Phase II Prostate Trials Use Pre-Prostatectomy Study Design to Identify Promising Prevention Agents and Biomarkers
A short window of opportunity between the histologic diagnosis of prostate cancer and definitive treatment (prostatectomy) is being used in several phase II prostate cancer trials to identify promising prevention agents and biomarker end points. The goal is to obtain key information about the effects of novel study agents on intermediate end point biomarkers (IEBs) and about the distribution of the agent in prostate tissue.
Because prostate cancer has a long natural history, IEBs such as serum markers (e.g., prostate-specific antigen [PSA]), histopathological markers, or tissue-based markers are used to find preliminary evidence of efficacy or biologic activity in phase II trials. Evaluation of these agents may lead to the next generation of phase III chemoprevention trials for prostate cancer.
In this "pre-prostatectomy" trial design, men with early-stage prostate cancer are randomly assigned to receive the study agent or placebo for about 3 to 6 weeks between a diagnostic biopsy and a prostatectomy. Investigators have direct access to prostatic tissue from transrectal ultrasound (TRUS)-guided biopsies and the entire gland following surgery, to systematically assess the biologic activity of agents in the target organ.
This clinical model has the advantage of allowing rapid screening of agents in relatively small, randomized, placebo-controlled pilot trials with 60 subjects or less and that are conducted within the standard of care of patients scheduled for radical prostatectomy, according to Dr. Ronald Lieberman, program director in NCI's Division of Cancer Prevention (DCP) Prostate and Urologic Cancer Research Group.
A variety of agents are being tested with this phase II trial design, including androgen receptor antagonists, antiinflammatory agents (selective COX-2 inhibitors), vitamin D analogs, and micronutrient antioxidants. (See table.)
"The phase II pre-prostatectomy cancer prevention trials are a practical and efficient way to determine whether the chemopreventive agent concentrates in a man's prostate and has a biologic effect there. This is an important step in selecting agents for more definitive prostate cancer prevention trials," said DCP director Dr. Peter Greenwald.
One of these studies, for example, uses high-grade prostatic intraepithelial neoplasia (HGPIN) as a primary end point for toremifene. Since there is growing evidence that estrogens play a role in the development of prostate cancer, this study is evaluating the effects of toremifene, a selective estrogen receptor modulator. The trial is comparing the percent of HGPIN present in the radical prostatectomy tissue of patients with stage I or II adenocarcinoma of the prostate who were treated with toremifene orally once a day for up to 6 weeks, against the tissue of patients who received observation alone prior to prostatectomy.
Toremifene is the lead chemopreventive agent being developed by GTx, Inc., a Tennessee-based biotechnology company that focuses on men's health issues and is collaborating with DCP on this phase II study. Dr. Joel Nelson, principal investigator for the toremifene study at Hillman Cancer Center at the University of Pittsburgh Cancer Institute, noted that studies using this trial design are examining human tissues after defined exposure to a chemopreventive agent. The 4-week to 8-week lag time from diagnosis of prostate cancer until surgery provides a "unique window of opportunity to examine alterations in the prostate after exposure," he said.
Assuming that a chemopreventive agent will induce alterations after short exposure, the strategy is to identify those alterations and extrapolate to a longer exposure, according to Dr. Nelson. This is significantly easier and more cost effective, particularly in this case when there are so many compelling chemopreventive agents. But the challenges of the model, using alterations in tissues as evidence for chemoprevention, remain unproven, he noted. The studies are clearly hypothesis generating, yet they must start somewhere, he stressed.
Dr. Jeri Kim, assistant professor in the Department of Genitourinary Medical Oncology at The University of Texas M. D. Anderson Cancer Center, completed the first phase II trial using this model to study selenium and vitamin E, recruiting 48 patients in 18 months. (See "A conversation with….") The trial used the same regimen currently being used in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to see if researchers could identify potential surrogate end point biomarkers in that large study. The analysis is still ongoing.
Dr. Lieberman noted that the preprostatectomy clinical model provides a way to evaluate both the structure/ anatomy of the epithelial compartments (i.e., normal, precancer, and cancer) and the biology/function (specifically, the interface between the epithelium and stroma), which in turn allows investigators to assess the cellular, molecular, and biochemical effects of the experimental agent.
"Furthermore, effects on biomarker modulation can be correlated with changes in histology, proliferation, apoptosis, angiogenesis, and specific molecular targets related to the presumptive mechanism of action(s) of the agent," Dr. Lieberman added.
Evaluating agents for prostate cancer prevention is a major DCP research focus. For instance, the SELECT study has been enrolling a record number of participants to determine if these two dietary supplements can protect against the clinical diagnosis of prostate cancer and the phase III Prostate Cancer Prevention Trial (PCPT) has shown that finasteride can reduce the chances of getting prostate cancer by nearly 25 percent.