between treatment arms.

The hazard ratio for the composite endpoint of first SSE or death was 0.89 (95% CI, 0.62–1.26). Median time to the composite event was not reached (NR; not estimable) in either the ¹⁷⁷Lu-PSMA-617 plus ADT and ARPI arm or the ADT plus ARPI arm, with confidence intervals not estimable.

When death was excluded and only time to first SSE was analyzed, results remained similar between groups. The hazard ratio for time to first SSE was 0.87 (95% CI, 0.58–1.31), and the median time to event was not reached in either arm (NR; not estimable).

Use of bone-protective agents differed modestly between treatment groups. In the ¹⁷⁷Lu-PSMA-617 plus ADT and ARPI arm (n = 564), denosumab was administered to 65 patients (11.5%) and bisphosphonates to 46 patients (8.2%). In the ADT plus ARPI arm (n = 565), denosumab use was reported in 89 patients (15.8%) and bisphosphonate use in 50 patients (8.8%).

What to take away from this research

These findings complement the previously reported rPFS benefit and support the feasibility of treatment intensification with PSMA-targeted radioligand therapy earlier in the disease course. Longer follow-up will be required to fully characterize durability of HRQOL recovery, late toxicities, and potential downstream effects on skeletal morbidity.

Reference

Morris M, Gupta S, Tagawa ST, et al. Health-related quality of life, pain and symptomatic skeletal events in the phase 3 PSMAddition study of [177Lu]Lu-PSMA-617 combined with ADT and ARPI in patients with PSMA-positive mHSPC. J Clin Oncol. 2026;44(suppl 7):18. doi:10.1200/JCO.2026.44.7_suppl.18.