Obesity is associated with better survival among men with metastatic castration-resistant prostate cancer (mCRPC), a protective effect that investigators are calling an “obesity paradox,” study findings presented at the AUA2021 Virtual Experience suggest.
The findings could have implications for clinical trial design and development of novel therapeutics that target certain genes that modulate fat synthesis, according to investigators.
Alberto Martini, MD, of Vita Salute San Raffaele University, Milan, Italy, and colleagues studied 1577 patients with mCRPC who participated in the phase 3 randomized controlled ASCENT2, MAINSAL, and VENICE clinical trials. The investigators selected patients from these trials because they had similar inclusion criteria. Patients had a median age of 69 years. Dr Martini’s team placed patients into 4 body mass index (BMI) categories: less than 20, 20-25, 25-30, and greater than 30 kg/m2.
To exclude possible effects attributable to a higher dose of chemotherapy (titrated according to body surface area), the investigators looked for eventual interactions between BMI and chemotherapy dose.
Of the 1577 patients, 655 died by the end of the studies. The median follow-up duration for survivors was 12 months. In adjusted analyses, obesity, defined as a BMI greater than 30 kg/m2, was significantly associated with a 29% decreased risk for death compared with overweight (BMI 25-30 kg/m2) and normal weight (BMI 20-25 kg/m2). Each 1 kg/m2 increase in BMI was significantly associated with a 4% decreased risk for death.
Higher BMI also was associated with reduced cancer-specific mortality (CSM). Obesity was significantly associated with a 35% decreased risk for CSM compared with overweight and normal weight. Each 1 kg/m2 increase in BMI was significantly associated with a 6% decreased risk for CSM.
Dr Martini and colleagues found no interaction between BMI categories and docetaxel dose.
He explained that the protective effect of obesity might be attributed to some oncogenes that are downregulated as a result of obesity. For example, among patients with metastatic kidney cancer, obesity is associated with downregulation of the FASN oncogene, which is implicated in fatty acid synthesis. Further research is needed in the context of prostate cancer to better elucidate this phenomenon, he said.
The latest findings could be useful when designing clinical trials, such as for stratifying patients based on BMI categories, Dr Martini said. The findings also highlight a need to better understand prostate cancer as a disease because this could lead to new ways to manage it. “The fact that some oncogenes might be downregulated in cases of obesity can help identify novel potential therapeutic targets,” said Dr Martini, adding that ongoing studies are examining a molecule that inhibits FASN.
Commenting on the study, Stephen J. Freedland, MD, professor of surgery and director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Medical Center in Los Angeles, who was not involved in the new research but has studied the relationship between obesity and prostate cancer, said another possibility is that obese men do not experience the muscle-wasting and weight loss that can accompany late-stage cancer and are thus in better health than those who do.
Martini A, Cirulli G, Gandaglia G, et al. The obesity paradox in metastatic castration resistant prostate cancer. Presented at: AUA 2021, held September 10-13, 2021. Abstract PD05-01.