The FDA has approved a new medication, niraparib, in combination with abiraterone acetate for patients with metastatic castration-resistant prostate cancer (mCRPC) who also have mutations in specific genes called BRCA1 and BRCA2. This means that patients with mCRPC (prostate cancer that has spread beyond the prostate and continues to grow despite low testosterone) have an additional treatment option. To determine whether a patient is eligible for and may benefit from this therapy, a doctor first orders a test of the patient’s tumor tissue to look for specific mutations.
This combination of medicines can be used as a “first line” treatment for mCRPC. It is given orally once per day and is known by the brand name AKEEGA™. Patients also take prednisone orally and continue standard androgen deprivation therapy (ADT).
This approval of niraparib means that doctors and patients have a new choice for treating mCRPC, a serious condition for which additional therapies are urgently needed. Niraparib is a medication called a PARP inhibitor that is already approved for use in ovarian cancer. PARP inhibitors work by blocking cells from repairing damaged DNA, leading to cell death; cancer cells are affected to a greater degree than normal cells. Furthermore, existing mutations in genes involved in DNA repair (such as BRCA1 and BRCA2) may cause cancer cells to be more sensitive to PARP inhibitors. Patients whose tumors have underlying mutations in these genes may experience greater benefit from this class of drugs vs. patients without such mutations.
Abiraterone is a type of hormone therapy that works by blocking the production of androgens. Androgens are the hormones that act as prostate cancer’s “fuel.” Combining treatments that attack cancer cells in different ways may be synergistic.
The approval is based on the results of a large Phase 3 clinical trial called MAGNITUDE. This trial compared outcomes among patients with mCRPC who received niraparib + abiraterone vs. patients who received placebo + abiraterone. (All patients received prednisone and standard ADT.)
Among 225 patients with mutations in the BRCA1 or BRCA2 genes, those treated with the addition of niraparib were 47% less likely to have worsening disease on scans or death compared to patients treated with abiraterone alone. Put another way, the average time to worsening disease on scans or death was 16.6 months for the niraparib + abiraterone group vs. 10.9 months for the abiraterone alone group. Patients receiving niraparib also fared better by other measures, including improved time to starting chemotherapy.
The most common side effects in patients who received niraparib + abiraterone (with prednisone) were musculoskeletal pain (44%), fatigue (43%), constipation (34%), high blood pressure (33%) and nausea (33%). Forty-one percent of patients in the niraparib + abiraterone treatment group had a serious side effect.
Early data that the PARP protein may be an important treatment target in prostate cancer came from a PCF-funded team led by Dr. Karen Knudsen. This team provided preclinical evidence that PARP is a critical driver of prostate cancer and that PARP inhibitors can suppress prostate tumor growth and progression to CRPC. In 2015, the PCF International Prostate Cancer Dream Team published a landmark study demonstrating that up to a third of mCRPC cases have mutations in BRCA1, BRCA2, and a number of other DNA repair genes. This study was momentous, as it provided rationale for testing PARP inhibitors as a precision medicine treatment in prostate cancer with such gene mutations.
What this means for patients: If you have metastatic prostate cancer that is progressing despite low testosterone (mCRPC), talk to your doctor about treatment options, including combination therapy. Ask about genetic testing for inherited mutations and biomarker testing of your tumor.