Clinical results demonstrate the potential of an investigational drug, exisulind (Aptosyn), to delay the need for androgen-deprivation therapy in men who have undergone prostatectomy and are at risk of prostate cancer recurrence. Detailed findings of the randomized double-blind, placebo-controlled phase II/III study, conducted at seven centers across the United States, were presented at the 95th annual meeting of the American Urological Association (AUA) by principal investigator Erik T. Goluboff, MD, of Columbia-Presbyterian Medical Center in NewYork.
Slowing the Rise of PSA
The primary objective of the 1-year study was to evaluate the efficacy and safety of exisulind in slowing the rise of prostate-specific antigen (PSA) in men with a rising PSA level following radical prostatectomy. A rising PSA level in such men is widely believed to indicate disease progression and is used by many physicians to determine treatment. Slowing the rise of PSA levels suggests a delay in disease progression, consequently delaying the need for hormone-deprivation therapy.
Results from 92 evaluable patients showed that the median 12-month change in PSA levels from baseline was significantly lower in the 45 men receiving exisulind than in the 47 men who received placebo (P = .0166). The results were also statistically significant (P = .0003) in men treated with exisulind who were prospectively classified as being at high-risk for metastatic disease. In addition, exisulind therapy significantly prolonged the median PSA doubling time in high-risk patients, as compared to placebo recipients (P = .048).
An increase in PSA doubling time is generally regarded as indicating a slowing of disease progression. Furthermore, high-risk patients receiving exisulind demonstrated a trend toward a longer time to PSA progression, compared to those receiving placebo. Treatment with exisulind was well tolerated, and the majority of reported side effects were mild to moderate.
Current Treatment Options Limited
Radiation therapy is currently the preferred treatment for local disease recurrences. However, many men experiencing a recurrence of prostate cancer have undetected metastatic disease beyond the range of radiation therapy.
Hormonal therapy (androgen deprivation) produces high response rates in metastatic prostate cancer but is not curative. Its effect on survival is controversial, and it is associated with significant morbidity and an adverse impact on the patients quality of life.
Hormone therapy is effective but has significant side effects, and resistance to hormones usually develops within 2 to 3 years, exhausting the current therapeutic arsenal, said Rifat Pamukcu, md, senior vice president of Research and Development and Chief Scientific Officer of Cell Pathways. By prolonging the time between initial PSA rise and hormonal treatment, exisulind may offer significant clinical benefits to patients at risk of prostate cancer recurrence. It could help to limit the cost and morbidity of subsequent therapy, increase patient quality of life, and extend the available treatment options.
Dual Mechanism of Action
Research reported recently at the annual meeting of the American Association of Cancer Research (AACR) demonstrated that exisulind halts the growth of prostate cancer cells in two ways. First, it directly kills cancerous prostate cells by inducing apoptosis. Second, it decreases the expression of the androgen receptor in cancerous prostate cells, making them less responsive to the growth-promoting effects of androgens in their environment.
Moreover, androgen-receptor expression occurs at concentrations of exisulind that produce apoptosis and cell death. As a result of this dual mechanism of action against prostate cancer cells, exisulind is effective in prostate cancer cells irrespective of their sensitivity or resistance to androgens.