PHASE-II STUDY OF SURAMIN PLUS AMINOGLUTETHIMIDE IN 2 COHORTS OF PATIENTS WITH ANDROGEN-INDEPENDENT PROSTATE-CANCER - SIMULTANEOUS ANTIANDROGEN WITHDRAWAL AND PRIOR ANTIANDROGEN WITHDRAWAL

Management of prostate cancer progression after failure of initial hor monal therapy is controversial, Recently, the activity of the simple d iscontinuation of antiandrogen therapy has been established by several groups, as well as the enhanced activity when combined with adrenal s uppression (i.e., aminoglutethimide and hydrocortisone), Furthermore, suramin has generated considerable interest following reports of respo nse rates ranging from 17 to 70%, More recently, suramin response rate s of 18 and 22% have been reported when the potential confounding vari ables of flutamide withdrawal and hydrocortisone were prospectively co ntrolled, On the basis of the activity of combining aminoglutethimide with flutamide withdrawal, we designed a protocol in which suramin was combined with aminoglutethimide in two cohorts of patients (those wit h simultaneous antiandrogen withdrawal compared to those who had previ ously discontinued antiandrogen therapy), Eighty-one evaluable patient s were enrolled in th:is study between June 1992 and November 1994, Pa tients were a priori divided into two cohorts, those receiving prior a ntiandrogen withdrawal (n = 56) and those receiving simultaneous antia ndrogen withdrawal (n = 25) at the time the patients were enrolled int o the trial, For the group that discontinued antiandrogen prior to enr olling in therapy, the partial response rate (>50% decline in PSA for >4 weeks) was 14.2%, whereas the partial response was 44% for those pa tients who discontinued their antiandrogen at the time of starting sur amin and aminoglutethimide, The median time to progression was 3.9 mon ths in patients failing prior antiandrogen withdrawal and 5.5 months i n those patients having concomitant antiandrogen withdrawal (P = 0.36 for the overall difference), The progression-free survival estimate at 1 year for patients having prior antiandrogen withdrawal was 19.8% [9 5% confidence interval (CI), 11-32.9%], For those patients who experie nced antiandrogen withdrawal simultaneous with the treatment, the prog ression-free survival estimates:it 1 and 2 years were 27.1 (95% CI, 13 .2-47.6%) and 4.5% (95% CI, 0.8-21.6%), The median survival time for t hose patients having prior antiandrogen withdrawal was 14.2 months, wh ereas the median survival was 21.9 months for those having concomitant antiandrogen withdrawal (P = 0.029 for the overall difference). In co nclusion, the partial response rate of 44% for those who had concomita nt flutamide withdrawal with adrenal suppression was consistent with t hat of other reports using a similar maneuver, Although this study was not randomized and thus we should not over-interpret the results, flu tamide withdrawal plus adrenal suppression appears to have greater act ivity than flutamide withdrawal alone, Furthermore, these data suggest that suramin adds little to the response rate observed for other adre nal suppressive agents in the presence of antiandrogen withdrawal, Thi s interpretation is in agreement with those studies controlling for ad renal suppression and flutamide withdrawal prior to suramin administra tion, which noted modest activity of short duration, Given that antian drogen withdrawal is now accepted as an active maneuver for a subset o f patients progressing after maximum androgen blockade, we propose tha t future trials attempting to maximize response rates incorporate this maneuver whenever possible into prospectively designed regimens.