Prostate UK - Current prospects for the Chemoprevention of Prostate Cancer

Prostate news article, July 2010

CURRENT PROSPECTS FOR THE CHEMOPREVENTION OF PROSTATE CANCER

Article by: Professor Roger Kirby, Chairman, Prostate UK

Unfortunately, Urologists often prefer to treat the disease at the stage they encounter it, rather than approaching the problem with a preventative frame of mind. A recent publication, however, evaluating the effect of dutasteride on prostate cancer¹ calls this view into question. The current lifetime risk of prostate cancer in the USA is estimated at 16.7%.² As the disease is both extremely common and generally slow to progress, potentially it provides a prime target for chemoprevention³.

The first chemopreventative strategy to be evaluated in a randomized controlled trial (RCT) was the combination of selenium (Se) and Vitamin E in the SELECT study. Notable results of SELECT after a median follow-up of 5.5 years can be summarised as follows:⁴

Hazard ratios and 99% confidence intervals (CIs) for developing prostate cancer were 1.04 for Se (CI 0.87-1.24), 1.13 for Vitamin E (0.95-1.35), and 1.05 for the combination of Se and Vitamin E (0.88-1.25) when compared with placebo.
No significant differences were noted in other pre-specified cancer endpoints.
A non-significant increase in risk of prostate cancer was noted for Vitamin E.
A non-significant increase in risk of Type 2 diabetes was noted for Se.

These data provide compelling evidence that neither Vitamin E nor selenium are capable of significantly reducing a man's risk of prostate cancer. Indeed the slight increase in risk of prostate cancer with Vitamin E is of concern. The mild increase in risk of diabetes with selenium has been previously reported, and adds to growing concerns regarding the safety of dietary supplements in the absence of large-scale trials that prove efficacy and safety⁵.

Another landmark study of chemoprevention of prostate cancer is the Prostate Cancer Prevention Trial (PCPT)⁶. In this trial, an endpoint (prostate cancer diagnosis or end of study biopsy) was available in 59.6% of the finasteride group and 63% of the placebo group. Of the 9,060 men who constitute the final analysis, prostate cancer was found in 803/4,368 (18.4%) of the finasteride group and in 1,147/4,692 (24.4%) of the placebo group. The relative risk reduction was 24.8% (p<0.001). When subjects were stratified by age, race/ethnicity, family history, and entry PSA, cancer was reduced with finasteride by a similar degree in all groups. Rates of acceptance of biopsy recommendations differed slightly between study groups. Biopsy recommendation was given to 2,122/9423 (22.5%) in the finasteride group and to 2,348/9,457 (24.8%) of the placebo group. However, there was no significant difference in the rates of acceptance of biopsy in the two groups. About half of biopsies were prompted by abnormal DRE and half by PSA. Mean PSA at biopsy was around 2.5 ng/mL in both arms (using an adjusted PSA value in the finasteride group). Study drug discontinuation at any time during the study for reasons other than death or prostate cancer was 36.8% in the finasteride arm and 28.9% in the placebo arm. Participants who temporarily discontinued drug were allowed to re-start the study medication at a later date and regardless of whether or not they were taking study drug, were still eligible for the end of study biopsy. The annual rate of drug discontinuation dropped from 10% and 6.3% (respectively for finasteride/placebo) in the first year to 3.6% and 3.4% in year 5. Side effects were the primary reason for temporary discontinuation seen in 18.3% in the finasteride group and 9.8% of the placebo group.

A secondary objective of the study was the measurement of Gleason score. Despite a 24.8% reduction in risk of cancer overall, there was a small increased risk, both absolute and relative, of high grade disease. Gleason 7-10 tumours constituted 280/757 graded tumours (37%) in the finasteride group as opposed to 237/1068 in the placebo group (22.2%). This excess of 43 cancers could be seen to be primarily due to the excess Gleason 7-10 tumors in the for-cause biopsies (excess of 40) compared to end-of study biopsies (excess of 3). The cause for this has been the subject of much debate, but it is now widely accepted that the 5 alpha-reductase inhibitor, finasteride affected PSA detection rate of prostate cancer. Studying 5112 and 4579 men in the placebo and finasteride groups, respectively, all of whom had a prostate biopsy and associated PSA, Thompson et al found that finasteride significantly enhanced the ability of PSA to detect both prostate cancer and high grade prostate cancer.⁷.

Redman and colleagues performed a comprehensive analysis, taking into account those factors that affected cancer detection in the two groups of the study including the lower biopsy rate in the finasteride group as well as the group of factors related to cancer detection.⁸. Examining only biopsy itself, the bias-adjusted rates of prostate cancer in the two groups were 21.1% (4.2% high grade) in placebo versus 14.7% (4.8% high grade) in finasteride, a highly significant 30% reduction of risk of cancer and a non-significant 14% increase in high grade disease. When the grade change between biopsy and prostatectomy (understanding that ‘true’ Gleason grade is best determined at radical prostatectomy when the entire prostate is available for analysis rather than the biopsy which is affected by sampling error) were incorporated, the analysis found that the true rates of high grade disease in the two groups were 8.2% placebo and 6.0% finasteride, a 27% risk reduction (p=0.02). Pinsky and colleagues from the National Cancer Institute, using a different analysis methodology and conducting an independent analysis, arrived at a similar conclusion that the rate of true high-grade disease may have been lower in the finasteride group compared to placebo⁹.

