Apalutamide for the treatment of prostate cancer

Abstract

Five new agents have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer, including two targeting androgen receptor signaling (abiraterone acetate plus prednisone; enzalutamide). Recognition that these tumors remain driven by androgen receptor signaling has prompted clinical evaluation of these agents at earlier states in the prostate cancer disease continuum, along with the continued development of new agents targeting this pathway. Areas covered: This article focuses on apalutamide, a next-generation nonsteroidal antiandrogen, with current literature queried in PubMed/Medline. A narrative review strategy describes studies from engineering of the compound through to a 5-year outlook. Expert commentary: In the phase III SPARTAN study, apalutamide significantly improved metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer - the first treatment approved by the US Food and Drug Administration for this indication. Phase III studies are under way to determine the clinical benefit of apalutamide in other disease states. Given the multiplicity of prostate cancer treatment options now available, there is a need to maximize individual patient benefit through the development and validation of predictive biomarkers of sensitivity to drugs that can be used in real time to determine the optimal sequence and combinations of treatments for patients in need.

Keywords: Androgen receptor inhibitors; apalutamide; efficacy; metastatic; nonmetastatic; pharmacodynamics; pharmacokinetics; prostate cancer; safety; tolerability.

Figure 1. Prostate cancer clinical states model (Prostate Cancer Clinical Trials Working Group 3 framework).

The prostate cancer clinical states model for patient treatment and drug development as developed by Prostate Cancer Clinical Trials Working Group 3. mCRPC: metastatic castration-resistant prostate cancer; nmCRPC, nonmetastatic castration-resistant prostate cancer; PSA: prostate-specific antigen. Source: Scher et al., 2016[44]. Reprinted with permission. © (2016) American Society of Clinical Oncology. All rights reserved.

Figure 2. Structure of apalutamide.

Apalutamide is a synthetic biaryl thiohydantoin compound discovered using a structure/activity relationship-guided medicinal chemistry program to design more potent antiandrogens without significant agonist activity.

Figure 3. Recommended phase II dose of apalutamide.

FDHT-PET imaging data from 16 patients in the phase I study support 240 mg as the optimal dose of apalutamide. FDHT: [¹⁸F]fluoro-5α-dihydrotestosterone; PET: positron emission tomography; SUV_max–avg: standard uptake value (maximum–average). Source: Rathkopf et al., 2013[39] (with permission). Reprinted with permission. © (2013) American Society of Clinical Oncology. All rights reserved.

Figure 4. Patient experience with apalutamide in phase II study of patients with mCRPC. (A) AAP-naïve and (B) post-AAP (B) cohorts.

[43] These swim lane plots show the duration of apalutamide treatment from shortest (top lane) to longest (bottom lane) in the AAP-naïve and post-AAP mCRPC cohorts. AAP: abiraterone acetate plus prednisone; PSA: prostate-specific antigen. Source: Rathkopf et al., 2017[42]. Reprinted with permission.

Figure 5. (A) SPARTAN study design. (B) metastasis-free survival in the SPARTAN study.

The study design of SPARTAN, a phase III study of apalutamide in patients with nonmetastatic castration-resistant prostate cancer, and the Kaplan–Meier curves for the primary end point of metastasis-free survival showing significant improvement in the apalutamide group. CT: computed tomography; IDMC: independent data monitoring committee; MFS: metastasis-free survival; nmCRPC, nonmetastatic castration-resistant prostate cancer; PSADT, prostate-specific antigen doubling time; QD: once daily. Source: Smith et al., 2018[46] and Small et al., 2018 [60](with permission from Small, EJ).