High Test: Exploring Genetics in Advanced Prostate Cancer

Because of a BRCA gene mutation in his prostate tumor, KEN TUCKER was eligible for a clinical trial of a PARP inhibitor. - PHOTO BY KEN CARL

Because of a BRCA gene mutation in his prostate tumor, KEN TUCKER was eligible for a clinical trial of a PARP inhibitor. - PHOTO BY KEN CARL

In 2012, Ken Tucker was diagnosed with a second recurrence of prostate cancer. This time, it had metastasized and was so aggressive he was told he had just six months to live. Then his doctors at the University of Chicago Medicine Comprehensive Cancer Center decided to send a tumor sample out for genomic testing, which revealed a mutation in the BRCA2 gene.

The mutation qualified Tucker for a clinical trial of a drug called veliparib, which was in an emerging class of medicines known as poly (ADP-ribose) polymerase (PARP) inhibitors. At the time, BRCA gene mutations were most closely linked to breast and ovarian cancers, and PARP inhibitors were being developed to treat those diseases. But because of a growing understanding that BRCA mutations might also drive aggressive prostate cancer, Tucker was accepted into the trial as the only patient with that disease.

After six cycles of veliparib combined with chemotherapy, Tucker’s prostate tumor disappeared, along with the cancer that had spread to his bowel, liver and lungs. He continued to take the PARP inhibitor by itself for the next four years, until 2016. Now 86, the father of five children works part time as a commercial real estate developer and spends his spare time swimming and golfing. He receives periodic hormone therapy to maintain low levels of prostate specific antigen (PSA), a protein made in the prostate that tends to be present in greater amounts as a cancer there grows. Other than that, he requires no treatment for his cancer.

“I feel good — I pretty much do what I want to do,” Tucker says. “My disease is under control. My doctor says I’ll probably die of something else.”

More than 164,000 cases of prostate cancer are diagnosed in the United States each year, according to the American Cancer Society. Four out of five cases are localized to the prostate, and the five-year survival rate for those patients is 100 percent. The survival rate is equally high when the cancer spreads to nearby areas of the body. When it metastasizes far beyond the prostate to lymph nodes, bone or distant organs, however, five-year survival drops to approximately 29 percent.

BRCA gene mutations can be inherited — known as germline mutations — or occur spontaneously within prostate tumors. Men who were born with mutations in the BRCA1 gene face up to a four times greater risk of developing prostate cancer, whereas those with mutations in BRCA2 have up to a ninefold higher risk. BRCA2 mutations have been associated with the more aggressive forms of the disease and an earlier diagnosis — at age 55 or younger.

The current standard of care for metastatic prostate cancer is the same for all men, regardless of BRCA status. The first step is to figure out whether the cancer is castration sensitive, meaning it responds to treatments that reduce the levels of testosterone in the body, or castration-resistant, meaning it doesn’t. Men with castration-sensitive prostate cancer are treated with testosterone suppression, also known as androgen deprivation therapy.

“Those tumors can respond well for years, but at some point they become castration-resistant,” says James Yu, M.D., an associate professor of radiation oncology at Yale Cancer Center in New Haven, Connecticut.

Castration-resistant disease occurs when, despite the lack of testosterone, patients experience a rise in PSA; other signs include scans that show new areas of metastasis or the development of new cancer symptoms. Oncologists typically combine androgen deprivation with other treatments, such as chemotherapy or radiation, in men with castration-resistant metastatic prostate cancer. Surgical removal of the prostate is also a treatment option for many with castration-sensitive or castration-resistant cancers that have not yet spread.

A growing number of oncology clinics use genomic testing to guide treatment in men whose cancer has become castration-resistant.

“For a very long time, (we’ve been likely to do) genetic testing in prostate cancer patients who are of Ashkenazi Jewish descent or have a family history of breast or ovarian cancer. What’s new and important is that we are now examining whether every patient with castration-resistant prostate cancer (CRPC) should get genetic testing for consideration of therapeutic benefit, along with considerations for (cancer risk) in family members,” says Susan Domchek, M.D., a professor of oncology and the director of the Basser Center for BRCA at the University of Pennsylvania in Philadelphia. “In BRCA1 and BRCA2, most mutations are germline, so if you find a mutation in a tumor, there is a standard recommendation that those individuals consider germline testing to know whether or not it was inherited.”

