Androgen Receptor Inhibitors: A Novel Therapeutic Option for Nonmetastatic, Castration-Resistant Prostate Cancer

Cora N. Sternberg, MD, is a medical oncologist at Weill Cornell Medicine and clinical director of the Englander Institute for Precision Medicine in New York, New York.

Her clinical areas of focus include genitourinary cancers and drug development related to their management. She was integral to the development of the original MVAC (methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin) chemotherapy regimen, as well as the double-dose/high-dose/accelerated-dose MVAC chemotherapy regimens in bladder and urothelial cancers. Her research has led to US Food and Drug Administration (FDA) approvals of abiraterone acetate and enzalutamide for the treatment of advanced prostate cancer, as well as the development of pazopanib, an antiangiogenic targeted therapy for patients with advanced clear cell renal cell carcinoma. 

What are current treatment options for nonmetastatic, castration-resistant prostate cancer (M0 CRPC)?

We have results from 3 well-conducted larger, international randomized trials in patients with M0 CRPC. The PROSPER trial (ClinicalTrials.gov Identifier: NCT02003924) looked at treatment with enzalutamide.¹ The SPARTAN trial (ClinicalTrials.gov Identifier: NCT01946204) evaluated apalutamide,² and the ARAMIS trial (ClinicalTrials.gov Identifier: NCT02200614) assessed treatment with darolutamide.³  Each of these clinical trials used conventional bone scan and computed tomographic (CT) imaging to evaluate patients with M0 CRPC and a prostate-specific antigen (PSA) doubling time of 10 months or less. In all 3 studies, metastasis-free survival (MFS) and/or overall survival/risk of death were significantly improved.

Are there QOL symptoms associated with use of androgen receptor (AR) inhibitors that may be concerning?

Patients with M0 CRPC, who by definition have no metastases, usually have an excellent QOL that is not worsened by treatment with enzalutamide, apalutamide, and darolutamide. Patient-reported outcomes were evaluated in the PROSPER trial.¹ In this trial, patients with M0 CRPC who received enzalutamide had longer MFS than patients randomly assigned to placebo while maintaining low pain levels, a low prostate cancer symptom burden, and no decrease in HRQOL compared with the placebo group. Enzalutamide also yielded a clinical benefit by delaying pain progression, symptom worsening, and decrease in functional status compared with placebo.

Final analysis of the SPARTAN trial showed that HRQOL was maintained after initiation of apalutamide in men who were asymptomatic with high-risk M0 CRPC.⁴ Importantly, results of the SPARTAN trial also showed that patients treated with apalutamide had longer MFS and a longer time to symptomatic progression compared with patients who received placebo.

In patients with M0 CRPC, who are generally asymptomatic, darolutamide maintained HRQOL by significantly delaying the time to deterioration of prostate cancer-specific QOL and disease-related symptoms compared with placebo.⁵ Similar results have been reported for all 3 trials.

How are AR antagonists changing CRPC progression, QOL, and life expectancy?

These agents, along with the androgen biosynthesis inhibitor abiraterone, have all moved into the front-line setting in patients with metastatic, hormone-sensitive prostate cancer (mHSPC). In several trials — including STAMPEDE (ClinicalTrials.gov Identifier: NCT0026847), LATITUDE (ClinicalTrials.gov Identifier: NCT01715285), ENZAMET (ClinicalTrials.gov Identifier: NCT02446405),  ARCHES (ClinicalTrials.gov Identifier: NCT02677896, and TITAN (ClinicalTrials.gov Identifier: NCT02489318) — a combination of ADT and AR-targeted agents was shown to improve overall survival. As a result, ADT alone is no longer an acceptable alternative for these patients.⁶[DD1] 
All 3 drugs have been associated with QOL improvement and increased survival rates when administered early with ADT.

How do results from clinical trials with darolutamide for prostate cancer compare with results from clinical trials with apalutamide or enzalutamide? How do these pharmacologic therapies compare with previous standard courses of treatment?

All 3 drugs are excellent and represent an important therapeutic improvement over ADT alone. However, it is difficult to compare these agents across trials. Darolutamide does not cross the blood-brain barrier, so patients treated with it may experience less fatigue. Following reported results of the ARAMIS trial, darolutamide has been approved for use only in patients with M0 CRPC.³ We eagerly await the results of the ARASENS trial, which evaluated the combined treatment of darolutamide and docetaxel in patients with mHSPC.

What factors, including risk/benefit profiles, should clinicians consider when selecting an AR inhibitor for patients with M0 CRPC?

A clinician must always consider comorbidities patients may have and concomitant medications when prescribing these drugs, some of which may have important drug-drug interactions. Current research reveals a high rate of drug-drug interactions with enzalutamide, particularly with proton pump inhibitors and central nervous system depressants.⁷

Apalutamide has been found to interact with CYP3A4, CYP2C19, CYP2C9, permeability glycoprotein (Pgp), breast cancer resistance protein (BCRP), and organic anion-transporting polypeptide 1B1 (OATP1B1) substrates.⁸ Darolutamide may interact with rosuvastatin, although the interaction does not seem to be particularly adverse.⁹

At which stage of disease progression might a clinician initiate treatment with AR inhibitors? What is the clinical rationale for doing so in a patient with no visible metastases?

AR inhibitors were first approved for use after chemotherapy with docetaxel in patients with mCRPC based on results from the Cougar 301 (ClinicalTrials.gov Identifier: NCT00638690) and AFFIRM trials (ClinicalTrials.gov Identifier: NCT00974311). It was later approved for use prior to chemotherapy in patients with mCRPC who are asymptomatic based on results from the Cougar 302 (ClinicalTrials.gov Identifier: NCT00887198) and PREVAIL trials (ClinicalTrials.gov Identifier: NCT01212991). As I’ve mentioned, AR inhibitors are indicated in both mHSPC and M0 CRPC.

What concerns or side effects have been identified with use of AR inhibitors?

Fatigue, falls, and fractures as well as drug-drug interactions have been the most important ones.