disease progression. In a randomized, multicenter, placebo controlled clinical trial, Andriole and colleagues (1995) randomized 120 men to either placebo or 10 mg ﬁnasteride following radical prostatectomy with residual PSA levels. Finasteride did not prevent biochemical recurrence, but it delayed the onset of PSA progression by 6 months and the rate of PSA progression by 14 months after 2 years of therapy. This study, however, did not demonstrate a survival beneﬁt for the ﬁnasteride group compared with placebo. Nonsteroidal antiandrogens (ﬂutamide, biclutamide, nilutamide) are competitive inhibitors for the androgen receptor. They do not suppress serum testosterone and thus, do not produce the side effects associated with castration (erectile dysfunction, loss of libido, “hot ﬂashes”, osteoporosis, fatigue, and muscle wasting). While adjuvant monotherapy with nonsteroidal antiandrogens after radiation therapy or radical prostatectomy is not indicated for localized prostate cancer (McLeod et al 2006), high dose bicalutamide (150 mg daily) may play a role in the adjuvant management of locally advanced (Iversen et al 2000) or metastatic prostate cancer (Tyrrell et al 1998). Combination therapy with nonsteroidal antiandrogens and 5AR inhibitors may provide better cancer control than antiandrogens alone, while continuing to avoid the toxicity of castration. In addition to decreasing intraprostatic DHT, 5AR inhibitors down-regulate androgen receptor expression and may decrease the rate of androgen receptor mutation and subsequent androgen-independent prostate cancer (Wang et al 2004). Combination therapy with bicalutamide and ﬁnasteride inhibit the in vitro proliferation of prostate cancer cells; although to a lesser degree than castration. The combination of finasteride and flutamide has been shown to decrease the total prostatic weight in an equivalent manner to medical castration in a rat model (Fleshner and Trachtenberg 1992). Several phase II trials have examined the effect of antiandrogens and ﬁnasteride as combination therapy for various stages of prostate cancer. Barqawi and colleagues (2003) noted a 58% rate of PSA regression to undetectable levels in 71 men with PSA recurrence after surgery or radiation therapy. Potency was maintained in all those evaluated. Combination therapy has also been used in advanced prostate cancer. Brufsky and colleagues (1997) treated 20 such men with ﬂutamide until PSA levels reached nadir (mean 9.1 weeks). The addition of ﬁnasteride further reduced PSA levels in 19 men. PSA levels continued to decline in 18 patients, declined to less than 1 ng/ml in 13 patients, and reached undetectable levels in 7 patients. Only 3 patients Clinical Interventions in Aging 2006:1(4) 5 alpha-reductase inhibitors in prostate cancer reported libido as “poor” and of the 11 patients potent at baseline, 8 were at least partially potent at last follow-up. Follow-up data demonstrates good durability of the PSA reduction, with a median time to failure of 30 months. At 7 years, 25% of the original group had remained castration- free. Five year overall survival was 65% (Oh et al 2003). A similar phase II trial with biclutamide and ﬁnasteride produced comparable results. Thirty of 36 patients with advanced prostate cancer reached a second PSA nadir after the addition of ﬁnasteride to biclutamide. Eleven were free of progression at last follow-up (mean 3.9 years). Of the 19 who progressed, 12 reached a third PSA nadir after transition to standard medical androgen deprivation. The average time to failure of the treatment protocol was 21.3 months. All potent patients at baseline remained potent at second PSA nadir (Tay et al 2004). The above studies have similar time to failure rates compared with castration (Potosky et al 2001). Unfortunately, the above studies are limited by their observational nature and small number of patients. While the combination of nonsteroidal antiandrogens and 5AR inhibitors seems like a viable option to avoid the toxicity of castration, long term, blinded, randomized, large scale clinical trials with survival data are necessary before deﬁnitive conclusions can be made. Intermittent androgen deprivation allows for transient recovery of testosterone levels and may improve quality of life compared with permanent castration (Spry et al 2006). In a retrospective review of 101 individuals undergoing intermittent androgen deprivation, the “time off period” (when androgen deprivation was ceased) was prolonged from 15 to 31 months in individuals taking ﬁnasteride 5 mg daily (Scholz et al 2006). Improved quality of life was inferred, but not objectively quantiﬁed. Additionally, there was no difference in disease speciﬁc survival (Scholz et al 2006). At the time of writing there have been no randomized clinical trials validating the treatment of prostate cancer with intermittent androgen deprivation therapy and 5AR inhibitors. Safety and tolerability of 5-alpha reductase inhibitors There are extensive data from randomized clinical trials demonstrating the tolerability and safety of finasteride (McConnell et al 1998, 2003; Thompson et al 2003). The PLESS (Proscar Long-Term Efficacy and Safety) trial randomized 3040 men with BPH to 4 years of daily therapy with either ﬁnasteride (5 mg) or placebo. Symptoms and 429