Treatment intensification for metastatic prostate cancer: New treatment landscapes in androgen deprivation-based therapy

1|BACKGROUND Since 2004,the treatment landscape of metastatic prostate cancer(mPC)has significantly changed.When added to androgen deprivation therapy(ADT),many treatments demonstrated to improve overall survival(OS)of mPC patients both in hormone-sensitive(mHSPC)[1]and castration-resistant(mCRPC)setting[2].With multiple available options,therapy selection and the optimal treatment sequence are currently crucial clinical challenges.

Overcoming the mechanisms of primary and acquired resistance to new generation hormonal therapies in advanced prostate cancer: focus on androgen receptor independent pathways

In recent years,many therapeutic advances have been made in the management of castration-resistant prostate cancer,with the development and approval of many new drugs.The androgen receptor(AR)is the main driver in prostate cancer growth and progression and the most effective therapeutic agents are still directed against this pathway.Among these,new generation hormonal agents(NHA)including enzalutamide,abiraterone acetate,apalutamide,and darolutamide have shown to improve overall survival and quality of life of prostate cancer patients.Unfortunately,despite the demonstrated benefit,not all patients respond to treatment and almost all are destined to develop a resistant phenotype.Although the resistance mechanisms are not fully understood,the most studied ones include the activation of both dependent and independent AR signalling pathways.Recent findings about multiple growth-promoting and survival pathways in advanced prostate cancer suggest the presence of alternative mechanisms involved in disease progression,and an interplay between these pathways and AR signalling.In this review we discuss the possible mechanisms of primary and acquired resistance to NHA with a focus on AR independent pathways.