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103rd Annual Meeting of the American Urological Association

Orlando, Florida / May 17-22, 2008

According to researchers here this week, new findings from the largest prostate cancer prevention study ever carried out suggest that men could reduce their risk of developing prostate cancer by between 25% and 30% if they took the 5-alpha reductase inhibitor (5ARI) finasteride on a daily basis, regardless of their prostate-specific antigen (PSA) levels.

These new findings represent a paradigm shift in the way physicians need to think about prostate cancer, as they potentially could reduce both unnecessary concern on the part of the patient along with the frequent morbidity that accompanies various treatment options. “If a curable cancer is one that is confined to the prostate and has no evidence of spread, cancers with a PSA in excess of 4 ng/mL are beginning to get into the realm when the cancer is no longer curable,” Dr. Ian Thompson, Chair and Professor, Department of Urology, University of Texas Health Science Center, San Antonio, told delegates here. “So from a public health standpoint, you have two choices: you can do the early detection and treatment, which has been what we have done before, or we can prevent it. Since we now know that men with even low PSAs can develop prostate tumours, if a man is worried about his risk, regardless of PSA score, he can take an agent that is now proven to be effective in lowering that risk.”

Dr. Thompson based his remarks on results from several new analyses that he and colleagues involved in the PCPT (Prostate Cancer Prevention Trial) presented here during the scientific sessions. In his own presentation, Dr. Thompson reminded delegates that the PCPT involved almost 19,000 men aged <u>></u>55 years with an entry PSA level of <3 ng/mL. Men were randomized to finasteride 5 mg/day or placebo for seven years. Biopsies were carried out for cause and at the end of the seven-year study, although only about 60% of men accepted the final biopsy, Dr. Thompson noted. At study end point, finasteride reduced the prevalence of prostate cancer from 24.4% in the placebo group to 18.4% in the active treatment arm, or a 24.8% relative risk reduction in favour of active therapy.

The PCPT Confounding Factor

However, there was an initial observation of a slight preponderance of higher-grade Gleason 7-10 tumours in the PCPT trial treatment arm. Dr. Thompson and colleagues set out to answer two key questions: Were the tumours prevented by finasteride in the PCPT clinically significant? Was the increase in high-grade prostate cancer in the finasteride arm real or not?

To answer the first question, the core pathology laboratory reviewed all available PCPT biopsies and compared Gleason score and measures of extent of tumour on biopsy from finasteride participants (n=671) vs. placebo controls (n=955). Another 275 radical prostatectomy specimens in the placebo group were also reviewed. Samples were graded into three tiers: Gleason score of <u><</u>6, Gleason score of 7 and Gleason score of <u>></u>8. Two definitions of “insignificant” cancer were used based on the following features: T1c; PSA density <0.15 ng/mL/g; Gleason of <u><</u>6 and either limited to fewer than three cores and no more than 50% involvement of any one core or a tumour limited to less than 3 mm involving one core.

According to the first definition, 27.7% of placebo specimens and 19.9% of finasteride specimens were judged to be insignificant. Based on the second definition, 30.5% of placebo and 21.4% of finasteride specimens were again judged to be insignificant—“or in other words, approximately 75% of the prostate cancers detected in the PCPT were felt to be clinically significant,” Dr. Thompson explained. This compares favourably to contemporary series of men undergoing prostate surgery where rates of insignificant disease are very similar and in some series higher than rates found in the PCPT, he added.

Concerning rates of significant cancer within PSA levels, Dr. Thompson and colleagues also found significant disease in almost half of those cancers with a PSA of 0 to 1.0 ng/mL; in over 60% of cancers with a PSA of between 1.1 and 2.5 ng/mL; in 80% of those cancers with a PSA of between 2.6 and 4.0 ng/mL; and between 90% and 100% in cancers with a PSA of 4.1 and 10 ng/mL. “So the answer to the first question [of whether] the cancers that finasteride prevented [were] significant: if you believe a significant cancer is a cancer that merits a radical prostatectomy, they were.”

The second question regarded the overall impact of the 5ARI on the tumours. Before they could answer this question, PCPT investigators reminded attendees that they only knew the cancer status in about 60% of the men because some men refused the end-of-study biopsy. They therefore imputed what the risk reduction would be in those who did not have the biopsy. They also had to take into account the fact that active treatment made the PSA test, the digital rectal exam and the biopsy more likely to detect prostate cancer, particularly the detection of high-grade cancer.

