New treatment approaches for and ongoing trials in metastatic hormone-sensitive prostate cancer

Background: For many years, therapy for metastatic hormone-sensitive prostate cancer (mHSPC) was dominated by monotherapy using androgen deprivation therapy (ADT). With the demonstration of survival benefit with intensified systemic therapy from the CHAARTED and STAMPEDE trials, this has fundamentally changed. We analyzed the phase III trials that led to the change in therapy in mHSPC. In addition, we summarized ongoing trials in mHSPC.Objectives: The ongoing studies and current data on systemic therapy in mHSPC were analyzed.Results: Monotherapy with ADT is no longer considered the standard therapy for mHSPC. Combination therapy with ADT and novel androgen receptor targeting agents (ARTAs: abiraterone, apalutamide, enzalutamide) is now the established standard option. The added value of further intensification of therapy was demonstrated in the first trials of triple therapy with ADT + docetaxel + darolutamide or abiraterone in mHSPC. Current studies are also investigating new forms of therapy. Lutetium177PSMA radioligand therapy is an established standard in metastatic castration-resistant prostate cancer (mCRPC) and is currently being evaluated in combination with ADT + ARTA in mHSPC. The use of PARP inhibitors (PARPi) have been established in mCRPC. Current studies are showing early evidence of benefit from novel combination therapies of PARPi+ ARTA, which represent a further expansion of the therapeutic landscape. Experimental therapies are testing another combination, such as an AKT inhibitor with ARTA in patients with PTEN (phosphatase and tensin homolog) loss. Based on the proof of principle in mCRPC, this combination is now being evaluated in earlier stage mHSPC. Other experimental therapies in clinical testing include inhibitors of cyclin dependent kinases (CDK).Conclusions: Combination therapies are the current standard of care for mHSPC, with the combination of ADT + ARTA dominating. Preliminary results underline the importance of further intensification of therapy by means of triple therapy. However, novel combinations with radioligand therapy or PARP inhibitors are also promising in the treatment of mHSPC. Preliminary results show the principle efficacy of AKT inhibitors in patients with PTEN loss, which similar to therapy with CDK4/6 inhibitors still have to prove their clinical relevance in randomized trials.