The U.S. FDA has approved olaparib in combination with abiraterone (plus prednisone or prednisolone) for patients with metastatic castration-resistant prostate cancer (mCRPC) who also have a mutation in specific genes (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. This combination can be used as a “first line” treatment for mCRPC.
Olaparib (Lynparza®) is an oral medication called a PARP inhibitor that was initially approved in 2020 as a treatment for patients with mCRPC who also have certain gene mutations. It works by blocking cells from repairing damaged DNA, leading to cell death; cancer cells are affected to a greater degree than normal cells. Abiraterone (Zytiga®, Yonsa®) is a novel hormone therapy that works by stopping 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, international Phase 3 clinical trial called PROpel. This trial compared outcomes among nearly 800 patients, all of whom received abiraterone plus prednisone or prednisolone. The study drug was olaparib: patients were randomized to the addition of either olaparib or placebo. Patients could not have previously received abiraterone.
Patients treated with the addition of olaparib were 34% less likely to have worsening disease or death compared to patients treated with abiraterone alone. Median time to disease progression on scans or death was 8 months longer in the olaparib group (24.8 vs 16.6 months). Patients receiving olaparib also fared better by other measures, including improved time to next cancer therapy.
Patients in the trial were tested for mutations in certain genes associated with prostate cancer, including BRCA1 and BRCA2. These mutations could be present in patients’ inherited DNA or in the tumor itself. Olaparib showed greater benefit among the 85 patients with mutations in BRCA genes. In this group, patients treated with olaparib + abiraterone were 76% less likely to have disease progression or death, and were 70% less likely to die, vs. patients treated with placebo + abiraterone.
This is an example of precision medicine: treatment based on a patient’s specific type of prostate cancer. Learn more about genetic testing and tumor biomarker testing.
Side effects were not different beyond what would be expected from each drug alone. Anemia is a known side effect of PARP inhibitors; moderate-to-serious anemia was more common in the olaparib arm (15.1% vs. 3.3% in the placebo arm). There was no increased risk of cardiovascular events with the combination treatment. More patients on the combination had blood clots in their veins as an “incidental” finding, such as blood clots in the lungs seen on a CT scan. This did not require discontinuation of therapy.
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 while on hormone therapy (mCRPC), talk to your doctor about treatment options, including combination therapy. Ask about genetic testing for inherited mutations and biomarker testing of your tumor.