New-generation androgen receptor signaling inhibitors (ARSIs) in metastatic hormone-sensitive prostate cancer (mHSPC): pharmacokinetics, drug-drug interactions (DDIs), and clinical impact

ABSTRACT

Introduction

The therapeutic scenario of metastatic hormone-sensitive prostate cancer (mHSPC) has dramatically changed in recent years, with the approval of new-generation Androgen Receptor Signaling Inhibitors (ARSIs), in combination with the androgen deprivation therapy (ADT), which was the previous standard of care. Despite showing a similar clinical efficacy, ARSIs, all of which are administered orally, are different in terms of pharmacokinetic and drug-drug interactions (DDIs).

Areas covered

This review covers the main pharmacokinetic characteristics of ARSIs that have been approved for the first-line therapy of mHSPC patients, underlying the differences among these molecules and focusing on the known or possible interactions with other drugs. Full-text articles and abstracts were searched in PubMed.

Expert opinion

Since prostate cancer occurs mainly in older age, comorbidities and the consequent polypharmacy increase the DDI risk in mHSPC patients who are candidates for ARSI. Waiting for new therapeutic options, in the absence of direct comparisons, pharmacokinetic knowledge is essential to guide clinicians in prescribing ARSI in this setting.

KEYWORDS:

• ARSI
• mHSPC
• pharmacokinetic
• drug-drug interactions
• abiraterone acetate
• apalutamide
• darolutamide
• enzalutamide

Article highlights

• Androgen Receptor Signaling Inhibitors (ARSIs) are now adopted in metastatic hormone-sensitive prostate cancer (mHSPC) patients in addition to androgen deprivation therapy (ADT).

• Despite a similar meaningful improvement in survival, they show different pharmacokinetic profiles and a high potential for drug-drug interactions (DDIs).

• Given comorbidities and the consequent polypharmacy, older mHSPC patients have an increased risk of DDI when receiving ARSI.

• Deep pharmacokinetic knowledge and future research will be able to overcome the problem of DDI and optimize the use of ARSIs in this therapeutic setting.

Declaration of interest

E. Francesco Giunta reports travel support from Janssen-Cilag and Bayer. UDG reports honoraria for advisory boards or speaker fees for Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Roche, Novartis, Clovis, GSK, AstraZeneca, institutional research grants from AstraZeneca, Sanofi and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgment

This work was partly supported thanks to the contribution of R Corrente by the Italian Ministry of Health

Additional information

Funding

This paper was not funded.