Antitumor Activity In Prostate Cancer Research Articles

Phase II study of 2-methoxyestradiol (2ME2) NanoCrystal Dispersion (NCD) in patients with taxane-refractory, metastatic hormone-refractory prostate cancer (HRPC)

5173 Background: 2ME2 is a non-estrogenic derivative of estradiol with antiproliferative and antiangiogenic activity. Preclinical data support antitumor activity in prostate cancer. Prior studies with 2ME2 capsules showed evidence for antitumor activity in chemotherapy-naive HRPC as evidenced by decreases in PSA velocity, despite suboptimal exposures. Here we report the phase II results of 2ME2 NCD in men with taxane-refractory HRPC. Methods: Pts with HRPC who had progressed on only one prior taxane-based regimen were eligible. All pts received 2ME2 NCD at 1500 mg orally four times daily, repeated in 28 day cycles. The primary endpoint was progression free survival at month 6, with a secondary endpoint of PSA response (consensus criteria). An exploratory endpoint was the metabolic response on FDG-PET imaging (baseline to 28 days). Results: A total of 50 pts was planned. The study was terminated after 21 pts when a futility analysis showed the primary endpoint was unlikely to be reached, as no pts remained on study for > 6 mo. The median number of cycles on study was 2 (range <1 to 4). Reasons for study termination include: disease progression (17) and adverse events (3). One pt remains on study. Adverse events (AE) of grade 3 or greater occurred in 12 patients (57%). Most frequent AE were: fatigue (48%), nausea (43%), anorexia (33%), and vomiting and diarrhea (28%). Transient transaminase elevations occurred in 3 patients. Paired FDG-PET scans were obtained for 11 pts. No metabolic responses were observed as defined by the protocol. Mean SUVmax change was -7.73% (range -27.05% to +20.45%). Conclusions: 2ME2 NCD did not appear to have clinically significant activity in this study and thus cannot be recommended for use as monotherapy in men with taxane-refractory HRPC. Given the aggressive biology in this taxane-refractory population, the potential benefit from a cytostatic agent like 2ME2 might better be realized in the pre-chemotherapy (or rising PSA only) stage. Of note, FDG-PET positive metastasis was found in 100% of pts with taxane-refractory HRPC (as opposed to reported 70% in the chemo-naive HRPC population). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration EntreMed EntreMed EntreMed EntreMed

Phase II Trial of Celecoxib in Prostate-Specific Antigen Recurrent Prostate Cancer after Definitive Radiation Therapy or Radical Prostatectomy

Recent evidence has shown that cyclooxygenase-2 (COX-2) inhibitors have potent antitumor activity in prostate cancer both in vitro and in vivo. However, human trials are absent. This study evaluated the efficacy of the COX-2 inhibitor celecoxib in prostate-specific antigen (PSA) recurrent prostate cancer after radiation therapy (X-ray therapy or XRT) or radical prostatectomy. Forty patients who had biochemical relapse after XRT or radical prostatectomy were treated with celecoxib 400 mg twice per day. Follow-up PSA levels were obtained at 3, 6, 12, and 18 months and subsequently every 6 months thereafter. Data were evaluated by calculating PSA doubling times and by calculating the slope of the curve of log(PSA) versus time to assess rate of PSA increase before and after celecoxib treatment for each patient. Thirty-six of 40 (90%) patients had a slowing effect on their rate of PSA after 3 months, including 11 of 40 with a decline and 8 of 40 with stabilization of PSA. Short-term responses at 3 months continued at 6, 12, 18 months. Comparison of rate of PSA increase before versus after celecoxib treatment showed significant flattening of slope of log(PSA) versus time from pretreatment for each of the time points. There was no significant change in testosterone levels, suggesting an androgen-independent mechanism. COX-2 inhibitors may have an effect on serum PSA levels in patients with biochemical progression after XRT or radical prostatectomy. These results suggest that COX-2 inhibitors may help delay or prevent disease progression in these patients and thereby help extend the time until androgen deprivation therapy.

Angiogenesis and prostate cancer: Important laboratory and clinical findings

Prostate cancer is the leading cause of cancer diagnosis in men and the second leading cause of cancer-related death. Androgen ablation is effective initially, and progression of disease often occurs in many patients. Although recent reports have noted a survival benefit when patients with androgen-independent prostate cancer are treated with docetaxel, patients still have disease progression. Angiogenesis plays a pivotal role for the growth, invasion, and metastasis of prostate cancer. Therefore, antiangiogenesis is a promising new therapeutic modality. More than 20 antiangiogenic agents are now in various stages of clinical trials. We discuss current knowledge on controlling tumor angiogenesis and advances in the development of antiangiogenic agents with promising antitumor activity in prostate cancer.