Dr Mar on Challenges With ARPI Rechallenge in Prostate Cancer

"In general, I do not rechallenge with an ARPI after [progression] on an ARPI, because [it is] common [for ARPI] resistance mechanisms [to] develop after someone has been exposed to an ARPI. We also want to consider the cost of health care right now. However, there have been recent developments [with rechallenge], which are still in the experimental phase."

Nataliya Mar, MD, an associate professor in the Division of Hematology/Oncology at the University of California, Irvine Chao Comprehensive Cancer Center, discussed the challenges associated with androgen receptor pathway inhibitor (ARPI) rechallenge in prostate cancer due to resistance mechanisms that arise following prior ARPI exposure, as well as early-phase research evaluating mechanisms that would make this approach more effective.

Rechallenge with an ARPI following progression on a prior agent is generally avoided in clinical practice, Mar noted. Resistance to ARPI therapy is a well-documented phenomenon in prostate cancer, and agents within this class typically lack efficacy once resistance to a similar drug has emerged. Additionally, rechallenging with another ARPI can be financially burdensome, particularly given the limited clinical benefit expected in this setting, Mar stated.

Despite these limitations, early-phase efforts have begun exploring mechanisms to potentially overcome ARPI resistance. One such approach is bipolar androgen deprivation therapy (ADT), which is being investigated as a strategy to resensitize tumors to subsequent ARPI treatment. This concept was evaluated in the phase 2 TRANSFORMER trial (NCT02286921), which compared bipolar ADT using high-dose testosterone vs enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received abiraterone acetate (Zytiga). The study demonstrated meaningful clinical activity and safety with bipolar ADT, as well as its ability to sensitize mCRPC to subsequent antiandrogen therapy. Although preliminary data have generated interest, bipolar ADT remains an investigational strategy and is not yet suitable for implementation in routine clinical care, Mar concluded.