The FDA has approved a new medication, talazoparib, in combination with enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC) who also have mutations in certain genes involved in DNA repair. 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.
This approval of talazoparib (Talzenna®) means that doctors and patients have a new choice for treating mCRPC, a serious condition for which additional therapies are urgently needed. Talazoparib is an oral medication called a PARP inhibitor that is already approved for use in certain breast cancers. 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 (termed “HRR genes;” one example is BRCA) may cause cancer cells to be more sensitive to PARP inhibitors. Patients who are found to have underlying mutations in these genes (through genetic testing) may experience greater benefit from the drug vs. patients without mutations.
Enzalutamide is a type of hormone therapy that works by blocking the actions of androgens in cells. 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 TALAPRO-2, comprising more than 800 participants; half of whom had mutations in HRR genes. This trial compared outcomes among patients who received talazoparib + enzalutamide vs. patients who received placebo + enzalutamide.
Among the 399 patients with HRR mutations, those treated with the addition of talazoparib were 55% less likely to have worsening disease on scan compared to patients treated with enzalutamide alone. The benefits of talazoparib were most striking in patients with mutations in the BRCA2 gene: patients treated with the combination were 80% less likely to have worsening disease. Patients receiving talazoparib also fared better by other measures, including improved time to next cancer therapy.
The data from the trial is still not mature enough to conclude whether the addition of talazoparib prolongs life. Investigators are continuing to follow patients and collect data.
Some patients in the talazoparib group experienced low blood cell counts. The most common side effects emerging with treatment resulting in dose reduction of talazoparib were low red blood cells, low white blood cells, and low platelets.
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.