Docetaxel (taxane chemotherapy) then 177Lu-PSMA-617

The pivotal VISION trial (NCT03511664; Sartor et al., NEJM 2021) that supported FDA and EMA approval of 177Lu-PSMA-617 (Pluvicto) enrolled adults with metastatic castration-resistant prostate cancer who had already progressed on at least one androgen-receptor pathway inhibitor (for example abiraterone or enzalutamide) and on one or two prior taxane-based chemotherapy regimens, typically docetaxel. Patients also had to have PSMA-positive disease on centrally read 68Ga-PSMA-11 PET-CT, with no qualifying PSMA-negative lesions. 177Lu-PSMA-617 (7.4 GBq every 6 weeks, up to 6 cycles) plus protocol-permitted standard care was compared with standard care alone; median overall survival was 15.3 months versus 11.3 months (hazard ratio 0.62, 95% CI 0.52-0.74, p<0.001).

Because prior taxane exposure was a trial entry requirement rather than a randomised comparison of sequencing strategies, VISION establishes an evidence-based treatment order — androgen-receptor pathway inhibitor, then taxane chemotherapy (commonly docetaxel), then 177Lu-PSMA-617 — rather than proving that giving the radioligand therapy after docetaxel is better than giving it before. Retrospective subgroup analyses of VISION found that survival benefit from 177Lu-PSMA-617 was preserved regardless of whether patients had received one or two prior taxane regimens, and regardless of the number of prior androgen-receptor pathway inhibitors.

This sequencing question is now being tested directly: the phase 3 PSMAfore trial (NCT04689828) enrolled taxane-naive patients progressing after one androgen-receptor pathway inhibitor and randomised them to 177Lu-PSMA-617 or to switching to a different androgen-receptor pathway inhibitor, explicitly to establish whether radioligand therapy can move earlier in the treatment sequence, ahead of chemotherapy, rather than only being used after it.