For men with BRCA-mutated metastatic castration-resistant prostate cancer, a newly approved treatment option may significantly extend their life.
Lynparza (olaparib) was approved by the U.S. Food and Drug Administration (FDA) on May 31, 2023, to treat BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC). This approval makes Lynparza the first PARP inhibitor approved in combination with Zytiga (abiraterone) and a corticosteroid, according to a statement released by AstraZeneca, manufacturer of the drug.
In the clinical trials, the Lynparza combination reduced the risk of disease progression or death by 76 percent versus abiraterone alone.
The oral medication is also approved for advanced or recurrent ovarian cancer, early or metastatic breast cancer, and metastatic pancreatic cancer.
“PROpel [the name of the phase 3 trial evaluating this treatment regimen] clearly shows a major improvement in delaying progression, maintaining excellent quality of life, and improving survival with the combination of abiraterone plus olaparib in this first-line mCRPC setting,” says Andrew Armstrong, MD, professor of medicine, surgery, and cancer biology at the Duke University School of Medicine in Durham, North Carolina, and co-investigator of the trial. “Delays in skeletal events and the need for chemo were also seen,” adds Dr. Armstrong.
This regimen significantly and meaningfully improves outcomes for patients with metastatic CRPC and a BRCA1/2 mutation, says Katharine Collier, MD, assistant professor and oncologist at The Ohio State University in Columbus, who wasn’t involved in the research. “The approval is practice changing and this combination regimen is a new first-line standard of care for this patient population,” says Dr. Collier.
PARP proteins help repair DNA damage in cells. PARP inhibitors, including Lynparza, work by preventing the PARP protein from repairing DNA in cancers, causing “a catastrophic amount of DNA damage in the cancer cells, in turn causing cancer cell death,” she explains.
Why Do We Need Better Treatments for Prostate Cancer?
Prostate cancer is the second most common cancer in men. In 2023, it’s estimated that there will be 288,300 new cases of prostate cancer and 34,700 deaths, according to the American Cancer Society.
When it’s detected at the distant stage (also called stage 4 prostate cancer, meaning the cancer has metastasized beyond the prostate and spread through the body), men with prostate cancer have an average five-year survival rate of 28 percent, which means that more than 7 in 10 die within five years of the diagnosis, per Hopkins Medicine.
Who Is Eligible for the New Prostate Cancer Treatment?
“The approval for Lynparza is limited to men with mCRPC with BRCA mutations, which is a small subset of patients — about 10 percent of people with mCRPC,” says Yuanquan Yang, MD, PhD, a medical oncologist who specializes in treating genitourinary malignancies, including prostate cancer. Dr. Yang was not involved in research for the drug.
“This is a very, very important approval for this group. Patients with a BRCA mutation, they tend to be younger patients and have more aggressive disease associated with the poorer outcomes,” says Yang.
BRCA stands for breast cancer gene, and there’s BRCA1 and BRCA2, says Yang. Everyone has these genes, which are sometimes called tumor suppressor genes, that are important for fighting cancer. If a person is born with a mutation in one of these genes, it can prevent normal functioning and cancer can develop, according to the National Cancer Institute.
A woman’s lifetime risk of developing breast or ovarian cancer is increased if she inherits a harmful variant in BRCA1 or BRCA2. But being born with a BRCA mutation can also increase the risk of some types of cancer in men, according to Penn Medicine, including prostate, pancreatic, and even breast cancer.
What Is Metastatic Castration-Resistant Prostate Cancer?
The backbone of all treatment regimens for metastatic prostate cancer involves medications that lower the body’s testosterone, which is called androgen deprivation therapy (ADT), says Collier.
“Initial treatment regimens for newly metastatic prostate cancer all use ADT, usually combined with an oral androgen receptor targeting agent, like abiraterone, or chemotherapy,” she says.
Nearly all metastatic prostate cancers will respond to these first-line testosterone-lowering treatments, and so this stage of the disease is called metastatic castration-sensitive (or hormone-sensitive) prostate cancer, Collier explains. “However, the prostate cancer will usually eventually progress despite ongoing ADT, at which point we refer to the disease setting as metastatic castration-resistant prostate cancer (CRPC),” she says.
