Polymerase Inhibitor Significantly Improves Progression-Free Survival for Metastatic Prostate Cancer

For immediate release
February 16, 2023

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Rachel Cagan Facci
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ASCO Perspective
“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, ASCO Expert in genitourinary cancers.

ALEXANDRIA, Va. – The TALAPRO-2 phase III clinical trial found that a polymerase inhibitor combined with an androgen receptor inhibitor had significantly better progression-free survival (PFS) versus the current standard of care for people with metastatic, castration-resistant prostate cancer (mCRPC), regardless of homologous recombination repair pathway status. Homologous recombination repair involves a pathway that can help fix DNA double-strand breaks and cross-links between DNA strands.

The study will be presented at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, taking place February 16-18, 2023, in San Francisco, California.

Study at a Glance

Study Focus

A polymerase inhibitor to treat mCRPC.

Study Type

Phase III randomized international clinical trial

People in Study

805 men, ages 36 to 91 (median age 71), with mCRPC from 25 countries in the United States (U.S.), Canada, Europe, South America, and the Asia-Pacific region.

Study Protocol

Analysis of talazoparib plus enzalutamide versus placebo + enzalutamide as first-line treatment to determine efficacy.

Findings

  • PFS, based on imaging the prostate, was 37% better for talazoparib + enzalutamide vs placebo + enzalutamide.
  • Based on imaging, PFS was 54% better in homologous recombination repair-deficient patients for the talazoparib + enzalutamide vs the placebo + enzalutamide arm. Homologous recombination repair is a DNA repair pathway that can help fix DNA double-strand breaks and cross-links between DNA strands.
  • PFS was 30% better for the talazoparib + enzalutamide vs placebo + enzalutamide arm in homologous recombination repair-non-deficient or unknown outcomes based on imaging; based on tumor tissue testing, it was 34% better in homologous recombination repair non-deficient tumors. 

mCRCP is a disease that spreads beyond the prostate despite medical or surgical treatment to lower testosterone levels. Approximately 10% to 20% of patients with prostate cancer develop mCRPC within 5 to 7 years of diagnosis[i]. In 2023, an estimated 288,300 new cases of prostate cancer will be diagnosed in the U.S. 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[ii].

“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 lead study author Neeraj Agarwal, MD, FASCO, 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 (Talzenna®) is a PARP inhibitor (these inhibitors block activity of the enzyme called poly ADP-ribose polymerase) which was approved by the U.S. 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 when unblocked, can promote prostate cancer.

The combination of talazoparib + 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 men with metastatic prostate cancer who had mild or unobservable symptoms to receive either a 0.5 milligram tablet of talazoparib daily or a placebo daily. All men also received a 160-milligram 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 PFS, based on imaging of the prostate, was 37% better in the talazoparib plus enzalutamide vs the placebo plus enzalutamide arm. The PFS 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, PFS 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-non-deficient tumors or tumors without a known homologous recombination repair status, based on imaging and was 34% better based on tumor tissue testing.

Concerning side effects were seen in 71.9% of patients taking talazoparib + enzalutamide and in 40.6% of patients receiving placebo + enzalutamide. The most common side effects were anemia and certain low blood cell counts in the talazoparib + enzalutamide arm compared to hypertension, anemia, and fatigue in the placebo arm. Side effects led to discontinuation of talazoparib in 19.1% of patients compared to 12.2% for patients who received a placebo. Median time to a decline in global health status and/or quality of life was significantly longer with talazoparib + enzalutamide vs placebo + enzalutamide (30.8 vs 25.0 months, respectively). 

Next Steps
Talazoparib is being studied in another trial including men with homologous recombination repair-deficient metastatic castration-sensitive prostate cancer.

This study received funding from Pfizer and Astellas Pharmaceutical provided enzalutamide.

View the full abstract 

For your readers:

View the disclosures for the 2023 ASCO Genitourinary Cancers Symposium News Planning Team: https://s3.amazonaws.com/files.oncologymeetings.org/prod/s3fs-public/2022-08/GU23-%20Committee%20Disclosure%20Report%20%281%29.pdf?mrQMAmMUytE1drtRz3uenQQS_P93k61y​ 

View the disclosures for Dr. Palhttps://coi.asco.org/share/GFC-MTJ7/Sumanta%20Pal

View the author disclosureshttps://coi.asco.org/Report/ViewAbstractCOI?id=394484

ATTRIBUTION TO THE 2023 ASCO GENITOURINARY CANCERS SYMPOSIUM IS REQUESTED IN ALL COVERAGE.

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[i] Kirby M, et al. Int J Clin Pract. 2011;11:1180-1192.

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