Targeting androgen-independent pathways: new chances for patients with prostate cancer?

- AR-independent pathways are an alternative mechanism contributing to PC progression.
- PARP inhibitors have shown clinical activity in patients with DNA-repair defects.
- Assessment of safety and benefit of AKT blockade in patients with PTEN loss is pending.
- Combination of PD-1 inhibitors and AR blockade is promising, but data need confirmation.
- Molecular stratification may drive treatment choices in specific subsets of patients.

Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC.