Randomized Phase II Trial of Neoadjuvant Everolimus in Patients with High-risk Localized Prostate Cancer - Beyond the Abstract

Localized prostate cancer with high-risk features represents a heterogeneous disease that is frequently managed with either radiation therapy (RT) or radical prostatectomy (RP). Patients who undergo radical prostatectomy can frequently be cured of their disease, but for many patients, significant risk of disease recurrence, progression and ultimately death from prostate cancer remains. In the population of prostate cancer patients with unfavorable pre-treatment features who undergo radical prostatectomy, there is significant interest in exploring potential neoadjuvant treatment options to mitigate this risk of disease recurrence.

To date, no agents have been shown to have a clinical benefit or have received FDA approval in this treatment setting, however, the neoadjuvant setting does present an opportunity to elucidate potential response mechanisms and underlying disease biology in this tumor by comparing pre-treatment tumor biopsies to post-treatment prostatectomy samples. This publication describes a randomized clinical trial of two doses of everolimus administered prior to radical prostatectomy in patients with high-risk localized prostate cancer.

This single-institution trial conducted at the Cleveland Clinic enrolled prostate cancer patients with high-risk features who were intended to undergo radical prostatectomy. High-risk disease was defined as meeting one of the following criteria: PSA ≥ 10 ng/mL (any grade or stage), clinical stage T2b, T2c, or T3 (any PSA level or grade); biopsy Gleason score of 7 (4 + 3 only) or ≥ 8 (any stage or PSA level), or patients with any stage/PSA/Gleason score and a 35% or greater chance of biochemical failure at 5 years based on Kattan’s nomogram. Patients were randomized to receive either 5 mg Daily or 10mg Daily dose of everolimus orally for 8 weeks prior to radical prostatectomy. Everolimus, which is currently FDA approved in a number of malignancies, although not in prostate cancer, is an inhibitor of the mTOR/PI3K/AKT pathway that regulates cell growth, proliferation, and survival. This pathway is commonly dysregulated in prostate cancer as it is in numerous other malignancies. Pre-clinical studies of everolimus suggested activity in androgen-independent prostate cancer cell lines, leading this neoadjuvant clinical trial to be undertaken.

The primary endpoint in this trial was pathologic response following radical prostatectomy. A number of secondary endpoints including changes in PSA and surgical outcomes were also pursued. Correlative endpoints included changes in tumor tissue expression levels of mTOR, 4EBP1, S6 and AKT which were assessed by immunohistochemistry (IHC). Despite the strong pre-clinical rationale, the trial was terminated due to lack of clinical efficacy after enrolling 17 patients (nine at 10 mg dose and eight at 5 mg dose). No pathologic complete responses were observed in these patients and 15/17 patients had a PSA increase during treatment. The treatment with everolimus was overall well tolerated and all patients completed the intended 8 weeks of therapy. Only three G3 TRAEs (2 in high dose group and 1 in low dose group) were observed and no G4/5 TRAEs were reported. There were no surgical complications attributed to neoadjuvant treatment and overall the surgical complications were felt to be in line with what is expected in this patient population. The correlative analyses showed a decrease in the expression of 4EBP1 following treatment with everolimus.

Overall, this study showed that while neoadjuvant everolimus is well tolerated in high-risk prostate cancer patients undergoing radical prostatectomy, and does impact potentially relevant growth and proliferation pathways in prostate tumor tissue, it nevertheless did not generate any signal suggestive of clinical benefit in this patient population. To date, no treatment has shown conclusive clinical benefit in this space and consequently the recommended therapy, even for high-risk prostate cancer patients undergoing surgery, is to proceed to radical prostatectomy without any neoadjuvant treatment. Neoadjuvant androgen deprivation therapy (ADT), while potentially improving the rate of complete resection in high-risk patients, has not been shown to improve any long-term clinical outcomes in this patient population. The success of novel antiandrogens such as enzalutamide and abiraterone in a hormone-sensitive disease that is metastatic or lymph node positive has led to the consideration of these agents in the neoadjuvant setting as well. A randomized phase II trial of neoadjuvant ADT/enzalutamide with or without abiraterone has shown initial promising results and is currently in long-term follow-up. More neoadjuvant trials like these are needed to help advance the standard of care for men with high-risk localized prostate cancer.

Written by: Vadim S Koshkin, MD, Assistant Professor, Division of Hematology/Oncology, Department of Medicine, The University of California San Francisco

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