BERKELEY, CA (UroToday.com) - Prostate cancer is the most common malignancy in men in the United States with an estimated 220 800 new cases and 27 540 deaths in 2015. In 2004, two landmark trials, TAX 327 and SWOG 99-16, revealed an overall survival (OS) benefit in men with progressive metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel,[2, 3] however benefits remain limited. In recent years, agents such as abiraterone and enzalutamide have shown an OS benefit, similar to docetaxel, in the mCRPC population.[4, 5] Several agents that target angiogenesis have been combined with docetaxel in an attempt to improve OS, but unfortunately, the results of these trials have proved to be disappointing. Alternative approaches to targeting tumor vasculature and attempting combination therapies need further investigation. One such alternative approach is targeting CD105, which is involved in normal vascular development, is expressed on proliferating endothelial cells, and has been implicated in prostate cancer survival. This first-in-human dose-escalation phase I trial evaluated the safety, pharmacokinetics, and pharmacodynamics of TRC105, a chimeric IgG1 monoclonal antibody that binds endoglin (CD105) in patients with metastatic castration-resistant prostate cancer (mCRPC). Twenty patients were treated in a standard 3+3 phase I design with escalating doses of TRC105. The maximum tolerated dose was found to be 20 mg/kg every two weeks on a 28-day cycle. TRC105 was found to be well-tolerated with the most common adverse events being infusion-related reaction (90%), grade 1 or 2 headache (67%), anemia (48%), epistaxis (43%), fever (43%), nausea (33%), vomiting (24%), bone pain (19%), and oral hemorrhage (19%). PSA declines were observed across all dose levels without any clear dose response. Eight patients had PSA declines, two of which were > 50%. Sixteen patients had measurable soft tissue disease. Seven of these 16 patients had stable disease after 2 treatment cycles, and 3 patients had stable disease after 4 treatment cycles. Of 4 patients with bone-only disease, 3 had stable disease after cycle 2 and one elected to come off study.
Of note, an exploratory analysis demonstrated the potential anti-angiogenic activity of TRC105. CD105 reduction was dose dependent and inversely correlated with vascular endothelial growth factor (VEGF) levels. VEGF induction was specifically associated with reduction of CD105 in plasma whereas the patients without reduced plasma CD105 exhibited no VEGF induction. Thus, VEGF induction is associated with a potential therapeutic mechanism of TRC105 whereby VEGF is induced in a possible compensatory mechanism. In addition, when the patients were divided into subgroups based on the CD105 depletion by TRC105, the group without CD105 depletion showed a median increase in PSA of 57% when compared to baseline PSA (p = 0.0015), while the group with a substantial reduction of plasma CD105 had a median increase in PSA of 16% (p = 0.132). Thus, the exploratory analysis suggests a potential association between the effects of TRC105 and decreased PSA velocity.
The past several years have heralded multiple new treatment options in mCPRC with re-emphasis on the androgen receptor (AR) as a significant target for patients. Large phase III trials have shown improved OS in mCRPC with agents such as abiraterone, enzalutamide, immunotherapy with sipuleucel-T, and the radiopharmaceutical radium-223.[6, 7, 8, 9] Optimizing treatment regimens -- with particular focus on resistance mechanisms -- to be utilized in combination with chemotherapeutic agents, anti-androgens, or anti-angiogenesis agents will need exploration. Development of resistance in VEGF pathways, as seen in this study, may be overcome with dual angiogenesis pathway blockade. Future studies with TRC105 in combination with chemotherapy, immunotherapeutic agents, anti-androgens, or VEGF inhibitors will further elucidate the clinical activity of TRC105 in mCRPC.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: A Cancer Journal for Clinicians 2015;65:5-29.
- Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12.
- Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-20.
- Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424-33.
- 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.
- 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.
- 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.
- Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-22.
- Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213-23.
Fatima Karzai, Ravi A. Madan, and William L. Dahut as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Medical Oncology Service, National Cancer Institute, Bethesda, Maryland. Building 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD USA