Lutetium Lu 177 Vipivotide Tetraxetan Plus ADT and an ARPI Maintains QOL in mHSPC

Treatment with lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in combination with androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI) resulted in similar quality-of-life (QOL) outcomes compared with ADT plus an ARPI alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to findings from the phase 3 PSMAddition study (NCT04720157).¹

These data follow previous reports showing that at the second interim analysis of PSMAddition, the median radiographic progression-free survival (rPFS) was significantly improved with the addition of lutetium Lu 177 vipivotide tetraxetan (HR, 0.72; 95% CI, 0.58-0.90; P = .002).²

In a presentation of the data at the 2026 Genitourinary Cancers Symposium, presenter Michael J. Morris, MD, said that the efficacy findings prompted evaluation of patient-reported outcomes (PROs) to determine whether clinical benefit was achieved without compromising daily functioning or symptom burden.¹

At a median follow-up of 23.6 months (range, 17.7-42.8), longitudinal analyses demonstrated that health-related QOL (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 QOL and pain…when the patient has the decline in QOL, the patient is censored, and even if the patient’s QOL improves later in the study, you will not see that…We are presenting today the actual QOL data longitudinally, which is much more illuminating,” Morris, section head of prostate cancer in Genitourinary Oncology and the Steven A. Greenberg Chair in Prostate Cancer Research at Memorial Sloan Kettering Cancer Center in New York, New York, said.

What are the background and methods associated with the PSMAddition study?

PSMAddition was designed to test whether adding lutetium Lu 177 vipivotide tetraxetan to ADT plus an ARPI could prolong rPFS and overall survival (OS) in patients with PSMA-positive disease identified on gallium-68 PSMA 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 lutetium Lu 177 vipivotide tetraxetan 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 lutetium Lu 177 vipivotide tetraxetan (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 lutetium Lu 177 vipivotide tetraxetan 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 end points were prespecified and defined as the time from random assignment 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% or higher 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.

What were the HRQOL findings from the PSMAddition trial?

Composite analyses of time to worsening in HRQOL and pain showed HRs 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 lutetium Lu 177 vipivotide tetraxetan 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 lutetium Lu 177 vipivotide tetraxetan 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 lutetium Lu 177 vipivotide tetraxetan 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 lutetium Lu 177 vipivotide tetraxetan when added to ADT plus ARPI.

What were the times to first SSE in the QOL analysis of the PSMAddition trial?

The times to first SSE or death were comparable between the treatment arms. The HR for the composite end point of first SSE or death was 0.89 (95% CI, 0.62-1.26). The median time to the composite event was not reached (NR) in either the lutetium Lu 177 vipivotide tetraxetan 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 HR for time to first SSE was 0.87 (95% CI, 0.58-1.31), and the median time to event was NR in either arm.

Use of bone-protective agents differed modestly between treatment groups. In the lutetium Lu 177 vipivotide tetraxetan 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%).

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.

References

1. 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.
2. Tagawa ST, Sartor O, Piulats JM, et al. LBA6 phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Ann Oncol. 2025;36(suppl 2):S1627-S1628. doi:10.1016/j.annonc.2025.09.101