The AR signaling pathway is a major therapeutic target in prostate cancer, but resistance to AR-targeted drugs is a problem. Data from clinical trials evaluating existing and emerging AR-targeted agents were presented at the recent ESMO Congress 2024.

Following these proceedings, featured expert Matthew R. Smith, MD, PhD, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Smith’s clinical perspectives on these findings are presented here.

AR signaling is critical to the development and growth of the normal prostate gland, as well as cancers that arise from the prostate. Indeed, the AR is the best validated target in prostate cancer. There are 2 main categories of AR axis–targeting treatment. One category is ADT, which has been the cornerstone of systemic treatment for prostate cancer for many decades, particularly as an initial systemic therapy for metastatic prostate cancer. ADT has also been demonstrated to have an important role in patients who are being treated with the intention of cure.

The second category of AR axis–targeting treatments is ARPI therapy. There are 4 commercially available ARPIs. Enzalutamide, apalutamide, and darolutamide directly bind the AR to inhibit AR signaling. The fourth ARPI, abiraterone acetate, is an androgen biosynthesis inhibitor that targets the CYP17 enzyme.

There are no robust head-to-head comparisons of these ARPI agents, but cross-trial comparisons suggest that the efficacy of the 4 ARPIs is indistinguishable; each appears to similarly improve clinically important outcomes across a range of disease states, from metastatic castration-sensitive prostate cancer to nonmetastatic castration-resistant prostate cancer (CRPC). Although the 4 drugs have different labeled indications due to the different timelines of their development and the different studies that led to their US Food and Drug Administration (FDA) approvals, most experts view the efficacy of these drugs as interchangeable. Darolutamide appears to have the best safety profile, however, so many providers and patients prefer this drug.

In metastatic castration-sensitive prostate cancer, the current FDA label for darolutamide requires it to be used in combination with ADT and docetaxel, based on the ARASENS trial. Since the FDA approval of darolutamide, the prostate cancer field now generally reserves docetaxel for patients who have particularly poor prognoses. So, the phase 3 ARANOTE study was designed to understand the evidence for darolutamide with ADT without chemotherapy. The primary results of ARANOTE were reported at the ESMO Congress 2024 and concurrently published (abstract LBA68). The ARANOTE study met its primary end point with a marked improvement in radiographic progression-free survival (rPFS); overall survival data are still immature, but I believe that the rPFS data are sufficiently compelling that the label for darolutamide may be expanded to eliminate the current labeled requirement for the coadministration of docetaxel.

Although most prostate cancer initially responds to an ARPI, nearly all patients eventually develop resistance, and there is nearly complete cross-resistance between these drugs. Therefore, a major unmet need is having drugs that either extend the benefit of the ARPIs or overcome the drug resistance. A variety of approaches are under consideration to overcome resistance to these ARPIs.

A very interesting abstract from a small phase 1 study evaluated BMS-986365, a drug that may overcome ARPI resistance by being both a potent AR inhibitor and an AR degrader in patients with heavily pretreated metastatic CRPC (mCRPC; abstract 1597MO). A very respectable 50% of patients who received the highest dose of BMS-986365 (ie, 900 mg twice daily) achieved a PSA50, and the median rPFS was 8.3 months. While these are early results, I believe that this activity warrants the further development of the drug.

At the ESMO meeting, there was also an updated report from the phase 2 CYPIDES trial evaluating opevesostat, a selective CYP11A1 inhibitor that suppresses the production of all steroid hormones and their precursors in patients with ARPI-pretreated mCRPC (abstract 1605P). Opevesostat has shown promising activity in patients with progressive mCRPC despite prior treatment with abiraterone acetate and/or enzalutamide. Based on the phase 2 results, opevesostat is now in phase 3 clinical development.