Abstract 2070: Androgen deprivation and its impact on DNA repair in combination with ionising radiation and Radium-223 in prostate cancer

Abstract

Abstract Abiraterone acetate and Enzalutamide are novel anti-androgens shown to be one of the few treatments to improve both progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. However, many questions exist regarding the optimal combination and scheduling with radiation, the degree of additivity or synergism and the underlying mechanisms governing any potential synergy. This study is attesting the biological rationale for the selection of Abiraterone or Enzalutamide as, currently, the choice of therapy is a clinical decision based on experience and side effect profiles. As well as external beam radiotherapy a key unexplored area of interest is the combination of these inhibitors with the α-emitter radium-223, which targets bone metastases, with preliminary studies, such as the ERA-223 study, highlighting the need for further studies to mechanistically determine if these combinations are effective and safe. To better understand this, we conducted a detailed analysis of the effects of Abiraterone (10µM), Enzalutamide (10µM) or DMSO (Control) alone or in combination with a dose range of X-rays and radium-223 exposure on cell cycle, DNA damage, DNA repair and cell viability across a panel of androgen-insensitive (PC3), androgen-sensitive (LNCaP) and osteoblastic bone models (SJSA-1, SAOS-2). We report significant differences in the synergy of these AR inhibitors in combination with radiation, with Abiraterone causing significant radiosensitisation regardless of AR status and radiosensitisation with Enzalutamide being dependent on AR-sensitivity. This suggests a potential alternative mechanism of action of Abiraterone, not dependent on AR status. AR suppression alone was also shown to impact cell-cycle distribution, with most notable changes being increases in sub-G1 at the expense of S phase, with observed increases in PARP-cleavage supporting this being a result of increased levels of apoptosis and potential reductions in RAD51 levels. Studies with radium-223 confirmed the highly damaging nature of α-particles, with radium-223 treatments shown to be highly cytotoxic compared to equivalent doses of X-rays. Compared to X-rays, radium-223 induced cell cycle distribution changes in the form of much larger shifts towards G2, which also took longer to recover. As well as increased levels of apoptosis through observed increases in PARP-cleavage. Combinations of radium-223 with Abiraterone or Enzalutamide led to a loss of all additive or synergistic effects previously measured with X-rays. Most likely due to the highly cytotoxic nature of α-particles due to the induction of non-reparable DNA dsb. In conclusion, these results support the use of Abiraterone and Enzalutamide in combination with X-rays and radium-223 to enhance tumor response independently of androgen receptor status. Citation Format: Timothy Wright, Victoria Dunne, Aidan Cole, Kevin Prise. Androgen deprivation and its impact on DNA repair in combination with ionising radiation and Radium-223 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2070.