Bipolar Androgen Therapy (Bat) Plus Olaparib In Men With Metastatic Castration-Resistant Prostate Cancer (Mcrpc)

BAT leads to a rapid fluctuation in testosterone (T) between near-castrate and supraphysiologic levels and has shown promise in mCRPC. Its clinical effects may be mediated through induction of DNA damage, and preclinical studies suggest synergy in combination with the PARP inhibitor olaparib. This is a single center phase II trial testing olaparib (300 mg PO BID) plus BAT. BAT entails intramuscular T cypionate/enanthate 400 mg every 28 days while continuing androgen deprivation to suppress endogenous T. Subjects were required to have no cancer-related pain and to have previously received abiraterone (abi) and/or enzalutamide (enza). The primary objective was to assess the PSA50 response rate (proportion with PSA decline ≥50%) following ≥12 weeks of therapy. The primary analysis was based on the entire study cohort; however, we also assessed outcomes stratified by homologous recombination repair (HRR) gene mutational status and required 50% of men enrolled to have at least one HRR gene alteration. Thirty-six patients (pts) enrolled and 6 discontinued prior to response assessment, leaving 30 response evaluable pts. Pts discontinued early for progression (n=2), nausea (n=2), stroke (n=1) and myocardial infarction (MI) (n=1). The median age was 70 yrs (range: 51-88). Thirteen pts received prior abi, 7 received prior enza and 10 received both. Fourteen (47%) pts had a PSA50 response. With a median follow up of 22.7 mos (IQR: 13.3-NR), the median progression free survival (PFS) was 12.6 mos (95% CI: 8.3-15.4). PSA50 responses were seen in 7/15 (47%) pts with and 7/15 (47%) pts without an HRR mutation. PFS in the HRR-intact group was longer than the HRR-mutated group (median PFS: 14.8 vs. 7.5 mos, P=0.015). Five pts had grade (G) ≥3 treatment-related adverse events (AE), including 1 stroke (G4) and 1 MI (G5). Following an amendment to exclude history of MI, no additional cardiovascular (CV) AEs were observed. BAT plus olaparib is associated with high response rates and long PFS. Clinical benefit was observed regardless of HRR gene mutational status. Treatment was well tolerated, although caution should be taken in using this in men with a history of CV disease. Larger studies evaluating this regimen are warranted.