Within the next few years, the number of therapies that can effectively target prostate cancer at a cellular and molecular level are likely to experience exponential growth-and provide new options to the oncologist treating this cancer, according to several speakers at an educational session at the 2010 Genitourinary (GU) Cancers Symposium in San Francisco, titled "Prostate Cancer-Future Pathways: What Is on the Way?" The symposium was cosponsored by ASCO, the American Society for Therapeutic Radiology and Oncology (ASTRO), and the Society of Urologic Oncology.

Androgen Receptor Targeting

The androgen receptor plays a critical role in maintaining the proliferation of prostate cancer cells, and is an important driving force for castration-resistant prostate cancer cells-both before and after androgen ablation, according to Donald J. Tindall, PhD, of the Mayo Clinic. But novel therapeutic strategies are focusing on inhibiting androgen receptor function-including MDV-3100, abiraterone, and 17-AAG. These drugs block the nuclear localization of the androgen receptor, inhibit enzymes necessary for testosterone synthesis, and destabilize the androgen receptor, Dr. Tindall said. "The androgen receptor is playing a critical role in current prostate cancer research," he said. Dr. Tindall noted that understanding the functions of the androgen receptor and identifying its interacting proteins are important areas of research in designing novel and targeted therapies, particularly for castration-resistant prostate cancer.

The early success of androgen receptor-targeted therapies such as MDV-3100 and abiraterone serve as a validation of the androgen receptor-targeting approach, noted Charles J. Ryan, MD, of the University of California, San Francisco. Efficacy studies on abiraterone reveal that this drug is highly active in some patients, with response proportions ranging from 45% in heavily pretreated patients to 75% in patients without extensive secondary hormonal therapy or chemotherapy.1,2 "Some responses are incredibly durable, and complete responses do occur," Dr. Ryan said. New research reveals that some patients-depending on genetic variance-are more likely to respond to abiraterone, he noted. New research is attempting to answer questions about this therapy-whether it can be used with hormonal therapy to prolong survival in symptomatic metastatic disease, and whether it should be continued even after progression of disease to protect against tumor growth exacerbation.

Investigators have also shown that MDV-3100 has clinical activity even in heavily pretreated patients, and is now being tested in phase III studies. Clinical trials that answer the questions of whether MDV-3100 could be used as initial androgen deprivation therapy and whether it could be utilized in a noncastrate setting may be warranted, although such trials may require significant expense and time, Dr. Ryan said.

Tumor Microenvironment

In addition to the androgen receptor pathways, numerous agents that disrupt the outlaw pathways that contribute to tumor proliferation and resistance are under investigation, according to William Kevin Kelly, DO, of the Yale Cancer Center. The tumor microenvironment also plays a critical role in the development and progression of advanced prostate cancer. For instance, cancer cells, macrophages, and fibroblasts within the tumor can secrete multiple proangiogenic cytokines such as the soluble growth factors VEGF and tumor necrosis factor-alpha. "Most of the therapies that target the outlaw pathways and microenvironment in castration-resistant prostate cancer are in early-phase clinical trials, but we're likely to see the landscape concerning these therapies change drastically over the next year as results from ongoing studies mature," Dr. Kelly said. Therapies that target the outlaw pathways and tumor cell microenvironment include cediranib (a new agent that inhibits VEGF-1 and VEGF-2), bevacizumab (Avastin), thalidomide (Thalomid), and radioisotope therapies such as samarium Sm-153 lexidronam (Quadramet), Dr. Kelly noted.

Immunotherapy

Prostate cancer immunotherapies are also under development, and may play a role in prostate cancer treatment in the near future, according to Charles G. Drake, MD, PhD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer. The newly approved antigen-specific immunotherapy product sipuleucel-T (Provenge) has shown a survival benefit in phase III trials. In one phase III study of sipuleucel-T published in 2006, the investigators did not meet their primary endpoint of time to progression but did show a statistically significant survival benefit, which was a secondary endpoint in the study.3 Another phase III trial presented in 2009 showed a statistically significant survival benefit, with a hazard ratio of 0.78 in favor of sipuleucel-T.

Other approaches to immunotherapy include those that involve blocking immune checkpoints-ie, cell surface molecules that restrict antitumor response. Among these agents, ipilimumab is farthest along in clinical development, Dr. Drake said.

The viral-based vector ProstVac-VF has also shown a survival benefit in initial clinical studies, and a phase III clinical trial is in the planning stages and could be initiated within the next year. Such studies are proof of the concept that immunotherapy might provide real survival benefit for patients with castration-resistant prostate cancer, according to Dr. Drake.

The most promising use of immunotherapy may be in combination with conventional treatments, because single-agent immunotherapy is usually not sufficient to induce an optimal antitumor response, particularly in patients with advanced disease. However, several factors need to be taken into account when combining immunotherapies with standard treatments, Dr. Drake noted. "Dose matters-the dose of chemotherapy used in combination has to be very different than that used in single-agent treatment, and the optimum schedule (for efficacy and safety) needs to be carefully assessed. But combination therapies may be the wave of the future," he said.

Research on drugs that target the androgen receptor pathway, outlaw pathways, and tumor cell microenvironment as well as immunotherapies represent important strides forward in cancer research, commented Maha Hussein, MD, of the University of Michigan, Chair of the GU Cancers Symposium. "We have had an incredible expansion of science and knowledge about the different pathways important in prostate cancer, as well as treatments that target these pathways," she added. "It's an exciting time for prostate cancer research, and will provide a better future for prostate cancer patients." ■

References

1. Ryan CJ, Rosenberg J, Lin A, et al: Phase I evaluation of abiraterone acetate (CB7630), a 17-alpha hydroxylaseC17, 20-lyase inhibitor in androgen-independent prostate cancer (AiPCa). ASCO Prostate Cancer Symposium Proceedings ( abstract 278), 210, 2007.

2. Attard G, Yap TA, Dearnaley AH, et al: Activity, toxicity, and effect on steroid precursor levels of abiraterone (A), an oral irreversible inhibitor of CYP17 (17α hydroxylase/17,20 lyase), in castrate men with castration refractory prostate cancer (CRPC). ASCO Prostate Cancer Symposium Proceedings ( abstract 264), 203, 2007.

3. Small EJ, Schellhammer PF, Higano CS, et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089-3094, 2006.