Resistance to Poly (ADP-ribose) polymerases inhibitors (PARPi) has emerged as a significant challenge in cancer treatment, particularly in the context of targeting cancers with defects in DNA damage repair (DDR) pathways. While PARPi initially show promise in treating various cancers with DDR gene mutations, specifically those play crucial role in homologous recombination repair (HRR) pathway (Fig. 1), a substantial number of patients eventually develop resistance to these drugs, leading to disease progression and relapse (Heidenreich et al., 2014, Von Eyben et al., 2023). Understanding the mechanisms underlying this resistance is crucial for developing strategies to overcome or prevent it.

Prostate Cancer with HRR defects are particularly aggressive and therapy resistant (Cresta & Mateo, 2022). Therefore, the emergence of PARPi as a targeted therapy for prostate cancers characterized by HRR deficiency (HRD), has instilled substantial optimism within the field of oncology (Castro et al., 2013, Leongamornlert et al., 2014). PARPi like Olaparib (Falchi et al., 2017), Rucaparib (Fizazi et al., 2023), Talazoparib (Zhang et al., 2021), Niraparib (George et al., 2020) exploit the concept of synthetic lethality, leveraging on the inherent vulnerabilities of cancer cells with compromised DNA repair mechanisms (Lord & Ashworth, 2017). PARPi impede the maturation of nascent DNA strands during DNA replication, leading to cell death specifically in HR-deficient cancer cells (Heidenreich et al., 2014).

Nevertheless, similar to other targeted therapies, a significant clinical obstacle has emerged in the form of acquired resistance to PARPi. (Dias, Moser, Ganesan, & Jonkers, 2021). As time progresses, a percentage of cancer patients treated with these inhibitors undergo relapse and disease progression, emphasizing the immediate need to comprehend the complex molecular mechanisms responsible for this resistance phenomenon. It is essential to understand the adaptive strategies employed by cancer cells to evade the effects of PARP-inhibition to develop effective strategies to surmount or prevent resistance.

mCRPC, often harbors mutations in genes involved in DDR pathways, such as BRCA2, BRCA1, ATM and other HRR-related genes (Congregado et al., 2022, Von Werdt et al., 2021). While PARPi initially elicit promising responses in these subset of patients, resistance mechanisms can emerge through various avenues (Congregado et al., 2022, Faraoni and Graziani, 2018). These encompass the restoration of HRR functionality, either by secondary mutations in HRR genes or by the activation of alternative DNA repair pathways (Ghose, Moschetta, Pappas-Gogos, Sheriff, & Boussios, 2021). Additionally, alterations in drug efflux mechanisms and the loss of PARP trapping efficiency contribute to PARPi resistance (del Rivero and Kohn, 2017, Dias et al., 2021).

This review article seeks to provide a comprehensive overview of the ongoing research endeavors dedicated to unraveling the intricate molecular basis of PARPi resistance in prostate cancer with DDR deficiencies. By delving into the dynamic interplay between DDR pathways, genomic alterations, and adaptive responses, we aim to shed light on the multifaceted nature of resistance mechanisms. Ultimately, an improved understanding of these processes will pave the way for the development of novel therapeutic strategies that target and potentially overcome resistance, thereby enhancing the long-term clinical outcomes for patients with prostate cancer and DDR mutations.