Off of a clinical trial, what we now recognize, is that there is an intermediate level of hormonal sensitivity that we call, for lack of a better term, androgen- independent-but-not-yet-hormone-refractory disease where patients will respond to alternative hormonal manipulations. So typically what we do is, for a patient who is on combined androgen blockade, we will first stop the anti-androgen, Casodex or flutamide, because in about 25-50% of patients with stopping that drug the patients will go into a remission, generally of short duration. The mechanism here is not completely known but it is felt to be mutations that occur within the androgen receptor that allow the androgen receptor to become somewhat promiscuous and be stimulated by the anti-androgen. When you withdraw the anti-androgen, those clones will die off and that’s what one see clinically.
Next, one can introduce an alternative anti-androgen, specifically high dose Casodex or flutamide, and one can see patients respond, interestingly, to an alternative anti-androgen when the other anti-androgen was used. And finally, one can use an anti-adrenal agent. My drug of choice here is ketoconazole or Nizoral, which is tolerated by most but not all people. Some develop fatigue or GI symptomatology. In general, one can use 200 mg three times a day of this drug, although higher doses have been used with greater toxicity. If one tells the patient that one should take it without an H2 blocker on an empty stomach, one can get by with lower doses because one needs acid in the stomach for adequate absorption of ketoconazole. Aminoglutethimide has been used but it has greater toxicity than ketoconazole but similar response rates.
Now what about chemotherapy in this disease? Chemotherapy had been felt not to be very active in this disease for many years as a result of pilot studies, phase II studies, randomized studies, etc. until this study was done. Very clever study done by Ian Tannic and his colleagues in Canada. A study that looked at quality of life as its primary endpoint, in 161 patients with symptomatic advanced prostate cancer. Patients were either treated with 10 mg of prednisone per day or alternatively with prednisone plus mitoxantrone at 12 mg per meter squared every three weeks. Once again, primary endpoint was pain palliation. What they found was there was a difference in the rate of pain relief and the duration of pain relief, both of which were statistically significant. Another study that we did in parallel to this study in CLGB, almost 250 patients randomized to hydrocortisone plus mitoxantrone or hydrocortisone alone. Unfortunately we looked at survival as a primary endpoint. No difference in overall survival but we also tallied quality of life endpoints and in this particular study we did see a difference in quality of life associated with mitoxantrone. So on the basis of this study and the Canadian study, mitoxantrone was approved as a first chemotherapy drug for use as palliation in patients with advanced prostate cancer. Since that time, we’ve recognized that the old drug, estromustine – which was initially made as a designer drug to be targeted to hormone sensitive cells deliver a nitrogen mustard – very modest activity by itself but when combined with microtubule inhibitors generated response rates that were very respectable. With 50% reductions in PSA seen in over 50% of patients.
So these remain the most active regimens and are now being used clinically but have never been compared to either mitoxantrone/prednisone or to no therapy, and there have been no chemotherapy agents or regimens that have ever been demonstrated to improve survival in this disease. Although we do suspect at the present time that if one did a randomized study using Estromustine-based regimens that one would see a benefit in survival. So in summary, with regard to chemotherapy, mitoxantrone is used in this context for palliation. Estromustine-based regimens have greater activity but we are still uncertain, in terms of their impact in overall survival – since no randomized studies have yet been done – and certainly no randomized studies have yet been done in the context of earlier disease using chemotherapy, although those are planned now as well. Clearly we have to move beyond chemotherapy in this disease and there are a number of strategies, experimental trials, in the clinic right now that offer potential for exciting advances in this disease.