Up to date, docetaxel, sipuleucel-T , cabazitaxel, abiraterone acetate, enzalutamide, and radium-223 showed overall survival benefit in CRPC patients.

Cabazitaxel is a new-generation and semisynthetic derivative of a natural taxane. It is formerly known as XRP-6258. It is a microtubule inhibitor. It was tested in a phase III trial with 755 men for the treatment of castration-resistant prostate cancer , median survival was 15.1 months for patients receiving cabazitaxel versus 12.7 months for patients receiving mitoxantrone. Cabazitaxel was associated with more grades 3–4 neutropenia than mitoxantrone. Cabazitaxel in combination with prednisone is a treatment option for hormone-refractory prostate cancer following docetaxel-based treatment [1].

Abiraterone acetate blockade CYP17 inhibits androgen synthesis. Abiraterone was tested in patients received first- or second-line chemotherapy in CRPCP (COU-301) [2]. Abiraterone acetate approved for use with prednisone for metastatic castration-resistant prostate cancer following docetaxel. This phase III study demonstrated a statistically significant improvement in OS in patients receiving abiraterone acetate compared with patients who received the placebo (HR = 0.646; 95% CI: 0.543, 0.768; P = 0.0001). The median OS was 14.8 months for patients who received abiraterone acetate compared with 10.9 months OS for patients who received the placebo. An updated OS analysis, conducted after 775 events, demonstrated a median OS of 15.8 months for patients who received abiraterone acetate compared with 11.2 months for patients who received the placebo (HR = 0.740; 95 percent CI: 0.638, 0.859).

Enzalutamide has FDA approval for metastatic CRPC patients. The approval was based on a single randomized placebo-controlled multicenter trial that enrolled 1199 patients with metastatic castration-resistant prostate cancer who had received prior docetaxel. Patients were randomly assigned to receive enzalutamide 160 mg orally once daily (N = 800) or placebo (N = 399).

Grades 3–4 adverse reactions were reported in 47% of patients treated with enzalutamide and in 53% of those who received placebo. Seizures occurred in 0.9% of patients treated with enzalutamide [3].

Other new-generation drugs targeting the AR are orteronel and ARN-509 , ODM-204 , and galeterone .

Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. Orteronel was tested in phase III study in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy (ELM-PC 5). In this study, there was no statistically significant improvement in OS with orteronel-prednisone versus placebo-prednisone. Furthermore, the longer rPFS and higher rate of ≥50% PSA decrease suggest that orteronel may have antitumor activity in mCRPC after docetaxel therapy [4].

ARN-509 (apalutamide ) is another nonsteroidal antiandrogen being actively investigated in the nonmetastatic CRPC setting. This compound inhibits binding of androgens to the AR and prevents nuclear translocation and DNA binding of the receptor to androgen response elements. An ongoing phase II trial of ARN-509 that recruited 47 patients between November 2011 and June 2012 is studying this drug in patients with nonmetastatic CRPC. The primary endpoint is PSA response at 12 weeks according to PCWG2 criteria. Inclusion criteria included nonmetastatic CRPC and high risk for disease progression, based on PSA level ≥8 ng/mL within 3 months of enrollment and/or PSA doubling time of ≤10 months. Patients were given 240 mg of ARN-509 per day and had their PSA level checked every 4 weeks and imaging studies every 16 weeks. The median follow-up was 13.4 months. The PSA response rate at both 12 and 24 weeks was 91%, and the median metastasis-free survival has not been reached. AEs in the metastatic CRPC group included grade 3 or higher fatigue back pain, constipation, musculoskeletal pain, and vomiting.

An ongoing phase III trial is randomly assigning men with nonmetastatic CRPC 2:1 to ARN-509 versus placebo (ClinicalTrials.gov identifier: NCT01946204). Participants must have a PSA doubling time of ≤10 months.

Earlier use of AR pathway targeting drugs have been tested in de novo metastatic patients (latitude study-abiraterone). Abiraterone is also testing in de novo metastatic patients in combination with local radiotherapy (PEACE-1).

There are emerging drugs target in CRPC. PARP inhibitors, PI3K/Akt, immune checkpoints, and PD1 and PDL1 inhibitors are intensively studied and some promising results were published.