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Abstract Disclosure: E. Wheeler: None. N. Traphagen: None. R. Li: None. A. Tewari: None. X. Qiu: None. M. Brown: None. Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors as a potential treatment for advanced prostate cancer. Despite promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. As such, combination AR pathway inhibition and PARP inhibition has been approved by the US FDA only in the HR-deficient setting. To elucidate this discrepancy between preclinical and clinical results, we aimed to comprehensively profile the effects of PARP inhibition on AR function in HR-proficient prostate cancer models. In pursuit of this goal, we conducted experiments using HR-proficient prostate cancer cell lines, including LNCaP, 22RV1, VCaP, LN95, and LNCaP-abl, and assessed the effects of the PARP1/2 inhibitors olaparib, rucaparib, talazoparib, and the PARP1-selective inhibitor AZD-5305. Our findings reveal impacts of PARP inhibitor treatment on AR function. RNA-sequencing analysis demonstrates inhibition of AR transcriptional function in PARP inhibitor-treated cells. Treatment with PARP inhibitors inhibited androgen-induced expression of a subset of genes, with analysis revealing enrichment for Hallmark MYC targets in this gene set. Conversely, treatment with PARP inhibitors also inhibited androgen-induced repression of a subset of genes. However, despite these PARP inhibitor-mediated effects on AR function, our testing of the combination of PARP inhibitors and enzalutamide showed no evidence of synergy or enhanced growth-inhibitory effects at physiologically relevant doses of these inhibitors. Additionally, contrary to previously published data, we observed no evidence that androgen deprivation inhibits the expression of DNA damage response gene sets. This is concordant with the lack of synergy between PARP inhibitors and AR inhibition found in these HR-proficient models. Finally, our analysis comparing PARP1/2 with PARP1-selective inhibitors suggests that these drugs exhibit similar biological effects, both in terms of their growth-inhibitory effects and in modulating AR activity. Collectively, our results indicate that while PARP inhibitors influence AR transcriptional function, they do not synergize with androgen deprivation or AR inhibition in HR-proficient prostate cancer cells. Presentation: 6/2/2024
Wheeler et al. (Tue,) studied this question.