SAN FRANCISCO, CA USA (UroToday.com) - Dr. Marijo Bilusic presented 3 studies published over the past year.
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The first study presented was the phase III randomized controlled trial of the use of radium-223 in metastatic castrate resistant prostate cancer (mCRPC) (Parker C, et al., NEJM (2013) 369(3): 213-23). Radium-223 targets new bone growth in and around bony metastases and induces DNA damage in nearby tumor cells. The study cohort consisted of men with symptomatic mCRPC and at least 2 bony metastases. Patients with visceral metastases were excluded. Patients were randomized in a 2-to-1 ratio to one of two treatment arms: radium-223 with best standard of care or placebo with best standard of care. This was an international study carried out from 2008 to 2011. The study showed that radium-223 improved median overall survival by 3.6 months when compared to placebo (14.9 vs 11.3 months). Radium-223 also significantly increased the median time to a first skeletal-related event by 5.5 months. The adverse effects seen were limited. Dr. Bilusic pointed out that the use of “best standard of care” by the study may improve the generalizability of the study as patients received a variety of complementary treatments while receiving radium-223. He pointed out a potential limitation however in that patients with visceral metastases were excluded and these patients comprise up to 25% of men with mCRPC.
The second article presented by Dr. Bilusic looked at the effect of metformin on all-cause mortality (ACM) and prostate cancer specific mortality (PCSM) in diabetic patients diagnosed with prostate cancer (Margel D, et al., J Clin Oncol (2013) 31(25):3069-75). Metformin could potentially have an inhibitory effect on prostate cancer proliferation through activation of the AMPK pathway with downstream inhibition of the mTOR pathway. It also potentially could decrease prostate cancer growth by inhibiting insulin/IGF-mediated cell proliferation. This study hypothesized that metformin use after prostate cancer diagnosis would be associated with lower PCSM and ACM. It was a population-based retrospective cohort study with data obtained from health databases from Ontario, Canada. Overall 42% of the approximately 3800 patients included in the study were exposed to metformin after diagnosis. A linear improvement in PCSM was seen with metformin exposure after diagnosis, with a 24% risk reduction in PCSM for each additional 6 months of metformin use. This effect was not seen with other anti-hyperglycemic medications. A non-linear improvement in ACM was seen in patients exposed to metformin, with the first 6 months of metformin use after diagnosis being associated with a 24% risk reduction. Use of metformin at 24 to 30 months after diagnosis was associated with only a 7% decrease in ACM. The conclusions of the study are very interesting but are limited by the retrospective design of the study. A randomized controlled trial examining the true effect of metformin on prostate cancer is necessary to validate these findings.
The final study presented by Dr. Bilusic looked at the role of the glucocorticoid receptor in the development of resistance to enzalutamide (Arora VK, et al., Cell (2013) 155(6):1309-22). Enzalutamide resistance usually develops within 6-12 months and previously the mechanism for this was unknown. Utilizing a xenograft model this group found that the glucocorticoid receptor (GR) is highly upregulated after prolonged exposure to enzalutamide. They showed that GR expression was significantly elevated on immunohistochemistry in bony metastases of poor enzalutamide responders. They also found that administration of dexamethasone reversed enzalutamide growth inhibition in an androgen receptor positive prostate cancer cell line. Use of a GR antagonist in the same cell line resulted in restoration of enzalutamide sensitivity. Put together, this data demonstrates the potential for development of acquired resistance to enzalutamide through upregulation of the GR. It highlights that corticosteroids could be harmful in some prostate cancer patients and creates an opportunity for further research into the potential use of GR antagonists to prolong response to enzalutamide.
Highlights of a presentation by Marijo Bilusic, MD, PhD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
Fox Chase Cancer Center, Philadelphia, PA USA
Written by Timothy Ito, MD, medical writer for UroToday.com