Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Doce taxel, the standard of care for these patients, provides a modest prolongation of survival, but there is an urgent need for novel treatment strategies. Recently, the biological and molecular mechanisms driving prostate cancer growth and progression have become better understood, and this has resulted in widespread clinical testing of numerous new targeted therapies. At least some of these may extend and ideally even save the lives of the 218,000 men who develop this disease annually, some 32,000 of whom will die of prostate cancer under current therapies.1
Several forms of immunotherapy made news in 2010, most strikingly the antigen-specific product sipuleucel- T, which became US Food and Drug Admin - istration (FDA)-approved on April 29, 2010, for metastatic castration-resistant prostate cancer (CRPC) based on survival benefits shown in phase 3 trials. Sipuleucel-T is an active cellular immunotherapy, that is, a type of therapeutic cancer vaccine. It is derived from autologous peripheral blood cells that are collected during leukapheresis to contain only antigen-presenting cells. This product is cultured ex vivo with a recombinant fusion protein containing prostatic acid phosphatase (a prostate antigen) and granulocytemacrophage colony-stimulating factor to produce the vaccine that is infused into the patient to boost T-cell response against prostate cancer cells.
In the phase 3 IMPACT trial, patients receiving the vaccine had a median survival time of 25.8 months and 3-year survival of 32.1%, compared with 21.7 months and 23%, respectively, for patients receiving placebo.2 Although this amounted to a 22% relative reduction in risk of death, the vaccine did not delay disease progression, which occurred at approximately 14 weeks in each arm.
Treating men with an immunotherapy when they have metastatic and castration-resistant disease is “an uphill battle that probably involves barriers that have not yet been defined,” according to Dan Longo, MD, of the National Institute on Aging, who wrote an accompanying editorial to the publication of the IMPACT results. He noted that a 22% reduction in mortality in this challenging group may bode well for use of the drug earlier in the disease, although he felt the lack of an effect on progression is concerning. Benefits to be gained from this drug may become clearer with the final results of the ongoing phase 2 ProACT trial. Androgen Receptor Targeting Prostate cancer is a hormonally sensitive disease that can be controlled for long periods with androgen-deprivation therapy. The androgen receptor plays a critical role in maintaining the proliferation of prostate cancer cells, not only before androgen ablation but also after hormonal treatments fail. Novel therapeutic strategies aim to inhibit and destabilize the function of this receptor and its interaction with key proteins. Early success with these oral compounds is being observed.
Abiraterone acetate is an orally administered small molecule that irreversibly and specifically inhibits cytochrome P17, a key enzyme in the generation of androgens and thus the production of testosterone. Testosterone levels in the testes and adrenals are thought to stimulate the growth of prostate cancer cells. Therefore, by selectively inhibiting the target enzyme, abiraterone consequently blocks testosterone production in both the adrenals and testes and suppresses cancer cell growth. Abira terone has proven highly active in some men, with responses ranging from 45% in heavily pretreated patients to 75% in patients without extensive secondary hormonal therapy or chemotherapy.3 In a phase 2 trial reported this year by investigators from the United King dom, half of the 47 docetaxel-treated patients had ≥50% declines in prostate-specific antigen (PSA), and median time to PSA progression was 169 days.4 One fourth of the patients were still benefiting from the treatment after almost 1 year.
Additional studies reported at the 2010 meeting of the American Society of Clinical Oncology showed durable responses (ie, median time to PSA progression of 71 weeks) in 58% of chemotherapy-naïve CRPC patients receiving abiraterone5 and prolonged remissions in patients with less than five circulating tumor cells after 1 month of abiraterone treatment.6
Also showing promise in this class of agents is MDV3100. This small-molecule androgen receptor antagonist inhibits androgen receptor function by blocking nuclear translocation of the receptor and DNA binding. The drug’s researchers claim that MDV3100 differs from other antiandrogens in its robust affinity for the androgen receptor and its multifaceted approach to stifling androgen production and activity. It works by three complementary actions: blocking testosterone binding to the androgen receptor, impeding movement of the androgen receptor to the nucleus of prostate cancer cells, and inhibiting the binding to DNA.
In a recent phase 1/2 trial, more than half the patients with CRPC had ≥50% reduction in PSA, and median time to progression was 47 weeks.7 In addition, 22% of patients had soft-tissue responses and 56% had stabilized bone disease. “We were encouraged to see antitumor activity in men whose disease had spread after either becoming resistant to previous hormone treatments or progressing following chemo therapy,” said the study’s lead author Howard Scher, MD, of Memorial Sloan-Kettering Cancer Center, in a press release. “These findings strengthen the drug’s potential to change the outlook for a group of patients who currently have limited effective treatment options.” MDV3100 is being further evaluated in the 1200-patient AFFIRM trial.