The REDUCE trial is a multi-center, international study; subjects were randomized to receive either the dual 5 alpha-reductase inhibitor dutasteride or placebo for a study period of 4 years. Eligibility criteria include PSA between 2.5 – 10 ng/mL and a previous negative prostate biopsy within 6 months of randomization. Biopsies were performed after 2 and 4 years of follow-up. Because of the study entry prostate biopsy, an advantage of REDUCE over the PCPT (with its ‘for-cause’ prostate biopsies performed frequently for PSA which can be affected differentially by 5AR inhibitors), there were few additional PSA-prompted biopsies beyond those dictated by the protocol. The results have recently been reported by Andriole et al1. Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001).

Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 (6.7%) tumours with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (6.8%) (P = 0.81). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in this study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P = 0.03). It was concluded that over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia.

In a recent editorial Dr Patrick Walsh¹⁰ reviewed these results, arguing that reduction of cancer diagnosed on the basis of a biopsy driven by PSA rise or alteration of the consistency of the prostate on palpation was more clinically relevant than a reduction in cancer detected by protocol driven biopsy. Although he makes a relevant point, it is difficult to conceive how one could design a convincing trial to assess the impact of 5ARIs on the risk of developing biopsy detectable prostate cancer without employing a protocol-driven biopsy regime. Because this class of drug is well documented as having a significant impact on the sensitivity and specificity of both PSA and DRE in prostate cancer diagnosis, any trial relying on PSA or DRE triggered biopsies would fail to distinguish between the impact of these drugs on the risk of developing prostate cancer versus their impact on the likelihood of detecting a tumour. Dr Walsh also questions the relevance of the reduction in incidence of lower Gleason score cancers, which possess a much lower tendency to progress or result in death compared with higher score cancers. From a clinical viewpoint however, Gleason pattern 6 cancers are the most problematic since it is often difficult to decide whether active treatment or active surveillance is the best treatment strategy, and patients are often perturbed by this uncertainty. In addition, it may be the case that, if left undetected, some of the Gleason 6 tumours identified in the study would have progressed to represent clinically significant disease. He also argued that the deployment of a 5ARI in a chemopreventative setting carries the potential risk of delaying the diagnosis of more poorly differentiated cancers. This however is at variance with the literature^11,12 which suggests that both finasteride and dutasteride in fact improve the sensitivity and specificity of PSA and DRE in the detection of prostate cancer. Moreover, all other endpoints of prostate cancer risk, namely the incidence of prostatic intraepithelial neoplasia (PIN), atypical small acinar proliferation (ASAP) and tumour volume, were all improved in the 5ARI arm compared with placebo.

It is relevant in this context to compare the design of the PCPT study and the REDUCE trial. The key differences lie in the patient selection, men recruited in the REDUCE study were potentially at higher risk of developing prostate cancer and arguably a more clinically relevant group to evaluate. The follow-up protocol was also considerably more rigorous in the REDUCE study with over 70% of patients in both the active treatment and placebo completing the biopsy protocol which adds credibility to the results.

In conclusion, the FDA and European regulatory authorities will doubtless come to their own conclusions about the safety and efficacy of dutasteride as a chemopreventative agent in prostate cancer, and will do so in the light of a more complete analysis of the data than is possible simply from a review of the publication in the New England Journal of Medicine¹ which is inevitably a summary of a very large volume of material. In the interim, Urologists seem certain to face questions from their patients about the advisability of the use of these agents in a chemopreventative setting. Recent developments in molecular genetics are beginning to allow us to identify a sub-group of patients with an especially high risk of developing prostate cancer¹³. These highly susceptible men and their families are precisely those who might be expected to benefit from effective chemoprevention for this disease. In the interim clinicians must decide for themselves who are most likely to benefit from these medications.

References

1. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010;362:1192-202.
2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer Statistics 2008. CA Cancer J Clin 2008;58:71-96.
3. Thompson IM, Tangen CM, Goodman PJ, Lucia MS, Klein EA. Chemoprevention of Prostate Cancer. J Urol 2009;182(2):499-508.Lippman SM, Klein EA, Goodman PJ, Lucia MS.
4. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers. The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009.301:39-51
5. Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, Cappuccio FP, Ceriello A, Reid ME. Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med. 2007:147(4):217-23.
6. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-24.
7. Thompson IM, Chi C, Ankerst DP, Goodman PJ, Tangen CM, Lippman SM, Lucia MS, Parnes HL, Coltman CA Jr. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst. 2006;98:1128-33.
8. Redman MW, Tangen CM, Goodman PJ, Lucia MS, Coltman CA, Thompson IM. Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach. Cancer Prevention Research 2008;1:174-181.
9. Pinsky P, Parnes H, and Ford L. Estimating Rates of True High-Grade Disease in the Prostate Cancer Prevention Trial. Cancer Prevention Research 2008;1:182-186.
10. Walsh PC. The Chemoprevention of Prostate Cancer. NEnglJMed 2010; 362;13.
11. Thompson IM, Tangen CM, Goodman PJ, et al. Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection. J Urol 2007;177: 1749-52.
12. Andriole GL, Bostwick D, Brawley O, Gomella L, Marberger M, Montorsi F, et al. The utility of PSA for detection of prostate cancer in men treated with dutasteride: Results from the REduction by DUtasteride of prostate Cancer Events (REDUCE) study. Journal of Men's Health 2009 Sep;6(3):269.
13. Kirby RS, Eeles R, Kote-Jarai, Screening for Prostate Cancer: the Way Ahead. BJUInt 2010; 295-6.