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Adding Lu-PSMA-617 to Standard Hormonal Therapy Reduces Progression Risk by 28% in Hormone-Sensitive Prostate Cancer
In a phase 3 randomised trial of 1,144 men with PSMA-positive metastatic hormone-sensitive prostate cancer, adding [177Lu]Lu-PSMA-617 to androgen deprivation therapy plus an androgen receptor pathway inhibitor reduced the risk of radiographic progression or death by approximately 28% compared with standard hormonal therapy alone (HR 0.72, 95% CI 0.58–0.90; p=0.0021). The trial met its primary endpoint at the second interim analysis, supporting the potential role of radioligand therapy earlier in the prostate cancer disease course than previously established.
What Was Studied
The PSMAddition trial investigated whether adding the PSMA-targeted radioligand therapy [177Lu]Lu-PSMA-617 to the current standard of care — androgen deprivation therapy (ADT) combined with an androgen receptor pathway inhibitor (ARPI) — could prolong radiographic progression-free survival in men with PSMA-positive metastatic androgen pathway modulator-naive or androgen-sensitive (APMN/S) prostate cancer, a population in which radioligand therapy had not previously been formally evaluated in this combination.
How It Was Studied
PSMAddition is an ongoing, open-label, phase 3 superiority randomised controlled trial conducted across 169 sites in 20 countries. Eligible participants were male patients with treatment-naive or minimally treated metastatic APMN/S prostate cancer and at least one PSMA-positive lesion confirmed by centrally read [68Ga]Ga-PSMA-11 PET imaging. A total of 1,144 patients were randomly assigned 1:1: 572 received [177Lu]Lu-PSMA-617 (7.4 GBq intravenously every 6 weeks for up to six cycles) in addition to investigator-chosen ADT plus ARPI, while 572 received ADT plus ARPI alone. Control arm patients whose disease progressed with central radiographic confirmation were permitted to cross over to [177Lu]Lu-PSMA-617. The results reported here reflect the second interim analysis, with a median time from randomisation to data cutoff of approximately 23.6 months and a median radiographic progression-free survival follow-up of 19.6 months.
What Was Observed
- Radiographic progression-free survival was significantly prolonged in the [177Lu]Lu-PSMA-617 arm: only 24% of patients in the experimental arm experienced radiographic progression or death compared with 30% in the control arm, translating to an approximately 28% lower relative risk (HR 0.72, 95% CI 0.58–0.90; p=0.0021). Median radiographic progression-free survival was not reached in either arm at the time of this analysis, indicating that the majority of patients in both groups had not yet progressed.
- Grade 3 or worse adverse events were more frequent in the [177Lu]Lu-PSMA-617 arm, occurring in 51% of patients (286 of 564) versus 43% in the control arm (243 of 565), reflecting a clinically meaningful increase in treatment-related toxicity with the addition of radioligand therapy.
- Dry mouth was the most common adverse event associated with [177Lu]Lu-PSMA-617, affecting 46% of patients in that arm compared with just 4% in the control arm. Importantly, all cases were grade 1 or 2 in severity and none were classified as serious adverse events.
- Serious adverse events occurred in 32% of [177Lu]Lu-PSMA-617 arm patients versus 29% in the control arm; of these, only 3% were attributed to [177Lu]Lu-PSMA-617 itself. Additional adverse events with higher incidence in the experimental arm included cytopenias and gastrointestinal disturbances, consistent with the known profile of radioligand therapy.
Why This Matters
The current standard of care for metastatic APMN/S prostate cancer is ADT plus ARPI, and PSMAddition demonstrates that layering PSMA-targeted radioligand therapy onto this regimen can meaningfully delay disease progression. This finding challenges the prevailing approach of reserving [177Lu]Lu-PSMA-617 for later stages of prostate cancer treatment, raising the possibility that PSMA-targeted therapy may have a role much earlier in the disease course. The absence of unexpected safety signals from this drug combination provides an important initial reassurance regarding feasibility of this intensified approach.
How to Read This Result
While this large, multi-centre phase 3 trial provides high-quality evidence for an rPFS benefit, results derive from a second interim analysis with a median follow-up of less than two years, median rPFS has not been reached in either arm limiting the precision of long-term survival estimates, and the permitted crossover from the control arm may complicate future assessments of overall survival.
Limitations
This report represents a second interim analysis rather than a final analysis, and the relatively short median follow-up of approximately 23.6 months means the full durability of the radiographic progression-free survival benefit cannot yet be assessed. Because median rPFS was not reached in either arm, survival estimates carry inherent imprecision. The open-label design introduces potential for performance or assessment bias, and the permitted crossover of control arm patients to [177Lu]Lu-PSMA-617 upon confirmed progression could substantially confound future comparisons of overall survival between the two arms.