PSMA radioligand therapy has been a late-line treatment. PSMAddition tested it much earlier, randomising 1,144 men with PSMA-positive metastatic androgen-pathway-modulator-naive prostate cancer to lutetium-177 PSMA-617 added to ADT plus an androgen receptor pathway inhibitor, or to ADT plus ARPI alone. Half had de novo metastatic disease and 68% had high-volume disease.
At the second interim analysis, radiographic progression or death had occurred in 24% of the radioligand arm against 30% of controls, a hazard ratio of 0.72. The primary endpoint was met. Median radiographic progression-free survival was not reached in either arm, at a median follow-up of about 20 months.
The toxicity is real and predictable. Grade 3 or worse adverse events occurred in 51% against 43%. Dry mouth affected 46% against 4%, though all were grade 1 or 2 — an almost universal, mild, permanent-feeling complaint that patients should hear about before consenting. Cytopenias and gastrointestinal disturbance were also more frequent.
What this does not yet show is longer life. Overall survival data are immature and median rPFS has not been reached, so the honest statement to a patient is that progression is delayed, not that survival is extended. In Indian practice the constraint is more basic: PSMA radioligand therapy needs a licensed nuclear medicine facility and is largely self-funded, so this changes the referral conversation far more than the prescription.
- Consider PSMA PET staging earlier if radioligand therapy is a realistic option locally — eligibility here required PSMA positivity.
- Consent explicitly for dry mouth: 46% against 4%, mild but persistent.
- State clearly that this is a progression benefit; overall survival is immature.
- Expect more grade 3 events, 51% against 43%, and plan blood count monitoring for cytopenias.
- Where radioligand therapy is unavailable, this does not change ADT plus ARPI as the standard.
The statistics, in plain English
A hazard ratio of 0.72 means the rate of radiographic progression or death was about 28% lower at any given moment, and the interval of 0.58 to 0.90 sits clear of 1.0. Two things temper it. This is a second interim analysis, so the trial was stopped for benefit at a pre-planned look — interim analyses tend to overstate effect size, because a trial is more likely to cross the boundary when random variation is running in its favour. And median radiographic progression-free survival was not reached in either arm, meaning fewer than half the men in either group had progressed; the curves are separating early and how they behave later is unknown. Radiographic progression-free survival is also a surrogate: it counts scan changes, not deaths, and drugs have improved it before without extending life.
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