We need to understand each patient’s cancer and its microenvironment well enough to develop targeted treatments that will kill the tumor the first time-for if we let it escape, 70 years of prostate cancer research teaches us that our job will only get harder.
Derleth and Yu provide a comprehensive overview of the current landscape of agents that target androgen receptor (AR) signaling and other molecular targets in prostate cancer, with an emphasis on phase III clinical trials. We would like to begin by complementing the report with some additional context-an historical accounting of targeted therapies that have left the battlefield humbled and defeated. Even when one limits that historical perspective to targeted therapy trials that included docetaxel (Taxotere), the record of phase III trials is 0 for 8. The Table provides a summary of this disappointing history.
Main Results From All Reported Phase III Trials of Targeted Therapies in Combination With Docetaxel (Taxotere) in Metastatic Castration-Resistant Prostate Cancer
In recent years, phase III trials of several classes of broadly acting agents, including chemotherapy, immunologic therapy, and a radiopharmaceutical, have demonstrated improved survival.[9-12] However, it is striking that the contribution of targeted therapies to this progress has been limited to a single target-the AR. Indeed, AR has been the principal therapeutic target in prostate cancer for over 70 years.
AR and androgen ligands that activate the AR have proven important time and time again for promoting castration-resistant prostate cancer (CRPC) progression through a variety of mechanisms. These include: AR gene amplification, AR splice variants, AR mutations, and alterations in AR binding proteins.[14-20] AR is a particularly compelling target because resistance to androgen deprivation therapies (ADTs) frequently occurs in the setting of persistent synthesis of intratumoral androgens.[21-23] The effectiveness of newer and more potent forms of ADT-abiraterone (Zytiga)[24,25] and enzalutamide (Xtandi)-that improve survival in phase III trials confirms the importance of AR signaling in castration-resistant disease. Additionally, progression on these newer forms of ADT invariably occurs in the setting of a rise in serum prostate-specific antigen (PSA) level, an AR target gene, and persistent AR expression. Therefore, evidence from patients confirms what preclinical experiments suggest: that AR continues to be a core driver of prostate cancer even after exposure to the highly potent agents abiraterone or enzalutamide. If we are to build on recent progress, we should strive to understand all of the mechanisms of AR-mediated resistance to therapy and seek to impede them through the development of new and better therapies, and perhaps through the development of multi-agent regimens that more completely abrogate AR signaling.
In addition to the dominant role played by the AR, trial design and scientific approach have also limited our success in advancing targeted therapy in prostate cancer. Most targeted agents perturb only one target or a handful of related targets at a time. Trials that evaluate these agents have generally been designed without a comprehensive understanding of how the cancer cell circumnavigates this single perturbation and how the normal host tissue is affected. They have also been designed without efforts to enrich study populations to include those patients whose tumors possess molecular characteristics that point towards specific targeted agents.
To improve on our track record, we need to understand the effect of our treatments on both the tumor and the host, and we need to appreciate the complexity of the tumor-host interface. Recently, for example, by examining human prostate tumors before and after chemotherapy, we identified a spectrum of proteins secreted in the tumor microenvironment. The secretion of Wnt ligand WNT16B in the tumor microenvironment was found to activate the Wnt pathway in tumor cells in a paracrine manner. Wnt pathway activation, in turn, induced chemotherapy resistance in tumor cells. This is but one example of the complexity of adaptive resistance and the importance of host microenvironmental factors.
This example illustrates the point that in addition to molecular speciation of tumor cells to individualize therapy, we need to turn our attention to the host-tumor interface. To do so, we would do well to study advanced prostate cancer in its natural environment, ie, human metastases. Analysis of human metastatic CRPC tumors, as well as preclinical studies of drugs using orthotopic models and/or immunocompetent animals, are therefore essential components of successful target development.
To this end, two “Prostate Cancer Dream Teams,” funded by the Stand Up To Cancer Foundation, the Prostate Cancer Foundation, and the American Association for Cancer Research, are working to understand the drivers of lethal patient CRPC tumors by using comprehensive sequencing-based approaches to characterize human tumor specimens in the context of treatment response and resistance. It is our hope that this work will clarify the relevant resistance mechanisms and enable sophisticated, individualized cotargeting strategies, and that this work will give rise to a new era of success in the development of targeted therapy for prostate cancer.