Results on the first analysis, which took into consideration the fact that men who had undergone biopsy had a higher risk of cancer, demonstrated similar observed and estimated rates of cancer: 16.6% and 14.7%, respectively, for the finasteride arm and 22.9% and 21.1%, respectively, for placebo controls. For high-grade cancer, the observed rate was 5.8% in the treatment arm vs. 4.8% for the placebo arm, while the estimated rates were 4.8% and 4.2%, the latter two rates no longer being statistically different. In a second analysis in which investigators included all the radical prostatectomy specimens, the 5ARI was associated with a 30% relative risk reduction in cancer rates overall compared with placebo (P<0.0001). For cancers graded Gleason <u><</u>6, active therapy was associated with a significantly lower 32% relative risk reduction in prostate cancer rates (P<0.0001) while for cancers graded Gleason <u>></u>7, it was associated with a 28% relative risk reduction in prostate cancer rates relative to placebo (P<0.02).

“A man who is undergoing regular prostate cancer screening should be informed that he may reduce his risk of prostate cancer by about 25% with daily finasteride,” Dr. Thompson concluded, “and the concept that we can now eliminate some men’s chances of ever being diagnosed with prostate cancer is a very big deal.”

Affirmation of the PCPT Findings

In a published editorial on the importance of these new findings, Dr. Christopher Logothetis, President, American Urological Association, reaffirmed that “a substantial portion of the cancers prevented by finasteride… were clinically significant according to well-studied biopsy criteria” (Cancer Prev Res 2008; Online First 2008). He also concurred with previous analyses by Dr. Thompson and colleagues that initially reported differences in high-grade disease may have been attributable to a detection bias in the treatment arm. “Taken together, these data provide convincing evidence that the reduced frequency of detected cancer is clinically significant,” Dr. Logothetis stated. Related analyses clearly showed that the true rate of high-grade prostate cancer in men treated with finasteride was 27% lower than the rate in In a published editorial on the importance of these new findings, Dr. Christopher Logothetis, President, American Urological Association, reaffirmed that “a substantial portion of the cancers prevented by finasteride… were clinically significant according to well-studied biopsy criteria” (Cancer Prev Res 2008; Online First 2008). He also concurred with previous analyses by Dr. Thompson and colleagues that initially reported differences in high-grade disease may have been attributable to a detection bias in the treatment arm. “Taken together, these data provide convincing evidence that the reduced frequency of detected cancer is clinically significant,” Dr. Logothetis stated. Related analyses clearly showed that the true rate of high-grade prostate cancer in men treated with finasteride was 27% lower than the rate in placebo controls, he noted. “The effect of finasteride in reducing the frequency of detected meaningful cancer and the paucity of evidence of irreversible toxicity induced by the drug support the authors’ conclusions that finasteride is a safe and effective prevention option that should be offered to men at risk for prostate cancer.”

Revisiting Prostate Volume and Biopsy Sampling in the PCPT

In two related presentations by Dr. Steven Kaplan, Professor of Urology, Weill Cornell Medical College, New York, PCPT investigators noted that finasteride induced a 24% reduction in prostate volume and led to a 27% increase in biopsy sampling density in the trial. This, they hypothesized, led to an ascertainment error at the time of biopsy which they felt was likely a uniform effect occurring across the general study population. If so, then the finasteride-induced increase in biopsy sampling needed to be adjusted in order to obtain an accurate assessment of its effect on prostate cancer risk.

An exploratory analysis with sampling density measurements was carried out in a subset of 8827 patients among whom 1739 men had detectable prostate cancer, 22.5% in the placebo arm and 16.7% in the finasteride arm. Investigators found that the most frequently detected prostate cancers in PCPT were Gleason score 5, 6 and 7, grades which represent over 70% of all prostate cancers diagnosed in the US, Dr. Kaplan observed. Examining the effect of finasteride over placebo across individual Gleason scores (adjusted for biopsy sampling density), investigators documented a 62% reduction in Gleason 4 prostate cancer; a 58% reduction in Gleason 5 prostate cancer (P<0.001); a 52% reduction in Gleason 6 prostate cancer (P<0.0001) and a 22% reduction in Gleason 7 prostate cancer. Very few cancers from grade 8 to 10 were seen in the trial so there were no meaningful differences between the two treatment arms (Figure 1).

