Efforts to unravel prostate cancer‘s genetic fingerprints lag behind other cancers, notably breast cancer, experts agree. But, mutations seen in the DNA-repair genes of men with advanced disease have emerged as promising therapeutic targets that may close that gap.
Earlier this year, in fact, the National Comprehensive Cancer Network (NCCN) updated its clinical practice guidelines for prostate cancer, recommending doctors consider testing for inherited mutations in DNA-repair genes, such as BRCA1 and BRCA2, in men classified as “high risk, very high risk, regional, or metastatic.”1
The NCCN also recommends that doctors consider testing men with prostate cancer who have strong family histories of this disease, including brothers or fathers diagnosed with the illness before age 60.
The recommendations stem, at least in part, from a pivotal 2016 study in The New England Journal of Medicine, which found that nearly 12% of men with prostate cancer harbored one of these genetic errors, as did 6% of men with localized, high-risk prostate cancer and 2% with low-to-intermediate risk.2
“We’re at the point where the data support the idea that there’s a meaningful subset of patients with these targetable mutations,” says Ravi Madan, MD, clinical director of the genitourinary malignancies branch at the National Cancer Institute in Bethesda, Maryland. When to do testing, however — early in the disease, or after frontline therapy — remains an open question, he says.
For now, most of the advances in the treatment of prostate cancer have come from targeting the hormonal drivers of this systemic disease, according to Dr Madan and others. And genomic testing, increasingly done at diagnosis, may not measure errors in DNA-repair genes — but it can capture the presence of some point mutations, which could help guide treatment decisions in newly diagnosed patients.
The American Cancer Society estimates that there will be nearly 165,000 new cases of prostate cancer in the United States in 2018.3 Although research has shown that most men diagnosed with this disease die from other causes, prostate cancer is the second-leading cause of death in men (behind lung cancer), with approximately 29,430 deaths expected this year.
Hormonal strategies physicians use to battle these often slow-growing cancers include blocking or suppressing androgens in the testicles, or when that no longer works, blocking receptors on cancer cells with next-generation drugs, such as enzalutamide or apalutamide.4 Another drug that is now undergoing widespread testing, abiraterone acetate, blocks an enzyme that acts as a secondary source of androgen production, which investigators suspect comes from the cancer cells themselves and fuels further growth.
Although these strategies represent the most effective therapies in the clinic today, Dr Madon says, PARP inhibition, radiopharmaceuticals, and immunotherapy could revolutionize how prostate cancer is treated in the coming decade. In a recent article entitled “The Winds of Change: Emerging Therapeutics in Prostate Cancer,” Dr Madan and researchers from Monash University in Melbourne, Australia, focused on these evolving fields, especially in advanced disease, when survival statistics are most grim.5 The paper was published in the 2018 American Society of Clinical Oncology Educational Book ahead of the society’s June 2018 meeting in Chicago.