Radioligand, ADT, and ARPI Combo Betters Patient Outcomes in Prostate Cancer

Adding [¹⁷⁷Lu]Lu-PSMA-617 to androgen deprivation therapy (ADT) with an androgen receptor pathway inhibitor (ARPI) led to better disease control in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to findings from the phase 3 PSMAddition study (NCT04720157).¹

These results prompted investigators to carefully evaluate patient-reported outcomes (PROs) to ensure that clinical benefit did not come at the cost of daily functioning, comfort, or overall well-being.

Presenting the results at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium, Michael J. Morris, MD, noted, “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 is head of the Prostate Cancer Section at Memorial Sloan Kettering Cancer Center in New York, New York.

During a median follow-up of nearly 2 years, longitudinal analyses demonstrated that overall health-related quality of life (HRQOL) and pain were largely maintained with the triplet regimen compared with ADT plus ARPI alone. Time to the first symptomatic skeletal event (SSE), whether including or excluding death in the composite end point, was similar across both treatment groups.

Background and Rationale for the PSMAddition Study

The PSMAddition study was designed to assess whether adding ¹⁷⁷Lu-PSMA-617 to standard therapy could extend the time patients live without disease progression and improve overall outcomes in prostate-specific membrane antigen (PSMA)–positive mHSPC. Trial participants had been either untreated or minimally treated, had PSMA-positive disease confirmed by gallium-68 PSMA PET imaging, and were fully functional or had only minor limitations (ECOG performance status 0 to 2).

Participants were randomly assigned to receive either standard ADT plus an ARPI or the same therapy with up to 6 cycles of ¹⁷⁷Lu-PSMA-617 delivered over a maximum of 36 weeks.

The primary end point was radiographic progression-free survival (rPFS). Secondary end points included overall survival (OS), HRQOL, pain, and the time to first SSE.

Patient-reported outcomes (PROs) were measured using validated tools: the Functional Assessment of Cancer Therapy–Prostate (FACT-P) for prostate cancer–specific well-being, the EQ-5D-5L for general health status, and the Brief Pain Inventory–Short Form (BPI-SF) to assess pain intensity and interference with daily activities. PROs were collected every 6 weeks during active treatment, then at longer intervals during follow-up.

Questionnaire Completion and Assessment

Baseline questionnaire completion was high across both treatment arms, providing reliable data for longitudinal evaluation. In the triplet arm, the majority of patients completed baseline FACT-P, EQ-5D-5L, and BPI-SF assessments, and completion rates were only slightly lower in the ADT plus ARPI arm.

Time-to-event end points were predefined to capture meaningful worsening during therapy. For FACT-P, a drop in scores signaled a decline in overall or functional well-being, whereas the EQ-5D-5L captured shifts in general health status. Pain worsening was tracked by changes in intensity and interference on the BPI-SF. SSEs included fractures, spinal cord compression, tumor-related bone surgery, radiotherapy for bone pain, clinical disease progression, or death.

These definitions allowed investigators to monitor both disease control and the patient experience over time.

HRQOL and Pain Findings

Overall, longitudinal analysis showed that HRQOL and pain were preserved with the addition of ¹⁷⁷Lu-PSMA-617. FACT-P scores indicated a small, temporary dip in the triplet arm during the period when patients were actively receiving radioligand therapy.

This early dip was mostly related to functional well-being and prostate cancer–specific concerns. However, once patients returned to ADT plus ARPI alone, scores recovered and became similar between both groups.

EQ-5D-5L scores remained stable throughout treatment and follow-up, indicating that patients’ overall perception of health did not meaningfully change with the addition of ¹⁷⁷Lu-PSMA-617. Pain scores on the BPI-SF were also comparable between groups, showing that the triplet regimen did not increase discomfort or limit daily activities.

Skeletal Outcomes

Time to first SSE, whether including or excluding death, was similar between treatment arms. Most patients did not experience skeletal complications during follow-up. Use of bone-protective medications, such as denosumab and bisphosphonates, was modest in both arms and did not appear to influence overall outcomes.

What to Understand

These findings complement the previously reported improvement in disease control and support the feasibility of integrating PSMA-targeted radioligand therapy earlier in mHSPC. Importantly, patients receiving triplet therapy were able to maintain QOL and pain control throughout treatment.

Temporary dips in functional scores during active radioligand therapy were recovered once standard therapy resumed, demonstrating that early intensification does not result in lasting declines in HRQOL.

Skeletal complications were not increased with the triplet regimen, further supporting the safety of this approach. Longer-term follow-up will help clarify the durability of QOL recovery, any late toxicities, and downstream impacts on bone health.

REFERENCE

1. Morris MJ, 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):Abstract 18. doi:10.1200/JCO.2026.44.7_suppl.18