Investigational approaches for the treatment of advanced prostate cancer
- Janet R Walczak, MSN, RN, CRNP
Janet R Walczak, MSN, RN, CRNP
- Roberto Pili, MD
Roberto Pili, MD
- Robert Wallace Miller Professor of Medicine, Director of GU Oncology Division of Hematology/Oncology
- Department of Medicine Professor of Pharmacology and Toxicology Indiana University School of Medicine
- Michael A Carducci, MD
Michael A Carducci, MD
- Aegon Professor of Prostate Cancer Research
- Professor of Oncology and Urology
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Emmanuel S Antonarakis, MD
Emmanuel S Antonarakis, MD
- Associate Professor of Oncology and Urology
- Sidney Kimmel Comphrehensive Oncology Center
- Johns Hopkins University
- Section Editors
- Nicholas Vogelzang, MD
Nicholas Vogelzang, MD
- Section Editor — Prostate Cancer
- Professor of Medicine
- University of Nevada School of Medicine
- US Oncology Research
- W Robert Lee, MD, MS, MEd
W Robert Lee, MD, MS, MEd
- Section Editor — Prostate Cancer
- Professor of Radiation Oncology
- Duke University Medical Center
- Jerome P Richie, MD, FACS
Jerome P Richie, MD, FACS
- Section Editor — Cancer of the Urethra, Penis, and Ureter; Urologic Surgery; Prostate Cancer
- Elliott Carr Cutler Professor of Surgery
- Harvard Medical School
Androgen deprivation therapy (ADT) is highly effective therapy for men with advanced or metastatic prostate cancer, providing at least temporary disease control in over 80 percent of cases. However, the vast majority eventually develop progressive disease.
Once disease progresses, men are considered to have castration-resistant disease. A number of new therapies have been shown to prolong survival in this setting (table 1), but there remains a need for additional approaches that can control disease and prolong survival.
An increasing understanding of the biology of prostate cancer is leading to the development of new therapies that can target specific abnormalities in prostate cancer. Although a number of agents have failed in phase III or randomized phase II trials, other experimental approaches are in advanced stages of development. These are discussed in this topic. The overall approach to men with advanced disease is discussed separately. (See "Overview of the treatment of disseminated prostate cancer".)
Prostate cancers are frequently characterized by abnormalities in a variety of growth factor signaling pathways that control the cell cycle and apoptosis. As these pathways are being understood, new therapeutic targets are leading to the development of new agents with activity against advanced disease. (See "Molecular biology of prostate cancer".)
Cabozantinib — Cabozantinib is an inhibitor of MET, VEGFR2, and RET. A phase II trial in patients with progressive, metastatic prostate cancer provided preliminary evidence of activity in men with bone metastases [1,2].
- Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2013; 31:412.
- Smith MR, Sweeney CJ, Corn PG, et al. Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J Clin Oncol 2014; 32:3391.
- Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol 2016.
- Chi KN, Eisenhauer E, Fazli L, et al. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst 2005; 97:1287.
- Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2010; 28:4247.
- Chi KN, Higano CS, Blumenstein B, et al. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol 2017.
- Fizazi K, Hotte J, Saad F, e and cabazitaxel/prednisone t al. Final overall survival from the AFFINITY phase 3 trial of custirsen and cabazitaxel/prednisone in men with previously treated metastatic castration-resistant prostate cancer. Abstract LBA9, presented at the European Society for Medical Oncology 2016 meeting.
- Pili R, Häggman M, Stadler WM, et al. Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J Clin Oncol 2011; 29:4022.
- Sternberg C, Armstrong A, Pili R, et al. Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2016.
- Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013; 31:1748.
- Sandhu SK, Omlin A, Hylands L, et al. Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer. Ann Oncol 2013; 24:1416.
- Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016.
- Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373:1697.
- Hussain M, Daignault S, Twardowski P, et al. Co-targeting androgen receptor (AR) and DNA repair: A randomized ETS gene fusion-stratified trial of abiraterone + prednisone (Abi) +/- the PARP1 inhibitor veliparib for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) (NCI9012)—A University of Chicago phase II consortium trial. J Clin Oncol 34, 2016 (suppl; abstr 5010).
- Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 2013; 14:882.
- Rothermundt C, Hayoz S, Templeton AJ, et al. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol 2014; 66:468.
- McKay RR, Zurita AJ, Werner L, et al. A Randomized Phase II Trial of Short-Course Androgen Deprivation Therapy With or Without Bevacizumab for Patients With Recurrent Prostate Cancer After Definitive Local Therapy. J Clin Oncol 2016; 34:1913.
- Schweizer MT, Antonarakis ES, Wang H, et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci Transl Med 2015; 7:269ra2.
- Schweizer MT, Wang H, Luber B, et al. Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study. Prostate 2016; 76:1218.
- Roberto Pili, MD