Defects in DNA repair genes are now understood to be common in patients with metastatic castration-resistant prostate cancer (mCRPC) according to studies sequencing tumor samples [1] and the germline [2]. In a proof-of-concept study to demonstrate that such defects could be exploited therapeutically, patients with mCRPC with mutations in DNA repair genes had responses when treated with olaparib [3]. The mechanism by which PARP inhibition leads to cell death, is in part via induction of DNA double-strand breaks, which go unrepaired in cells harboring defects in the homologous recombination repair pathway [4].

We have previously reported on the therapeutic potential of high-dose testosterone in men with mCRPC [5]. Preclinical studies demonstrated that rapid cycling between high and low levels of androgen, termed bipolar androgen therapy (BAT), could disrupt DNA relicensing and produce DNA double-strand breaks in CRPC cells. Given the emerging data on DNA repair defects in prostate cancer and the mechanism of BAT, we postulated that men with such defects may be particularly susceptible to BAT. Here we report a case of an exceptional responder to BAT and the underlying tumor mutations that possibly explain his susceptibility to the therapy.