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
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.