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Provocative data reveal changing paradigms in prostate cancer
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The pace of research in prostate cancer is increasing, and several interesting themes have emerged recently.
There are provocative data that suggest that the use of statins, the cholesterol-lowering agents, improves prognosis in prostate cancer.
A team at Dana-Farber Cancer Institute recently reported in JAMA Oncology that, from a series of more than 900 patients with prostate cancer, those on statins had a significant reduction in all-cause and prostate cancer-specific mortality. They also showed preclinical evidence that DHEAS and statins compete for the SLCO2B1 cellular transporter, which facilitates their entry into prostate cells, thus providing a potential mechanism of action.
Derek Raghavan
This is consistent with work from Yu and colleagues, who showed newly diagnosed patients with nonmetastatic disease had a 24% reduction in risk for prostate cancer death and a 14% reduction in all-cause mortality if they underwent statin therapy during the study period. The effect was even larger for those on statins prior to the diagnosis of prostate cancer.
A meta-analysis from Zhong and colleagues reviewed outcomes in nearly 1 million reported cases from 39 cohort studies and two case-control studies. They showed that patients receiving statins after the diagnosis of prostate cancer had a HR of 0.81 for all-cause mortality and 0.77 for prostate cancer mortality. Similarly, Song and colleagues have shown that the use of statins after radical prostatectomy is associated with a statistically significant reduction in biochemical recurrence.
By contrast, Cuaron and colleagues reported no impact of statins on outcomes for brachytherapy of prostate cancer. Also relevant, Jesperson and colleagues — in a Danish study of 42,480 known cases of prostate cancer and 212,400 controls — reported a 6% reduction in the incidence of prostate cancer associated with statin use, with a larger impact for those patients treated with statins longer than 10 years.
My take is that statins probably do reduce mortality from prostate cancer, although the fine details and extent of this effect will require a specifically designed, large randomized trial.
A new standard
Another important area in which we can see real change is in the treatment of poor-risk, metastatic prostate cancer at first presentation.
Last year, Sweeney and colleagues — reporting the CHAARTED trial — showed clear evidence of a clinically relevant and statistically significant survival benefit by treating 397 newly presenting patients with metastatic prostate cancer with docetaxel (DOC) plus androgen deprivation therapy (ADT) compared with 393 who received ADT alone.
Results showed a median survival of 57.6 months for DOC plus ADT vs. 44 months for ADT alone (P = .0003). Of importance, the most noteworthy survival improvement applied only to men with high-volume metastatic disease, with the combined therapy yielding 49 months median survival vs. 32.2 months for ADT alone.
The situation seemed to be complicated by the presentation of the GETUG-15 study by Gravis and colleagues, who also compared DOC plus ADT vs. ADT alone. In a significantly under-powered study, with only 385 randomized cases, the French investigators failed to confirm this effect in their initial analysis, reporting median survival of 58.9 months for the combination and 54.2 months for ADT alone (P = .95).
With further follow up, they changed course and confirmed — as a statistical trend — a benefit from DOC plus ADT, again only among poor-risk patients. The results showed median survival of 60.9 months for DOC plus ADT vs. 46.5 months for ADT alone (P = .44). Once again, this illustrates the folly of large groups economizing in trial design, reporting too early and failing to achieve meaningful power for their trials.
I think that the jury has finally returned to the courtroom, with the presentation by James and colleagues of the first report from STAMPEDE, an international randomized trial that compared standard of care (hormonal deprivation of some type) alone vs. three other regimens:
This well-powered study showed conclusively that DOC provides an additional 10 months of median survival to the impact of standard of care, reducing the HR for death by 24% (P < .003). Also of interest, zoledronic acid had no impact on survival, a predictable result.
In my view, the initial study was paradigm-shifting, but with the availability of this trio of data, it is clear that patients with poor-risk metastatic prostate cancer should be treated initially by the combination of DOC and ADT, and a new standard has been developed. The peer-reviewed publication will need to consider how many of the patients in each group received subsequent DOC, but it seems likely that the experience will be similar to the CHAARTED study, in which more than 80% of ADT patients received DOC.
Other advances
Other important advances that I have covered elsewhere but bear brief further mention include the Johns Hopkins University group’s demonstration that the androgen receptor (AR) V7 transcriptional variant is associated with resistance to enzalutamide (Xtandi; Astellas, Medivation) and abiraterone (Zytiga, Janssen), and can be identified in circulating tumor cells (CTC) of patients with prostate cancer. In an era focused on the value proposition, the report by Jeff Michalski, MD, MBA, on the NRG/RTOG-0126 phase 3 comparison of high-dose (79.2 Gy) vs. standard-dose (70.2 Gy) radiation for intermediate-risk prostate cancer was significant. This large randomized trial showed increased toxicity and increased local control but no impact on overall survival.
Another important step forward for this discussion comes from Scher and colleagues, who seem to have finally nailed down the issue of surrogacy of CTC in prostate cancer.
Howard Scher, MD, Ken Pienta, MD, Johann DeBono, MD, PhD, and I collaborated some years ago to demonstrate the utility of CTC measurements in the management of castration-resistant prostate cancer, demonstrating that CTC levels have prognostic significance, and that a fall of CTC levels connotes a meaningful clinical response to chemotherapy in prostate cancer.
Scher and colleagues have now shown — in a secondary analysis of the COU-AA-301 trial, which evaluated the impact of the addition of abiraterone acetate to prednisone in castration resistant prostate cancer — that a useful risk algorithm can be developed by the conjoint use of CTC and lactate dehydrogenase (LDH) measurement, which fulfills the Prentice criteria for surrogacy.
This smoking gun has been held as circumstantial evidence for a long time, but it may be time to accept that CTCs — with or without LDH— provide a clinically important surrogate outcome in prostate cancer that should be incorporated into parsimonious trial design. Such studies will need meticulous follow-up, but this may be the correct next step for the FDA to adopt.
What is pleasing is that we are seeing clinically meaningful improvements in the management of prostate cancer — both in the domain of novel treatments that work, and biomarker studies that refine care and clinical trial design — and a focus on the elimination of waste without reduction in positive outcomes.
In parallel, careful preclinical, epidemiological and clinical observation seems to be pointing to a novel approach to bio-modulation of this disease via statin therapy, which appears to impact its genesis and survival in established cases.
References:
Cuaron J, et al. Brachytherapy. 2015;doi:10.1016/j.brachy.2014.05.019.
DeBono JS, et al. Clin. Cancer Res. 2008;doi:10.1158/1078-0432.CCR-08-0872.
Gravis G, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(12)70560-0.
Harshman LC, et al. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.0829.
Jesperson CG, et al. Cancer Epidemiol. 2014;doi:10.1016/j.canep.2013.10.010.
Scher HI, et al. Lancet Oncol. 2009;doi:10.1016/S1470-2045(08)70340-1.
Song C, et al. Prostate. 2015;doi:10.1002/pros.22907.
Yu O, et al. J Clin. Oncol. 2014;doi:10.1200/JCO.2013.49.4757.
Zhong S, et al. Cancer Treat Rev. 2015;doi:10.1016/j.ctrv.2015.04.005.
For more information:
Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Carolinas HealthCare System. He can be reached at derek.raghavan@carolinashealthcare.org.
Disclosure: Raghavan reports no relevant financial disclosures.