What is the best type of treatment to offer a man after primary and (perhaps) appropriate secondary forms of treatment leave him with a rising PSA?
Historically, the standard “next step” for a man with such a rising PSA (biochemical progression) after first-line radiation therapy or first-line surgery and second-line radiation therapy has been androgen deprivation therapy (ADT) with either a short course of an antiandrogen (normally bicalutamide or flutamide) and longer-term use of an LHRH agonist (e.g., leuprolide acetate) or combined ADT with a long course of an antiandrogen and an LHRH agonist. A subset of men has been managed with various types of intermittent ADT, sometimes including a 5α-reductase inhibitor (5-ARI) like finasteride or dutasteride as well.
A new article by Monk et al., published on line in Cancer in December, now offers us a different opportunity based on 10 years of follow-up of men managed with “peripheral” androgen deprivation (PAD) using a combination of an antiandrogen and a 5-ARI. This opportunity needs to be tested in a major, randomized, multicenter, Phase III clinical trial. (Additional information about the results of this trial are available in a report published on the Medscape web site.)
Monk et al. report enrollment of 101 patients with progressive prostate cancer into this multicenter study. All the patients had received “definitive local therapy” (although the details of this therapy are not available in the abstract of the paper). They also had a rising PSA (> 1 ng/ml) but there was no other evidence of recurrent disease. They were all treated with PAD using an antiandrogen (flutamide, 250 mg t.i.d.) and a 5-ARI (finasteride, 5 mg once daily) and followed to assess their PSA response and their quality of life.
Here are the results reported by Monk and his colleagues:
- 99/101 patients enrolled (98 percent) were eligible for assessment.
- The 5-year overall survival rate was 87 percent.
- The 5-year metastasis-free survival rate was 97 percent.
- Median follow-up is now 10 years.
- 22/99 patients (22 percent) remain on therapy.
- 43/99 patients (43 percent) have died (including 13 who died of progressive prostate cancer), which means that median overall survival has still not been reached.
- A decrease of ≥ 80 percent in patient’s PSA levels was observed in 96/99 patients (97 percent).
- PSA became undetectable (i.e., <0.2 ng/ml) in 72/99 patients (73 percent).
- The median time to a nadir PSA value was 3.2 months.
- The average (median) time to biochemical progression was 85 months (> 7 years).
- 18/99 patients (18 percent) stopped therapy because of side effects of treatment.
- 15 patients had diarrhea.
- 4 patients had gynecomastia.
- 3 patients had elevated levels of liver enzymes.
- There was a small but significant decrease in quality of life scores at 6 months post-enrollment in this trial.
It is worth noting that one of the rationales for this study was that PAD does not suppress serum testosterone levels in the same way that medical castration (with an LHRH agonist) or surgical castration (an orchiectomy) do.
Clearly PAD based on an antiandrogen and a 5-ARI “works.” And it appears to work with less than optimal agents. In general, it would be reasonable to think that if the combination of finasteride and flutamide can have this effect, then the combination of dutasteride (Avodart) and bicalutamide (Casodex) might work at least as well and perhaps with fewer side effects. (Bicalutamide does not have the same tendency to induce diarrhea that is common in patients taking flutamide.)
The “New” Prostate Cancer InfoLink is not aware of any other study that is addressing this precise use of PAD. There has been a study of dutasteride used alone in similar patients. Some data are provided on the ClinicalTrials.gov web site, but as far as we are aware there has been no formal publication of results of this trial, and it is certainly the case that the patients in this trial were followed for significantly less than an average of 10 years.