Moving Radioligand Targeted Therapy Earlier: Phase 3 Trial Opens a Path to Triple-Drug Combination Therapy for Metastatic Prostate Cancer

For patients with metastatic prostate cancer, the sequence of treatment is often as important as the drugs themselves. A phase 3 trial involving 1,144 people showed that lutetium-177–PSMA-617, a radioligand targeted drug previously used more often in later-line treatment, may further delay disease progression when added earlier while the tumor remains sensitive to hormonal therapy.

PSMAddition is an international, randomized, open-label trial comparing the triple-drug combination of lutetium-177–PSMA-617, an androgen receptor pathway inhibitor (ARPI), and androgen deprivation therapy (ADT) with the standard dual-drug treatment of an ARPI plus ADT. Trial registry data show that the experimental group received 7.4 GBq of lutetium-177–PSMA-617 intravenously every six weeks, with six cycles planned in total. The primary endpoint was radiographic progression-free survival, as determined by independent central review.

The results showed that, compared with the control group, the triple-drug group had a 28% lower risk of radiographic disease progression or death, with a hazard ratio of 0.72 and a 95% confidence interval of 0.58 to 0.90. Subgroup analyses released by the drugmaker indicated that the effect was broadly consistent among patients with high or low tumor burden and among those with metastases at initial diagnosis or after recurrence. However, subgroup results are used mainly to assess whether there are clear differences in efficacy and cannot prove that every patient category received the same degree of benefit.

Lutetium-177–PSMA-617 recognizes prostate-specific membrane antigen (PSMA), which is often highly expressed on prostate cancer cells, and then delivers radiation near the tumor. This mechanism distinguishes it from drugs that inhibit androgen signaling and provides a biological rationale for combining it with other treatments earlier. Another analysis from the same trial showed that the triple-drug group had a 58% lower risk of PSA progression. At week 48 of treatment, 87.4% of evaluable patients had PSA levels below 0.2 nanograms per milliliter, compared with 74.9% in the control group. However, a reduction in PSA is a surrogate endpoint and cannot be directly equated with longer survival or improved quality of life.

Adding the therapy also increased the treatment burden. Grade 3 or higher adverse events occurred in 50.7% of the triple-drug group and 43% of the control group. Common problems included dry mouth, fatigue, nausea, hot flashes, and anemia, while related literature has also mentioned gastrointestinal symptoms and reduced blood cell counts. Whether these side effects will accumulate because of earlier treatment, longer survival, or subsequent courses of therapy still requires longer follow-up.

The most critical gap at present is that the overall survival results remain immature, while quality of life, long-term safety, and healthcare costs have not been fully clarified. The trial used an open-label design and allowed patients in the control group to switch to lutetium-177–PSMA-617 after radiographic progression was confirmed centrally. This better reflects clinical ethical requirements but may also dilute the eventual survival difference between the two groups. The study therefore supports the possibility of moving radioligand targeted therapy earlier, but whether the evidence is sufficient to rewrite the standard treatment sequence for all patients with metastatic hormone-sensitive prostate cancer remains to be answered by the complete data.