[Toremifene P2B hgPIN results]
>>J Urol. 2006 Sep;176(3):965-70; discussion 970-1.
Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial.
Price D, Stein B, Sieber P, Tutrone R, Bailen J, Goluboff E, Burzon D, Bostwick D, Steiner M.
Regional Urology L. L. C., 255 Bert Kouns, Shreveport, LA 71106, USA. dprice@sport.rr.com
PURPOSE: A randomized, double-blind, dose finding, placebo controlled, parallel group clinical study was done to determine the incidence of prostate cancer in men with high grade prostatic intraepithelial neoplasia treated with toremifene. MATERIALS AND METHODS: A total of 514 patients with high grade prostatic intraepithelial neoplasia and no evidence of prostate cancer on screening biopsy were randomized to 20, 40 or 60 mg toremifene, or placebo daily for 12 months. Patients underwent re-biopsy at 6 and 12 months. RESULTS: The number of evaluable patients, that is those with 1 on study biopsy who were compliant, was 447. The cumulative risk of prostate cancer was decreased in patients on 20 mg toremifene compared with placebo (24.4% vs 31.2%, p <0.05). The annualized rate of prevention was 6.8 cancers per 100 men treated. In patients with no biopsy evidence of cancer at baseline and 6 months, the 12-month incidence of prostate cancer was decreased by 48.2% with 20 mg toremifene compared with placebo (9.1% vs 17.4%, p <0.05). The 20 mg dose was most effective but cumulative and 12-month incidences of prostate cancer were lower for each toremifene dose vs placebo with a cumulative risk of 29.2% and 28.1%, and a 12-month incidence of 14.3% and 13.0% for 40 and 60 mg, respectively. Gleason scores were similar across treatments. The overall incidence of drug related and serious adverse events did not differ between any of the toremifene groups and the placebo group. CONCLUSIONS: Toremifene decreased the incidence of prostate cancer by 1 year and had a tolerability profile comparable to that of placebo in a high risk population.<<
Oddly, this hasn't been posted here yet. The obvious red flag here is the inverse dose-response relationship. According to the link below, this is likely because lower doses have preferential binding to the ER receptor, and we saw the same thing in TRAMP mice. For review, the P3's got plenty of power (about 5X the P2b), with just the 20mg arm and placebo, and enrollment of 1260 men. In the P2B only the 20mg dose hit stat sig, and then just barely -- also see the link below:
Which link discusses the P2B pretty thoroughly, as well as some of the adjustments being made in the P3. Namely 18 month biopsies in additional to 12 month biopsies, and "The inclusion criteria have been altered to include only men with a negative minimum 10-core biopsy at baseline. The added effect of this will be to remove occult cancers at baseline. "
pubmedcentral.nih.gov
Will the addition of the 18 month biopsy should improve the odds of success for this trial? Given the results found here, one would think so:
>>J Urol. 2002 Oct;168(4 Pt 1):1415-8.Links
Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels.
Lefkowitz GK, Taneja SS, Brown J, Melamed J, Lepor H.
Deparment of Urology, New York University Medical Center, New York, New York, USA.
PURPOSE: Repeat biopsy has been advocated following the diagnosis of high grade prostatic intraepithelial neoplasia to exclude coexisting prostate cancer. We further define the natural history of high grade prostatic intraepithelial neoplasia by determining the incidence of prostate cancer 3 years following diagnosis. MATERIALS AND METHODS: A total of 31 men underwent followup interval biopsy 3 years after high grade prostatic intraepithelial neoplasia diagnosis in 1996 to 1997, regardless of change in serum prostate specific antigen (PSA) or digital rectal examination findings. A single pathologist reviewed all biopsy specimens. All men had a minimum of 12 biopsy cores taken at the time of diagnosis. RESULTS: A 3-year followup interval biopsy eight (25.8%) men had prostate cancer, 11 (35.5%) had high grade prostatic intraepithelial neoplasia only and 12 (38.7%) had no disease. Mean serum PSA at diagnosis and before the followup biopsy was 6.88 and 9.69 ng./dl., respectively (p = 0.008). Of the men 48% had less than a 1.0 unit increase in serum PSA. Upon univariate regression analysis change in serum PSA was not associated with the detection of prostate cancer (p >0.10). All 4 patients who subsequently underwent radical prostatectomy had organ confined disease. CONCLUSIONS: In a high proportion of men with high grade prostatic intraepithelial neoplasia prostate cancer will develop in a 3-year interval. Our findings support the concept that high grade prostatic intraepithelial neoplasia is a precursor to prostate cancer and that repeat biopsy at a delayed interval is recommended regardless of changes in PSA.<<
So here 26% of the group gets cancer at three years versus 17% for the placebo group in the P2B at 1 year. With the usual caveats about comparing trials, one could hope that this is a trend, and that the 18 month result for the P3 placebo group will approach 25%, giving toremifene a good chance to show its stuff.
It would seem the detection of more cancer in the untreated group as time goes by would be logical, but Taneja in his review article clouds this for me with this statement:
"Interestingly, the likelihood of detected cancer among the placebo-treated group increased at the 12-month biopsy relative to the 6-month biopsy (Figure 3). If one were to conclude that all cancers detected at 12 months were occult preexisting cancers (why would one make this conclusion?), then the likelihood of cancer should decrease on each serial sampling (I don't understand why). One could, therefore, cautiously conclude that a reduction in cancer incidence at 12- month follow-up biopsy is representative of prevention of HGPIN progression to prostate cancer. Clearly, further delayed follow-up biopsies would be helpful in strengthening this belief."
I guess I'm dense; can someone help me with the implications of that paragraph? TIA.
Comments?
I'm out right now, trying to decide if I should just watch or buy a call option position of some kind. IVs are high for May options, but not as high as I expected. Also, the farther out in time one goes in the series, the lower the IVs get. Has to be a strategy here. The obvious one is a moderately aggressive call bull spread, using the the June 15 and 17.5 calls. The IV difference isn't large, though, and may be due to the wider spread in the June options.
Cheers, Tuck |