We in the medical community have been down this road before, using an iterative approach that ultimately resulted in effective drug combinations. That is how we developed curative treatments for tuberculosis and how multi-drug cocktails have rendered HIV infection a chronic disease in much of the world. However, because of the way targeted therapies in CRPC have been historically developed and tested, we have not had the necessary knowledge to make the same strides as our infectious disease colleagues.
The German philosopher Friedrich Nietzsche is credited with the aphorism “that which does not destroy me, makes me stronger.” Nietzsche’s aphorism also applies to CRPC: Any cancer that is not cured by a treatment gains strength through surviving that treatment. We must do better. We need to understand each patient’s cancer and its microenvironment well enough to develop targeted treatments that will kill the tumor the first time-for if we let it escape, 70 years of prostate cancer research teaches us that our job will only get harder.
Financial Disclosure:Drs. Alumkal, Graff, and Beer have received research funding from Amgen, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Cougar Biotechnology, Dendreon, ImClone Systems, Janssen Pharmaceuticals, Medivation, Millennium, Novartis, OncoGeneX, and Sanofi-Aventis.
1. Scher HI, Jia X, Chi K, et al. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol. 2011;29:2191-8.
2. Small E, Demkow T, Gerritsen WR, et al. A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). Presented at the Genitourinary Cancers Symposium. 2009;83:abstr 07.
3. Carducci MA, Saad F, Abrahamsson PA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110:1959-66.
4. Fizazi KS, Higano CS, Nelson JB, et al. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013;31:1740-7.
5. Petrylak DP, Fizazi K, Sternberg CN, et al. A phase 3 study to evaluate the efficacy and safety of docetaxel and prednisone with or without lenalidomide in patients with castrate-resistant prostate cancer (CRPC): the MAINSAIL trial. Presented at the 37th ESMO Congress. 2012;23:ixe15 (Abstract LBA24).
6. Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012;30:1534-40.
7. Araujo JC, Trudel GC, Saad F, et al. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): results from the randomized phase III READY trial. J Clin Oncol; presented at the Genitourinary Cancers Symposium. 2013;31(suppl):abstr LBA8.
8. Tannock I, Fizazi K, Ivanov S, et al. Double-blind randomized trial of aflibercept versus placebo with docetaxel and prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol; presented at the ASCO Annual Meeting. 2013;31(suppl):abstr 5002.
9. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-54.
10. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.
11. Nilsson S, Franzen L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587-94.
12. Sartor AO, Heinrich D, O'Sullivan JM, et al. Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: interim results of a phase III trial (ALSYMPCA). J Clin Oncol; presented at the ASCO Annual Meeting. 2012;30(suppl):abstr 4551.
13. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-7.
14. Guo Z, Yang X, Sun F, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69:2305-13.
15. Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16-22.
16. Sun S, Sprenger CC, Vessella RL, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010;120:2715-30.
17. Gottlieb B, Beitel LK, Nadarajah A, et al. The androgen receptor gene mutations database: 2012 update. Hum Mutat. 2012;33:887-94.
18. Linja MJ, Savinainen KJ, Saramaki OR, et al. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res. 2001;61:3550-5.
19. Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401-6.
20. Ueda T, Bruchovsky N, Sadar MD. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem. 2002;277:7076-85.
21. Zong Y, Goldstein AS. Adaptation or selection-mechanisms of castration-resistant prostate cancer. Nat Rev Urol. 2013;10:90-8.
22. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-54.
23. Chang KH, Li R, Papari-Zareei M, et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2011;108:13728-33.
24. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
25. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-48.
26. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97.
27. Efstathiou E, Titus MA, Tsavachidou D, et al. MDV3100 effects on androgen receptor (AR) signaling and bone marrow testosterone concentration modulation: a preliminary report. J Clin Oncol; presented at the ASCO Annual Meeting. 2011;29(suppl):abstr 4501.
28. Sun Y, Campisi J, Higano C, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012;18:1359-68.