Histone deacetylase inhibitors also target androgen receptor activity, and clinical trials are evaluating vorinostat and panobinostat within this class.
The FDA recently granted approval to a promising new taxane, cabazitaxel, for the treatment of metastatic CRPC after docetaxel fails. Cabazitaxel works by disrupting the microtubular network that is essential for mitotic and interphase cellular functions and causes inhibition of cell division and cell death. Cabazitaxel showed a highly significant 30% reduction in mortality over mitoxantrone in the phase 3 TROPIC trial.8 In the final analysis of the study, median overall survival was improved from 12.7 months with mitoxantrone to 15.1 months with cabazitaxel.9 In a press statement, Richard Pazdur, MD, director of the Office of Oncology Drug Products at the FDA, commented on the potential value of cabazitaxel, “The FDA was able to review and approve the application for [cabazitaxel] in 11 weeks, expediting the availability of this drug to men with prostate cancer.” Future studies will evaluate the drug in less-advanced disease.
Endothelial Receptor Antagonists
Endothelins have been implicated in numerous physiologic and pathologic conditions. In prostate cancer, levels of endothelin-1 are increased, heightening the peptide’s ability to modulate mitogenesis and apoptosis upon binding to the endothelin-A receptor. Endothelin antagonism, therefore, may be useful in that it blocks the activation of endothelin-A and thereby inhibits tumor growth.
The investigational oral endothelin receptor antagonists have shown some biologic activity but have not yet improved clinical outcomes in CRPC. In phase 3 trials of atrasentan, clinical efficacy was minimal although responses in PSA and other biomarkers were observed.10,11 The phase 3 SWOG S0421 trial is currently investigating docetaxel plus atrasentan. Similarly, zibotentan has been shown safe when coupled with docetaxel in preliminary studies, but clinical efficacy of zibotentan has not yet been established.12 Treatment with zibotentan plus docetaxel is being further evaluated in an ongoing phase 3 program that includes patients with nonmetastatic disease (ENTHUSE M0), asymptomatic meta static CRPC (ENTHUSE M1), and symp tomatic metastatic CRPC (ENTHUSE M1C).
- National Institutes of Health. Prostate cancer. www.cancer.cancer.gov/cancertopics/ types/prostate. Accessed August 19, 2010.
- Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration- resistant prostate can cer. N Engl J Med. 2010;363:411-422.
- Ryan CJ, Rosenberg J, Lin A, et al. Phase I evaluation of abiraterone acetate (CB7630), a 17-alpha hydroxylase C17,20-lyase inhibitor in androgen-independent prostate cancer. Presented at the 2007 American Society of Clinical Oncology Prostate Cancer Sym po sium. Abstract 278.
- Reid AHM, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28: 1489-1495.
- Ryan CJ, Smith MR, Logothetis C, et al. Median time to progression in chemotherapy-naïve patients with castration-resistant prostate cancer treated with abiraterone acetate and low-dose prednisone. Presented at the 2010 American Society of Clinical Oncology. Abstract 4671.
- Danila DC, Anand A, Sung CC, et al. Molecular profiling of circulating tumor cells in patients with castrate metastatic prostate cancer receiving abiraterone acetate after failure of docetaxel-based chemotherapy. Presented at the 2010 American Society of Clinical Oncology. Abstract 4635.
- Sher HI, Beer TM, Higano CS, et al. Antitumor activity of MDV3100 in castration- resistant prostate cancer: a phase I-II study. Lancet. 2010;375:1437-1446.
- Sartor AO, Oudard S, Ozguroglu M, et al. Caba zitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: final results of a multinational phase 3 trial (TROPIC). Presented at the 2010 Genitourinary Cancers Symposium. Abstract 9.
- De Bono JS, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). Presented at the 2010 Annual Meeting of the American Society of Clinical Oncology. Abstract 4508.
- Michaelson MD, Kaufman DS, Kantoff P, et al. Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer. Cancer. 2006;107:530-535.
- Nelson JB, Love W, Chin JL, et al. for the Atrasen tran Phase 3 Study Group Institutions. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110:1959-1966.
- Trump DL, Payne H, Miller K, et al. Phase I study of the specific endothelin A receptor antagonist zibotentan combined with docetaxel in patients with metastatic castration-resistant prostate cancer: assessment of efficacy, pain, and safety. Presented at the 2010 American Society of Clinical Oncology. Abstract 4664.