Could BAT Make PARP Inhibitors Work Better in Prostate Cancer?

A new 2026 review proposes an interesting idea: bipolar androgen therapy (BAT) may help make prostate cancer more sensitive to PARP inhibitors, even in some tumours that do not carry the classic BRCA1/2 mutations usually associated with strong PARP responses.

BAT exposes prostate cancer cells to rapid swings between very high and very low testosterone levels. These supraphysiological androgen levels can create substantial DNA damage, but they may also reduce the activity of genes involved in homologous recombination repair, one of the main systems cells use to repair damaged DNA. The result could be a temporary “BRCAness-like” state, in which tumour cells become more dependent on PARP-mediated repair and therefore more vulnerable to PARP inhibition.

This concept is important because PARP inhibitors work best in cancers with clear homologous-recombination defects, especially BRCA2-mutated prostate cancer. Their activity in other DNA-repair alterations, such as ATM, is generally less consistent. BAT could potentially create an additional layer of repair weakness, making some of these less sensitive tumours more responsive to PARP inhibition.

The idea is not purely theoretical. A phase 2 study combining BAT with olaparib (here is the link) in metastatic castration-resistant prostate cancer showed activity in both HRR-mutated and HRR-proficient patients, supporting the possibility that BAT may act as a biological “primer” rather than simply as another anticancer treatment.

The review also raises the possibility that BAT could help overcome some forms of acquired resistance to PARP inhibitors by increasing DNA damage while simultaneously weakening repair pathways. However, this remains a hypothesis that needs prospective clinical confirmation.

The broader implication is that BAT may have a role beyond direct tumour control. By changing the biology of the cancer and making DNA repair less efficient, it could potentially widen the group of patients who benefit from PARP inhibitors and create new combination strategies for advanced prostate cancer.

Source.