The TALAPRO-2 phase III clinical trial found that combining the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib with the androgen receptor inhibitor enzalutamide resulted in significantly better progression-free survival vs the current standard of care for patients with metastatic castration-resistant prostate cancer, regardless of homologous recombination repair pathway status. The study was presented at the 2023 ASCO Genitourinary Cancers Symposium by Neeraj Agarwal, MD, FASCO, and colleagues (Abstract LBA17).
Approximately 10% to 20% of patients with prostate cancer develop metastatic castration-resistant disease within 5 to 7 years of diagnosis. In 2023, an estimated 288,300 new cases of prostate cancer will be diagnosed in the United States, and 34,700 people will die from the disease; the 5-year relative survival rate approaches 100% for most people diagnosed with localized or regional-stage disease, but drops to 32% for those diagnosed with metastatic disease.
Neeraj Agarwal, MD, FASCO
“Not only did the combination therapy delay disease progression, it also significantly delayed progression of PSA [prostate-specific antigen' readings and the time until chemotherapy was needed compared to the control group,” said Dr. Agarwal, Professor of Medicine and Director of the Genitourinary Oncology Program at the Huntsman Cancer Institute, University of Utah. “This is important because advanced prostate cancer can be associated with pain, fractures, suffering, and death. The current standard-of-care treatments were approved almost a decade ago, leaving a huge unmet need for novel drugs in this setting.”
About the Study
Two drugs were used in the trial:
- Talazoparib is a PARP inhibitor which was approved by the U.S. Food and Drug Administration (FDA) in 2018 to treat breast cancer. It aids in repairing DNA damage, thereby decreasing cancer cell growth and increasing cancer cell death. Talazoparib is not yet FDA-approved to treat prostate cancer.
- Enzalutamide blocks the activity of the androgen hormone receptor, which can promote prostate cancer when unblocked.
The combination of talazoparib plus enzalutamide was used in this trial because over the past decade, increasing preclinical evidence suggested interactions of PARP with the androgen receptor could drive the growth of advanced prostate cancer cells. Talazoparib is thought to be the most potent available PARP inhibitor, and enzalutamide was chosen based on its high efficacy and direct androgen receptor inhibition.
The study randomly assigned 805 patients with metastatic prostate cancer who had mild or unobservable symptoms to receive either a 0.5-mg tablet of talazoparib daily or a placebo daily. All men also received a 160-mg tablet of enzalutamide daily. The investigators examined the tumor tissue of the men to determine the cancer’s homologous recombination repair status. In about 20% to 25% of prostate cancer cases, at least one homologous recombination repair gene aberration can be detected.
Key Findings
The median progression-free survival, based on imaging of the prostate, was 37% better in the talazoparib plus enzalutamide arm vs the placebo plus enzalutamide arm; the progression-free survival appears to be the longest observed in a randomized clinical trial to date in this type of prostate cancer. Results showed a trend toward improved overall survival, a key secondary endpoint, at the time of the analysis, but the data are not yet mature.
Based on imaging, progression-free survival was 54% better in homologous recombination repair–deficient patients for the talazoparib plus enzalutamide vs placebo plus enzalutamide arm; it was 30% better in homologous recombination repair–nondeficient tumors or tumors without a known homologous recombination repair status (based on imaging), and was 34% better based on tumor tissue testing.
Side effects were seen in 71.9% of patients taking talazoparib plus enzalutamide and in 40.6% of patients receiving placebo plus enzalutamide. The most common side effects were anemia and certain low blood cell counts in the talazoparib plus enzalutamide arm, and hypertension, anemia, and fatigue in the placebo arm. Side effects led to discontinuation of talazoparib in 19.1% of patients compared to 12.2% of patients who received a placebo. Median time to decline in global health status and/or quality of life was significantly longer with talazoparib plus enzalutamide vs placebo plus enzalutamide (30.8 vs 25.0 months, respectively).
Next Steps
Talazoparib is being studied in another trial including patients with homologous recombination repair–deficient metastatic castration-sensitive prostate cancer.
Perspective
Sumanta Pal, MD, FASCO
“While much progress has been made in detecting and treating early-stage prostate cancer, the lack of new therapies over the past decade for treating newly diagnosed metastatic hormone-resistant prostate cancer has been concerning. With these positive results from the TALAPRO-2 trial, however, it looks like real strides could soon be made in treating people with advanced forms of the disease,” said Sumanta Pal, MD, FASCO, Co-Director of the Kidney Cancer Program, City of Hope and ASCO Expert in genitourinary cancers.
Disclosure: This study received funding from Pfizer, and Astellas Pharmaceutical provided enzalutamide. For full disclosures of the study authors, visit coi.asco.org.
