Treatment Landscape for Patients with Castration-Resistant Prostate Cancer: Patient Selection and Unmet Clinical Needs

Abstract

Metastatic castration resistant prostate cancer (CRPC) is an inevitably fatal disease. However, in recent years, several treatments have been shown to improve the outcome of CRPC patients both in the non-metastatic (nmCRPC) as well as the metastatic setting (mCRPC). In nmCRPC patients with a PSA doubling time <10 months, the addition of enzalutamide, apalutamide and darolutamide to androgen deprivation therapy (ADT) compared to ADT alone resulted in improved metastases free (MFS) and overall survival (OS). For mCRPC patients, several treatment options have been shown to be effective: two taxane based chemotherapies (docetaxel and cabazitaxel), two androgen-receptor pathway inhibitors (ARPI) (abiraterone and enzalutamide), two radiopharmaceutical agents (radium 223 and 177Lutetium-PSMA-617), one immunotherapy treatment (sipuleucel-T) and two poly ADP-ribose polymerase (PARP) inhibitors (olaparib and rucaparib). Pembrolizumab is US Food and Drug Administration (FDA) approved in all MSI high solid tumors, although a very small proportion of prostate cancer patients harboring this characteristic will benefit. Despite having a broad variety of treatments available, there are still several unmet clinical needs for CRPC. The objective of this review was to describe the therapeutic landscape in CRPC patients, to identify criteria for selecting patients for specific treatments currently available, and to address the current challenges in this setting.

Keywords: castration resistant prostate cancer; metastatic castration resistant prostate cancer; non-metastatic castration resistant prostate cancer; prostate cancer.

Figure 1

Timeline of treatments for mCRPC (year of reported positive pivotal trial). 1,2Tannock, IF et al. N Engl J Med 2004; 3De Bono, J et al. Lancet 2010, 4Oudard, S et al. J Clin Oncol 2017, 5Kantoff, P.W. et al. N Engl J Med. 2010; 6De Bono, J et al. N Engl J Med. 2011, 7Ryan, CJ et al. N Engl J Med. 2013, 8Scher, HI et al. N Engl J Med 2012; 9Beer, TM et al. N Engl J Med 2014, 10Parker, C et al. N Engl J Med. 2013, 11Nilsson S et al. Ann Oncol. 2016; 12De Bono, J et al. N Engl J Med 2020;13Sartor O et al. N Engl J Med. 2021. *Approval EMA withdrawn, not available in Europe; +symptomatic, bone only, LN<3cm, visceral mets. excluded; approval §EMA: BRCA1,2 FDA: HRD panel PROfound, Rucaparib (FDA only); **FDA only approval, not EMA.