Prostate news article, July 2009

FUTURE TREATMENTS OF PROSTATE CANCER   Article by:   Professor Roger Kirby, Chairman, Prostate UK

These are exciting times for those with an interest in new treatment possibilities for prostate cancer. Some of the latest advances are reviewed here:

Preventing prostate cancer – recent dutasteride chemprevention studies
Given that considerable challenges remain in eradicating prostate cancer once it has developed, what are the prospects for preventing it? Based on the knowledge that androgens play a key role in the development of prostate cancer, it might be predicted that agents which reduce androgen production might, in turn, prevent prostate cancer. In attempting to avoid the toxicity that would be associated with, say, abiraterone acetate, an alternative strategy is to block the final stage of androgen activation, that is, the conversion of testosterone to dihydrotestosterone, a process which is catalysed by the enzyme 5a-reductase. A randomised, placebo-controlled trial using the 5a-reductase inhibitor dutasteride has recently been reported. In this placebo-controlled, randomised controlled study, conducted in men at increased risk of developing prostate cancer on the basis of an elevated PSA but one negative biopsy, 4 years' of treatment with dutasteride 0.5 mg significantly reduced the incidence of prostate cancer, as judged by the numbers of positive second and third biopsies at 2 and 4 years respectively. Importantly, and in contrast to previous studies with finasteride, there did not appear to be an increase in the number of high-grade cancers among those treated in the active arm. Time will tell whether this reduction translates into real clinical benefit in terms of a reduction in prostate cancer mortality, but these early results are promising.

Abiraterone acetate
During the 1980s and 1990s, much attention was focused on maximal androgen blockade (MAB), that is, the combination of suppression of testicular and andrenal androgens, recognising that testicular suppression (e.g. With LHRHa alone), while reducing testosterone levels to those comparable with surgical castration, did not abolish them, and several randomised trials suggested that combining LHRHa with an oral anti-androgen might improve outcomes. An alternative approach was to develop a drug which would ablate testosterone production almost completely, and this was achieved with abiraterone acetate, a 17-hydroxylase/C-20 lyase inhibitor which could be taken orally. In the event, the rather modest improvements in outcomes seen with MAB did not encourage further development of abiraterone until studies at the Institute of Cancer Research indicated that this drug might induce further responses in patients who were so-called hormone-refractory. The important lesson from this is that prostate cancers which escape from control following conventional ADT are nonetheless driven by the androgen receptor, which may, in turn, be stimulated by extremely low levels of androgen including endogenous androgen produced by prostate cancer cells themselves, hence the term castrate-resistant (CRPC) rather than hormone-resistant. Abiraterone has now been studied in a phase III, placebo controlled trial in patients who have progressed following docetaxel chemotherapy, and the results of this study are eagerly awaited. Meanwhile, the phase II trial, indicating the activity of abiraterone in CRPC, has recently been published, showing a 66% biochemical and clinical response rate. These results are very encouraging.

LHRH antagonists
The LHRH agonists have been the mainstay of medical castration for so long that it seems almost de rigeur that they are the correct approach to the suppression of testicular androgen. The initial "flare" in testosterone, due to initial stimulation of the LHRH receptor, is generally well handled by the administration of a short course of oral anti-androgen, and the possible benefits of a new generation of LHRH antagonists were not immediately obvious. Furthermore, some LHRH antagonists appeared to be associated with hypersensitivity reactions, which on occasions were severe. However, potentially important data have emerged recently which indicate that testicular androgen suppression with LHRHa may not be complete, in that (a) "breakthroughs", in which testosterone levels peak above the lower limit of the castrate range, and (b) "mini-flares" or microsurges, in which the initial testosterone flare after the first LHRHa injection is replicated at lower levels on subsequent injections, may both occur. The clinical significance of these phenomena is, as yet, unknown, but in the light of the new biological insights afforded by the abiraterone story, merit further investigation. Reassuringly, data so far on intermittent androgen deprivation suggest that testosterone fluctuations in that context may not be adverse, although further data is needed from ongoing randomised trials, and the effects of androgen fluctuations at low levels could conceivably differ from those at higher levels. Recent data from a phase III study comparing degarelix, a new generation LHRH antagonist, with goserelin, indicate that degarelix has a faster onset of action, and does not result in testosterone breakthrough or miniflares. This agent appears to be well tolerated with only mild reactions at the injection site in comparison to other agents in this class, and has now received both FDA and EMEA approval.

Where may treatment go in the future
A number of other potentially important agents are under study in the management of prostate cancer. Immunotherapy has recently shown renewed promise, with the presentation of a phase III study in which dendritic cells are exposed to a fusion peptide comprised of prostatic acid phosphatase conjucated to GM-CSF. This cellular therapy resulted in a 4-month prolongation of overall survival in patients with CRPC, a startling result which is comparable or better than that achieved with docetaxel11. This agent (Provenge) is now awaiting FDA approval. Other biological approaches to the treatment of prostate cancer are also showing promise. The endothelin receptor is highly expressed in prostate cancer, and inhibition of this receptor results in a reduction in proliferation and inhibition of angiogenesis. A recent phase III trial has shown an improvement in overall survival with the endothelin receptor antagonist ZD4054, controversially without a concomitant reduction in progression-free survival. However, this agent has rightly aroused intense interest and further studies are awaited. Other agents under investigation in prostate cancer include histone deacetylase inhibitors, the VEGF antagonist bevacizumab, and other tyrosine kinase inhibitors such as sunitinib, dasatinib, and RANK-ligand inhibitors.

Impact of prevention and on tumour profiling on future treatment approaches
While efforts to improve treatments for established disease continue, the dutasteride data support the concept of chemoprevention, and the epidemiological data suggesting the importance of diet point the way towards future strategies which might combine chemoprevention with other measures designed to improve the Western diet. Further biological insights into the disease will also impact on treatment selection, and target identification and validation. For example, there are already data suggesting that the expression of specific TMPRSS2-ERG gene fusion proteins, recently described in prostate cancers, might help predict patients who respond to abiraterone. It seems likely that, as exciting new treatment options appear for this disease, the selection of patients most likely to benefit will have a far more rational basis than has been possible in the past. The prospects for taming the tiger in prostate cancer have never been so good.