CREATING SYNTHETIC LETHALITY

PARP inhibitors block an enzyme that cells need to repair their DNA. Scientists believe they work in concert with BRCA mutations, because cells harboring those abnormalities lose their ability to repair their DNA, which in healthy cells would happen via a process called homologous recombination. So, the presence of a BRCA gene mutation plus a PARP inhibitor creates “synthetic lethality” — two modes of blocking DNA repair that together cause tumor cells to die, says Ranjit Bindra, M.D., Ph.D., an associate professor of therapeutic radiology at Yale School of Medicine.

Three PARP inhibitors are approved to treat ovarian cancer: Lynparza (olaparib) and Rubraca (rucaparib), which are specifically for BRCA-mutated cancers, and Zejula (niraparib), approved as a maintenance therapy to help prevent recurrence in patients after chemotherapy, regardless of their genetic status. Lynparza is also approved to treat breast cancer that is associated with inherited BRCA mutations and has spread to other parts of the body.

Although several PARP inhibitors are being tested in prostate cancer, the most promising results to date came from a phase 2 trial of Lynparza, says Jorge Garcia, M.D., a genitourinary oncologist and the Kerscher Family Chair for Clinical Prostate Cancer Research at Cleveland Clinic. During the trial, which included 50 patients with castration-resistant disease who had previously received traditional treatments, 33 percent of participants responded to the drug, which they took in pill form twice a day. All seven patients in the trial with BRCA2 mutations responded “exquisitely” well to the drug, Garcia says: “The overall response rate was decent, but what’s important is that there was significantly improved efficacy in the patients who harbored any DNA repair deficiency.”

Mutations in ATM, CHEK2 and Fanconi’s anemia genes, among others, also can affect DNA repair. Overall, 88 percent of the patients with prostate cancer in the Lynparza trial who had any of the DNA-repair mutations responded well to the drug. A phase 3 trial is underway, with an estimated completion date of 2021. In January 2016, the Food and Drug Administration (FDA) granted Lynparza maker AstraZeneca breakthrough therapy designation for expedited review of the drug as a treatment for men with metastatic prostate cancer who have mutations in BRCA1, BRCA2 or ATM. That means that, once the phase 3 trial is complete and the data are handed over to the FDA, the agency should complete its review within two months.

The PARP inhibitor that worked for Tucker, veliparib, ultimately proved ineffective in larger prostate cancer trials. Data published in 2014 from a trial combining it with chemotherapy showed just modest efficacy in men with prostate cancer, even though the regimen was well tolerated. Another trial examined veliparib plus an FDA-approved oral biosynthesis inhibitor, Zytiga (abiraterone acetate), in men with metastatic CRPC and found no significant difference between that treatment and abiraterone acetate alone. Although veliparib is no longer in development for prostate cancer, the researchers studying the hormone/PARP inhibitor combination did find that patients with DNA repair deficiencies responded better and lived longer without their disease progressing than did men without the genetic mutations.

That’s why there’s a growing interest in testing PARP inhibitors combined with other therapies to treat metastatic prostate cancer, particularly in men with gene mutations that hamper DNA repair. At the June 2018 annual meeting of the American Society of Clinical Oncology, data were presented from a study of Lynparza plus Zytiga in men with metastatic prostate cancer. Median progression-free survival — the time until disease progression — was 13.8 months for those who took the combination compared with 8.2 months for those who took Zytiga alone. Men in the combination group who had homologous recombination repair mutations had progression-free survival rates of 17.8 months versus 6.5 months among men who took Zytiga alone.

One major holdup for PARP inhibitor combination treatments involves the potential for side effects. The most commonly reported problems include anemia, gastrointestinal problems, liver dysfunction and fatigue, but the drugs can cause more serious reactions. Early studies of heavily pretreated ovarian cancer patients revealed some cases of blood cancers. In the study of the Lynparza-Zytiga combination, a small number of patients reported pneumonia and heart attacks.