Figure 1. PCPT: Sampling Density-adjusted Logistic Regression Analysis of Prostate Cancer Risk by Gleason Score

A time-to-event analysis also indicated a clear separation between the two arms in terms of the probability of detecting prostate cancer at around year 2, “suggesting chemosuppression of existing cancers,” Dr. Kaplan observed, the magnitude of which continued to increase through year 7, “suggesting chemoprevention of new cancers. Given the relatively high frequency of occurrence of Gleason score 5 to 7 prostate cancer and the significant public health burden associated with these cancers, the present findings provide additional information that should be taken into account when physicians and patients consider chemosuppressive and chemopreventive options for prostate cancer,” Dr. Kaplan observed (Fig. 2).

Figure 2. PCPT: Weighted (Sampling Density-adjusted) Prostate Cancer T
(For-cause Biopsies)

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He further suggested that the next study that needs to be carried out should use an agent such as finasteride in men with diagnosed prostate cancer to see if their PSA levels go down and stay down. “If they did, then patients do not need to be treated,” he noted—in other words, the elevation in PSA was not because of the cancer, it was because of background noise from BPH, the cancer itself was simply indolent and found by chance. “I think the key here is to identify men you want to treat and I think we may be able to use these drugs to ultimately find out which ones they are.”

Prostate Volume Findings from MTOPS

In a separate presentation, Dr. Kaplan detailed the significant reduction in total prostate volume achieved with finasteride across the full range of baseline total prostate volumes in the MTOPS (Medical Therapy of Prostatic Symptoms) trial. As he pointed out, treatment with 5ARIs as monotherapy or in combination with an alpha blocker are currently used for treatment of BPH in men with enlarged prostates, usually defined as a total prostate volume of <u>></u>40 mL. However, in a predefined secondary analysis in MTOPS, an unexpected finding was that doxazosin/finasteride combination therapy had a beneficial effect on the overall risk of BPH progression vs. doxazosin alone in men with smaller prostates of between 25 and 40 mL. The hypothesis for this particular study was that finasteride significantly reduces total prostate volume in men with small- to medium-sized prostates and that this effect contributed to the observed clinical benefit on progression risk vs. doxazosin alone.

MTOPS involved over 3000 men with lower urinary tract symptoms (LUTS) who were randomized to placebo, doxazosin 4 to 8 mg, finasteride 5 mg or doxazosin/finasteride. Prostate volumes were measured in all patients using transrectal ultrasound and the mean duration of follow-up was 4.5 years. The mean prostate volume in MTOPS was 31 mL.

Across all quartiles of prostate volumes (<25; 25 to 30; >30 to <40 and <u>></u>40), the analysis showed that treatment with finasteride, either alone or in combination with doxazosin, led to a consistent, clinically significant 20% or greater reduction in prostate volume in men with a prostate volume both <25 mL and <40 mL as well as enlarged prostate at volumes of <u>></u>40 mL. “The previously reported finding in MTOPS, in which combination therapy with doxazosin plus finasteride led to a superior reduction in the risk of overall clinical progression of BPH compared to doxazosin alone in men with small- to moderately-sized prostates was likely due to the significant finasteride-induced total prostate volume reduction that occurred in the combination therapy group,” Dr. Kaplan concluded. He added that these findings should prompt physicians to reconsider the definition of the “right BPH/LUTS patient” for combination medical therapy.

Questions and Answers

The following question-and-answer session was conducted during interviews with Dr. Ian Thompson, Chair and Professor, Department of Urology, University of Texas Health Science Center, San Antonio; Dr. M. Scott Lucia, PCPT core pathologist and Associate Professor of Pathology, University of Colorado, Aurora; and biostatistician Dr. Mary Redman, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Q: Most organizations do not recommend biopsy confirmation until the PSA level is over 4 ng/mL. At this level, what are the chances that the cancer will not be curable?

Dr. Thompson: Some 20% of men will have disease outside the prostate or positive nodes at a PSA of 4 ng/mL. Now some of them will not die of prostate cancer but these are the men who are at greatest risk for failure.

Q: What was the main concern on the initial publication of the PCPT in terms of side effects from finasteride?

Dr. Lucia: The main concern was that finasteride might cause more high-grade tumours so if you were potentiating those kinds of cancers, that would not be a good thing. But I think we have put those concerns to rest with these findings. It is just not happening.

Q: Why does finasteride make it easier to detect cancer on biopsy?

Dr. Redman: Finasteride shrinks the prostate gland so the cancer takes up more prostate tissue in men who are treated with it. That is why it was easier to find prostate cancer in their biopsies. Cancer was probably missed more often in biopsies of men on placebo in the trial because the prostate gland itself was larger.