Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Advances and Treatment Strategies in the First-Line Setting

Abstract

The treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC) has changed radically in recent years. Androgen deprivation therapy (ADT) alone was for decades the standard of care for treating mHSPC. This changed when studies showed that the addition of docetaxel chemotherapy or abiraterone acetate to ADT significantly increases overall survival of patients with mHSPC, followed by more recent evidence showing the efficacy of androgen receptor antagonists, such as enzalutamide and apalutamide, in this setting. While this rapid therapeutic evolution is welcome, it presents clinicians with a crucial challenge: the choice of treatment selection and sequencing. In the first-line setting there are no comparative data currently available to guide treatment choice between the different available regimens, and no prospective data to guide clinical decision after progression. Decisions on treatment will now need to be personalised based on indirect comparison of the available efficacy data from multiple phase 3 studies, together with considerations of disease volume, comorbidities, treatment aims, toxicity profile and cost reimbursement within the healthcare setting. Here, we provide an overview of the clinical trial data to date and propose some biological and clinical insights which may be helpful in making decisions on treatment selection and sequencing.

Keywords: Androgen deprivation therapy; Antiandrogen drugs; Chemotherapy; Prostate cancer; mHSPC.

Fig. 1

a Mechanism of action of androgen deprivation therapy (ADT) and approved systemic therapies. The testes produce 90–95% of the total circulating testosterone, while the adrenal glands produce the remainder of the circulating androgens. Androgens, usually dihydrotestosterone (DHT), bind to the androgen receptor (AR), dissociating chaperone proteins. Ligand-bound AR molecules dimerise and translocate to the nucleus where they bind to androgen response elements and act as transcription factors to signal downstream targets. Apart from acting as AR antagonists, second-generation antiandrogens, such as enzalutamide, apalutamide and darolutamide, also prevent the translocation of AR to the nucleus. Abiraterone acetate, as a cytochrome P450 17A1 (CYP17) and α-hydroxylase inhibitor, largely prevents androgen biosynthesis. The detailed sites of action of abiraterone are not depicted in this diagram. GnRH Gonadotropin-releasing hormone, ACTH adrenocorticotrophic hormone, LH luteinising hormone. b Conventional treatment pathway of prostate cancer. mHSPC Metastatic hormone-sensitive prostate cancer, nmCRPC non-metastatic castration-resistant prostate cancer, mCRPC metastatic castration-resistant prostate cancer. *Cabazitaxel can be given in first-line treatment of mCRPC if docetaxel is given in the hormone-sensitive setting. Dates in parenthesis indicate month of US Food and Drug Administration approval; only drugs approved since 2018 have date of approval indicated

Fig. 2

Potential decision-making factors influencing choice of first line treatment for mHSPC. IV Intravenous