BERKELEY, CA (UroToday.com) - Many men who are diagnosed with high-risk localized prostate cancer are not cured with current standard-of-care therapies including prostatectomy and/or radiation combined with androgen deprivation therapy. In general, men with high-risk disease who relapse after potentially curative local therapy have shortened life spans and suffer the effects of chronic systemic therapy for advanced disease. In an effort to increase cure rates for men with high-risk localized prostate cancer who are candidates for prostatectomy, we have developed a clinical trial program committed to the investigation of neoadjuvant systemic therapy combined with prostatectomy. Genitourinary cancer investigators at Dana-Farber Cancer Institute, together with collaborators at Beth Israel Deaconess Medical Center and The University of Washington-Fred Hutchinson Cancer Center and others, have committed resources to this multidisciplinary program. The work was supported from the National Cancer Institute, The Prostate Cancer Foundation, and from Janssen Pharmaceuticals.
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The goals of our high-risk prostate cancer program include increasing the cure rate for these men and performing informative correlative science on serum and tissue from these patients to understand the mechanisms of cancer response and resistance. Data from our phase 2 trials will inform an effective regimen for phase three testing in this patient population. Neoadjuvant systemic therapy combined with surgical resection has shown survival benefits in other cancer types including breast, colon, bladder, and melanoma. To date there is no data supporting neoadjuvant therapy and surgery in prostate cancer. We believe that in 2015 the field has evolved to support the expectation for positive trials in this setting. We now have more accurate algorithms to stratify patient risk and identify men who need a novel approach to obtain a cure. At the same time we have an increased therapeutic armamentarium of drugs approved in metastatic castration-resistant prostate cancer which can be evaluated in the early disease but high-risk setting. Importantly, trial endpoints in the neoadjuvant space -- other than overall survival -- are needed to define patient benefit in a more expedited timeline. Endpoints such as pathologic response at prostatectomy, freedom from prostate specific antigen (PSA) failure, freedom from developing metastasis, or initiating additional prostate cancer therapy are relevant in this setting and could be surrogates for improved survival.
We recently published the report entitled “Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study.” This trial was designed in 2008 when abiraterone acetate (AA) was in early stage testing. It had become appreciated in the field that prostate tumor cells were capable of producing androgens in an intracrine fashion and we designed our trial to interrogate the prostate tissue effects of AA compared to standard androgen deprivation (leuprolide acetate). We believe that describing the phamacodyamic (PD) effect of AA in tissue was paramount to continued investigation of this approach. We demonstrated that treatment with leuprolide acetate plus AA and prednisone was able to markedly lower the levels of tissue androgens and androgen precursors.
Pathologic response was a secondary aim of this trial. There were more favorable pathologic responses (complete response and less than 5mm remaining tumor) in the cohort that received 6 months of AA compared to 3 months of AA. The trial was not designed to evaluate statistical differences between the two cohorts. Achieving a pathologic complete response or near complete response is uncommon with standard hormonal approaches and such favorable responses have not been previously described in such a high-risk cohort of patients as was included in this trial. There were patients who had a minor response to study treatment, and we hypothesize that tumors are primed to be exquisitely sensitive or insensitive to this approach, and we are currently further interrogating prostatectomy tissue for potential biomarkers of response and resistance. Subsequent phase two trials are now underway evaluating combination therapy in this setting. A phase three trial is needed to prove the value of neoadjuvant or adjuvant therapy for these patients. Together with our colleagues we are invested in developing the optimal outcome measures and regimen for evaluation in a phase three trial in order to improve patient outcome over current standard care.
Mary-Ellen Taplin, MD and Philip Kantoff, MD 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.
Dana-Farber Cancer Institute, Boston, MA USA
Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: Results of a randomized phase II neoadjuvant study - Abstract