The FDA has approved a new drug, 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 option for treating mCRPC, a serious disease for which additional therapies are urgently needed. Talazoparib is an oral drug called a PARP inhibitor that is already approved for use in certain breast cancers. PARP inhibitors work by blocking cells from repairing damaged DNA, causing cell death; cancer cells are affected to a greater degree than normal cells. Also, mutations in genes involved in DNA repair (called “HRR genes;” one example is BRCA) can make cancer cells more sensitive to PARP inhibitors. Patients who have underlying mutations in these genes (through genetic testing) may experience greater benefit from the drug compared to patients without mutations.
Enzalutamide is a type of hormone therapy that works by blocking the actions of androgens on cells. Androgens are the hormones that act as the “fuel” for prostate cancer. Combining treatments that attack cancer cells in different ways can be synergistic.
The approval is based on the results of a large international phase 3 clinical trial called TALAPRO-2, which includes more than 800 participants; half of which had mutations in the HRR genes. This trial compared outcomes between patients who received talazoparib + enzalutamide versus 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 at scan compared with 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 experience a worsening of the disease. Patients who received talazoparib also improved on other measures, including improved time to next cancer therapy.
The trial data are not yet mature enough to conclude whether the addition of talazoparib prolongs life. Researchers are continuing to follow patients and collect data.
Some patients in the talazoparib group experienced low blood cell counts. The most common treatment-emergent side effects that led to a dose reduction of talazoparib were low red blood cells, low white blood cells, and low platelets.
The first data that the PARP protein may be an important treatment target in prostate cancer comes 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 showing that up to one-third of mCRPC cases have mutations in BRCA1, BRCA2 and a number of other DNA repair genes. This study was momentous as it provided a rationale for testing PARP inhibitors as a precision medicine treatment in prostate cancer with these 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 for your tumor.
