Design issues with lutetium-177 PSMA-617 registration studies that bias the outcome of the experimental arm reflect an increasing misalignment of contemporary oncology trials with true patient benefit.

In the PSMAfore randomized controlled trial patients with chemotherapy naïve castrate resistant metastasized prostate cancer (CRPC) progressing after one line of a second-generation androgen receptor signaling inhibitor (ARSI) were randomized to the experimental arm of lutetium-177 PSMA-617 or the control arm of another ARSI. The trial showed an increase in the primary endpoint radiographic progression free survival in the experimental arm. Previously, the VISION trial led to the approval of lutetium-177 PSMA-617 in patients with CRPC progressing after at least 1 second generation ARSI and at least 1 line of chemotherapy with a taxane. We highlight several shortcomings in both trials concerning use of putative surrogate endpoints, control arm treatments not reflective of contemporary standards of care, informative censoring and inappropriate cross-over, that all bias results in favor of the experimental arms. Additional regulatory approval of lutetium-177 PSMA-617 for patients prior to receiving chemotherapy would not only lead to further exposure of patients to a treatment without proper proof of benefit but to unsubstantiated health care spending as well.