AUA 2018: Long-Term Impact of 7-year Finasteride Therapy on Prostate Cancer Incidence and Disease-Specific Mortality
Options for Control of Prostate Cancer:
1) Cure the disease when it presents symptomatically – unfortunately, symptomatic PCa is often metastatic PCa, which is not curable.
2) Screen for the disease – recent data from ERPSC demonstrates there is a survival benefit for screening; but many men get screened unnecessarily. Over-diagnosis also becomes an issues.
3) Prevention of PCa – attractive option. As most deaths from PCa occur late in life, if you delay development of the disease, you prevent death from PCa as a result of competing causes. If you never get it, you can’t be overdiagnosed, you don’t develop cancer anxiety, nor do you have the complications of treatment!
Rationale for PCPT:
1. 1991-1992: PCa incidence spiked rapidly due to introduction of PSA
2. 1992: Finasteride/Proscar was FDA approved to treat BPH and LUTS
3. As a result, the Board of Scientific Counselors of Division of Cancer Prevention recommended a trial of prostate cancer prevention
4. SWOG and Division of Cancer met (at NCI) and created the protocol for PCPT
PCPT study – planned enrollment of 18,000 men. Randomized to placebo or finasteride 1:1. Followed up every 3 months for 7 years. Plan for end of study exit biopsy (important!). For cause (high PSA or abnormal DRE) biopsy allowed anytime during the follow-up.
Accrual was greater than expected – almost 19,000 men
However, the study was closed in 2003 as the study endpoint had been met – finasteride reduced prostate cancer diagnoses. This resulted in the first, landmark publication.1 There was 24.5% relative risk reduction of prostate cancer diagnoses – in total and in all subsets. However, at the end of the day, there was a higher number of Gleason 8-10 tumors diagnosed (90 vs. 53 placebo) that was of concern. Dr. Scardino, in an editorial, therefore cautioned against its use until further evaluation was completed.2
This led to further study questioning this finding – did finasteride actually cause worse disease? Or was it involved in better detection? Does it affect PSA and DRE performance?
In an analysis of for-cause and end-of-trial biopsies, it was found that finasteride treated patients had a higher rate of Gleason 8-10 in the for-cause biopsies – but no difference in the end-of-trial biopsy. So, if it was a causal effect, 7-years of treatment should have result in worse disease in the exit biopsy – but it didn’t.
Over time, looking at the risk of high-grade PCa diagnosis, it was noted that most high-grade disease was diagnosed in the first 1 year after randomization – then there was no difference later on. This further supports that finasteride doesn’t cause high-grade cancers. Therefore, finasteride was presumed to increase sensitivity of PSA for PCa, increase sensitivity of DRE for PCa, and improve sampling of the prostate for PCa (40% improved biopsy detection in the finasteride arm).
Taking all of this into account,3 finasteride was found to have a 30% relative risk reduction of diagnosing any prostate cancer, and 27% risk reduction of developing high-risk PCa.
Next, they looked at long-term impact of finasteride.4 Regardless of low or high-grade disease, finasteride use was not associated with any change in overall survival. However, in a more recent analysis, Unger et al.5 found that the 7-year utilization of prostate has had a significant impact on subsequent PCa diagnosis – the gap between the groups has widened and has remained persistent up to 16 years post-randomization.
The impact on PCa death is not yet certain. If finasteride is associated with higher rate of high-risk PCa, then PCa-death may be higher – but if diagnosed earlier, then maybe it helps lower PCa-specific death? Unpublished data presented here, where they linked patient data to United States death certificates, the risk of PCa-specific death was reduced by 25% in the finasteride arm (not statistically significant, as CI crosses 1).
These results are exciting and further work is to be done looking at other outcomes, including QOL outcomes.
Presented by: Ian Thompson, Jr., MD
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA
References:
1. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003 Jul 17;349(3):215-24. Epub 2003 Jun 24.
2. Scardino PT. The prevention of prostate cancer--the dilemma continues. N Engl J Med. 2003 Jul 17;349(3):297-9. Epub 2003 Jun 24.
3. Redman MW, Tangen CM, Goodman PJ, Lucia MS, Coltman CA Jr, Thompson IM.
Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res (Phila). 2008 Aug;1(3):174-81. doi: 10.1158/1940-6207.CAPR-08-0092. Epub 2008 May 18.
4. Thompson IM Jr, Goodman PJ, Tangen CM, Parnes HL, Minasian LM, Godley PA, Lucia MS, Ford LG. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med. 2013 Aug 15;369(7):603-10. doi: 10.1056/NEJMoa1215932.
5. Unger JM, Hershman DL, Till C, Tangen CM, Barlow WE, Ramsey SD, Goodman PJ, Thompson IM Jr.. Using Medicare Claims to Examine Long-term Prostate Cancer Risk of Finasteride in the Prostate Cancer Prevention Trial. J Natl Cancer Inst. 2018 Mar 9. doi: 10.1093/jnci/djy035. [Epub ahead of print]