ASCO GU 2023: Polymerase inhibitor significantly improves progression-free survival for metastatic prostate cancer

16 Feb 2023
ASCO GU 2023: Polymerase inhibitor significantly improves progression-free survival for metastatic prostate cancer

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 was presented at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, February 16-18, 2023, in San Francisco, California.


Study at a Glance

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.

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 localised or regional-stage disease but drops to 32% for those diagnosed with metastatic disease.

“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 tumour 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 randomised 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 tumours or tumours without a known homologous recombination repair status, based on imaging and was 34% better based on tumour 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 anaemia and certain low blood cell counts in the talazoparib + enzalutamide arm compared to hypertension, anaemia, 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.


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.

Source: ASCO