Defective BRCA genes are well known for their ability to cause breast and ovarian cancers in women. But these same gene defects are also strong risk factors for aggressive prostate cancer in men. About 10% of men with metastatic prostate cancer — meaning cancer that is spreading away from the prostate — test positive for genetic mutations in BRCA genes. Fortunately, these cancers can be treated with new types of personalized therapies.
In May, the FDA approved two new drugs specifically for men with BRCA-positive metastatic prostate cancer that has stopped responding to other treatments. One of the drugs, called rucaparib, was approved on May 15. The other one, olaparib, was approved on May 19.
Both drugs work by shutting down the cancer cell’s ability to fix its DNA. Like all cells in the body, cancer cells are bombarded every day by free radicals, low-level radiation, and other stressors that cause DNA damage. BRCA genes ordinarily fix that damage so that cells can function normally and survive. But if the genes are defective, then the damage piles up. BRCA-positive tumors get around that problem by deploying an alternate DNA repair gene called PARP. Rucaparib and olaparib both inhibit PARP, leaving cancer cells without any way to fix their increasingly mangled DNA; eventually the cells die.
The drugs had each been approved already for other BRCA-positive cancers, and prior to their approval were given “off-label” to men with prostate cancer as well. The approvals “should ease some of the previously existing insurance barriers for coverage, enabling more patients to benefit,” says Dr. Marc Garnick, Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of HarvardProstateKnowledge.org.
What the studies showed
Clinical trial results showed the drugs were well-tolerated, with side effects similar to mild chemotherapy. Rucaparib was tested in a single-arm clinical trial (meaning there was no control group), enrolling nearly 400 men with BRCA-positive metastatic prostate cancer who were no longer responding to other treatments. Results showed that tumors shrank in 44% of the enrolled subjects, in some cases for up to two years. Olaparib was tested in a similar population and delayed disease progression by an average of 7.4 months, which was just over two times longer than a type of hormonal therapy used in the control arm of that study.
Both drugs have their shortcomings. As personalized therapies, they work only for men with BRCA-positive prostate cancer, and just half the treated men will benefit. Furthermore, the experience with PARP-inhibitors so far is that tumors become resistant to therapy within six to 12 months. Whether PARP-inhibitors actually lengthen survival for men with metastatic prostate cancer is still being investigated. And many other questions remain about how to use the drugs most effectively to maximize their benefits.
Still, Dr. Garnick describes the approvals as a major advance for prostate cancer therapies developed for specific subgroups in the population. “Genetic testing, which is required to determine a patient’s eligibility for receiving these drugs, has shown that mutations are much more common than previously thought,” he says. “In addition, other mutations in men with advanced prostate cancer are being uncovered, and many of them can be successfully treated with targeted drugs that can slow the progression of their disease.”