Mary-Ellen Taplin, MD, FASCO, on High-Risk Localized or Locally Advanced Prostate Cancer: PROTEUS Trial

Prostate cancer patients who are diagnosed with localized high-risk disease have high rates of relapse after standard-of-care treatment options of prostatectomy or radiation combined with androgen deprivation therapy. We designed the PROTEUS trial to test the hypothesis that 6 months of apalutamide combined with androgen deprivation therapy, given both before and after prostatectomy and compared to a control arm of placebo and androgen deprivation therapy, would improve two coprimary endpoints. These coprimary endpoints were major pathologic response, which was measured by either a complete response of tumor in the prostate or having a minimal amount of residual disease, less than 5 mm of tumor. And the second coprimary endpoint was metastasis-free survival. So PROTEUS was an international trial. It was done in 18 countries. A total of 2,109 patients were randomly assigned to these two cohorts and then followed, and the median time of follow-up was just over 5 years. When the data read out, what the data showed was that for the apalutamide ADT treatment, there was a ninefold improvement in the primary endpoint of a major pathologic response. This was measured by having no tumor or less than 5 mm of tumor. And there was an exploratory endpoint called residual cancer burden that also measures tumor cellularity and size, and that was 30% for apalutamide androgen deprivation compared with 11% for placebo androgen deprivation. So all of these pathology results show that apalutamide and ADT is killing more cancer cells in the prostate. The other coprimary endpoint is metastasis-free survival, and that was measured by PSMA PET imaging or conventional imaging, and that endpoint showed a 20% improvement for the apalutamide ADT. And in addition, if the MFS was measured by investigator-assessed MFS as opposed to the blinded central reviewer, there was a 24% improvement in MFS. These primary endpoints were supported by positive results in the secondary endpoints, a measure called event-free survival, which is recurrence of prostate cancer by any measure, PSA, local recurrence, any of the imaging that showed it’s also a significant benefit for apalutamide and ADT, with a 29% reduction for the apalutamide compared with the ADT alone. And then another secondary endpoint, which is called time to first subsequent therapy, was markedly positive, with almost a 3-year difference for the patients in the apalutamide ADT cohort needing another treatment. The known side effects of apalutamide, there was an incidence of rash. The rash was generally well controlled with standard algorithms that we use to treat rash that is seen with apalutamide and other stages of prostate cancer. So very excited about these primary and secondary endpoints. The exploratory endpoints support the other endpoints, and we’re very excited about the future work. There was a substudy in which 400 men were assigned to just going to prostatectomy or compared with the PROTEUS regimen, the 6 months of apalutamide and ADT before and after prostatectomy. So that study will read out later this year. We’re excited to see we are hypothesizing even a bigger difference, and the biomarker data will just be incredible. It’s 2,109 men that we will be able to look at metrics of favorable response versus resistance and be able to use generated hypotheses from PROTEUS to plan subsequent neoadjuvant and adjuvant work to improve the cure rates even more.