Still, several ongoing trials combine PARP inhibitors with other cancer treatments, including immunotherapies known as checkpoint inhibitors, which block certain proteins that normally prevent the immune system from recognizing and attacking cancer. Earlier this year, researchers presented data from a small trial of Lynparza plus Imfinzi (durvalumab), which inhibits the immune checkpoint protein PD-L1, in men with metastatic CRPC.

The results showed lowered PSA levels in 12 out of 17 patients treated with the combination, with eight experiencing PSA drops of more than 50 percent. Men with DNA damage-repair mutations had median progression-free survival rates of 16.1 months versus 4.8 months for men without the mutations. The most common side effects related to the combination were anemia, nausea, fatigue, diarrhea and abnormally low levels of white blood cells.

Ongoing trials are testing several other treatments that might work well with PARP inhibitors in prostate cancer, including radiation. “We know that radiation causes DNA damage,” Yu says, “so inhibiting DNA repair (with a PARP blocker) may be synergistic.”

The proliferation of clinical trials in metastatic prostate cancer, many of which include testing for DNA repair mutations, could allow patients to gain access to nextgeneration treatments, according to Yu. “This is all part of the precision medicine movement that began over a decade ago,” he says. “Rather than treat everybody the same, we’re starting to break open the genetic drivers of these tumors and try to select treatments that are preferentially beneficial.”

GENE TESTING TO GUIDE TREATMENT AND SURVEILLANCE

Harvey Singer - PHOTO BY TAMMY SWALES

Harvey Singer - PHOTO BY TAMMY SWALES

Harvey Singer was diagnosed with breast cancer in 2008 and successfully treated with a mastectomy and chemotherapy. His sister, Vicki Singer Wolf, had been diagnosed with breast cancer in 1995 and later learned she had a BRCA2 mutation. When Singer had his genes tested in 2009, he learned that he, too, had a mutation in BRCA2. The following year, he was diagnosed with aggressive prostate cancer.

Singer had been getting regular PSA testing, and his levels of the protein kept rising — a warning sign of possible cancer. But because a biopsy taken in 2007 was negative, Singer’s urologist wasn’t worried. “I knew I had the BRCA mutation, so I pressed my urologist. I said, ‘I need to do a prostate biopsy, because I think you’re missing something,’” Singer says. “I was right.” After receiving a diagnosis of prostate cancer, Singer underwent a full prostatectomy (removal of the prostate gland) and radiation, and his PSA has been zero ever since.

The perception that BRCA is a breast cancer gene can cause confusion among men, Singer says. His aunt and mother also had breast cancer, a family history that he initially thought put his sister at risk but not him. “Men should know that 50 percent of BRCA (mutation) carriers are men, so they shouldn’t push it aside just because it’s called the breast cancer gene,” he says.

Singer and his sister created the foundation HIS Breast Cancer Awareness in 2009 to provide more information about genetic risk factors for men.

Genetic testing is still rare in the treatment of prostate cancer, Yu says, because the oncology community has not yet defined the role of PARP inhibition in treating men with DNA repair deficiencies. But healthy men from families with histories of breast and ovarian cancer could benefit from knowing their BRCA status, which will help their physicians design a surveillance plan to detect prostate cancer early.

PSA testing has been controversial because it sometimes detects tumors that don’t need to be treated, and this may lead to unnecessary medical intervention. But because BRCA1 and BRCA2 mutations have been associated with the most aggressive, fastest-moving forms of prostate cancer, an abnormal PSA result in a man with one of those mutations might be taken more seriously. “If you detect deadly disease earlier, you’re more likely to be able to cure it,” Yu says. Men who carry BRCA mutations might also face a higher risk of other cancers, including breast cancer, pancreatic cancer and melanoma.

Singer gets an MRI of his remaining breast every year, a PSA test every six months, an annual melanoma screening and an annual endoscopic ultrasound to check his pancreas. He persuaded one of his two sons to be tested for BRCA mutations (he was negative) and is working on the other.

Now, Singer says, he advises any man he meets who has a family history of BRCA-associated cancers to pursue genetic testing. “Men need to be educated,” he says. “If there’s any family history, get tested, because then you can screen differently. If you don’t want to get tested for you, do it for your children.”