Pair of ACIS.

Top Line: Does dual inhibition of androgen synthesis and androgen receptor signalling improve outcomes for men with metastatic castration resistant prostate cancer? 

The Study: While abiraterone improves overall survival in patients with mCRPC, resistance eventually develops through androgen receptor (AR) gene amplification and overexpression. Androgen receptor inhibitors like apalutamide also improve outcomes when added to ADT for mCRPC. ACIS was a phase 3 study that randomized 982 men with chemo-naive mCRPC on ADT to the addition of standard abiraterone or abiraterone plus apalutamide. The idea here was that combining the two with the purpose of “androgen annihilation therapy” might improve investigator-assessed radiographic progression-free survival. Previously, the PLATO trial found that adding abiraterone to enzalutamide didn’t improve PFS. In IPATential150, adding the AKT inhibitor ipatasertib to first-line abiraterone (in men with PTEN loss) eked out an improvement in median radiographic PFS from 17→ 19 months. Here in ACIS, the combination of apalutamide + abiraterone significantly improved median radiographic PFS from 16.6→ 22.6 months. However, there was no significant improvement in median overall survival (36.2 vs 33.7 months). And while more patients had a > 50% reduction in PSA and PSA decline to undetectable with apalutamide + abiraterone, there was no difference in overall response rate or time to PSA progression. There was also no difference in time to initiation of cytotoxic chemotherapy. Toxicity was similar between groups. Perhaps Lu-177-PSMA-617 will fare better one day in this setting.

TBL: Combining apalutamide and abiraterone (as opposed to abiraterone alone) prolongs radiographic progression-free survival but not overall survival in men with chemo-naive mCRPC. | Saad, Lancet Oncol 2021

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