“Men with BRCA mutations and metastatic prostate, particularly those with BRCA2 mutations, tend to respond more poorly and for shorter periods of time to ADT and potent AR inhibitors such as abiraterone or enzalutamide,” she says.
Study Results Showed Impressive Improvements in Disease Progression and Death Rates
The FDA approval is based on the results of the PROpel trial, which enrolled 796 patients with metastatic prostate cancer that had recently become castration-resistant. There was no mutation requirement to enroll in the trial.
This trial compared the combination of abiraterone with Lynparza to abiraterone alone, which builds on the previous approvals of each of these drugs alone for metastatic CRPC.
Abiraterone with prednisone, given with ongoing ADT, has been FDA-approved for metastatic CRPC since 2011. “It has since been approved for use in other prostate cancer disease settings as well,” says Collier.
All participants received abiraterone with prednisone, and then half were randomized to also receive Lynparza and the other half received placebo.
There was a statistically significant improvement in radiographic progression-free survival (rPFS) for the Lynparza group compared with the placebo group. rPFS is the length of time during and after the treatment of a disease (such as cancer) that a patient lives with the disease but it doesn’t get worse.
In a further subgroup analysis of 85 patients with BRCA mutations, the survival rates were even more pronounced, the median rPFS was not reached in the Lynparza arm compared with eight months in the placebo arm and overall survival was also significantly improved in the men with BRCA mutations.
Bottom line: For the men in the group with BRCA mutations taking Lynparza, their overall survival has not been reached, meaning that most of the patients are still having ongoing responses, says Yang.
“If you look at the hazard ratio, which is a measure of how often a particular event happens in one group compared with how often it happens in another group, the rate of death in the Lynparza group is decreased by 70 percent — that’s pretty substantial,” he says.
All People With Metastatic CRPC Should Undergo Genetic Testing
“Given the magnitude of the survival benefit with this combination regimen in patients that do have one of these mutations, it is important that all patients with metastatic CRPC are tested,” says Collier.
Timing of genetic testing is also important and will need to occur earlier in the disease course — earlier than has likely been the practice of many oncologists, she says.
“All patients with metastatic castration-sensitive prostate cancer should have somatic genomic testing prior to, or promptly at, the onset of castration-resistance in order to receive this newly approved combination regimen,” says Collier. She also recommends germline genomic testing, ideally with a genetic counselor.
How Safe Is Lynparza for Prostate Cancer?
“If you look at the safety profile, it’s pretty well tolerated; there are really no new safety concerns,” says Yang.
In the clinical trial, the most common adverse (unwanted) reactions (greater than 10 percent) in people taking olaparib plus abiraterone were anemia (48 percent), fatigue (38 percent), nausea (30 percent), diarrhea (19 percent), decreased appetite (16 percent), lymphopenia (14 percent), dizziness (14 percent), and abdominal pain (13 percent).
Seventy-two patients — 18 percent — required at least one blood transfusion and 12 percent required multiple transfusions.
Blood counts, kidney function, and liver function should be monitored frequently, says Collier.
Treatment Will Include Injections Plus Pills
“It is important for patients to understand that though olaparib plus abiraterone with prednisone is an oral pill regimen, they must continue on ADT, which is often a subcutaneous or intramuscular injection to suppress testosterone levels,” says Collier.
The medication regimen involves taking a lot of pills, she says. “Depending on the dose of the pills provided by the pharmacy, the starting dose of olaparib is two to three pills (300 milligrams [mg]) twice per day with or without food; abiraterone is two to four pills (1000 mg) once per day on an empty stomach; and prednisone is one pill (5 mg) twice per day,” she says.
Lynparza Continues to Be Studied in Men Without BRCA Mutations
In clinical trials certain patients that lacked BRCA mutations still benefited from the combination treatment, and in Europe this regimen is approved more broadly, says Armstrong.
In the trial, the majority of subjects — almost 90 percent — didn’t have BRCA mutations.
Researchers are continuing to evaluate subsets of non-BRCA patients who derive the most benefit from Lynparza plus olaparib, and this remains an active area of research across trials, says Armstrong.
“Also underway is research that looks at the drug combination earlier in men with metastatic prostate cancer who are just starting hormonal therapy and have DNA repair alterations,” he says. There may be even more synergy between an androgen receptor and PARP inhibition earlier in the disease process, he adds.
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