1. Fuerst, Mark L.

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A combination of the PARP inhibitor talazoparib plus the current standard-of-care androgen receptor blocker enzalutamide significantly improves radiographic progression-free survival (PFS) in patients with metastatic, castration-resistant prostate cancer (mCRPC), regardless of homologous recombination repair (HRR) pathway status. Based on imaging of the prostate, PFS was 37 percent better for talazoparib plus enzalutamide versus placebo plus enzalutamide in the Phase III randomized international TALAPRO-2 clinical trial.

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"Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment in men with mCRPC regardless of HRR gene alteration status," said lead author Neeraj Agarwal, MD, Professor of Medicine and Director of the Genitourinary Oncology Program at the Huntsman Cancer Institute, University of Utah. He presented the study's results at the 2023 ASCO Genitourinary Cancers Symposium (Abstract LBA17).


"Not only did the combination therapy delay disease progression, but it also significantly delayed progression of PSA readings and the time until chemotherapy was needed compared to the control group," Agarwal noted. "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."


Over the past decade, increasing preclinical evidence suggested interactions of the poly (ADP-ribose) polymerase (PARP) enzyme 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. Talazoparib was approved by the FDA in 2018 to treat breast cancer but is not yet FDA-approved to treat prostate cancer.


TALAPRO-2 randomly assigned 805 men with metastatic prostate cancer who had mild or unobservable symptoms to receive either talazoparib 0.5 mg or a placebo daily. All men also received enzalutamide 160 mg daily. Patients were stratified by prior abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. About 21 percent of the patients harbored at least one HRR gene aberration, which is similar to reported literature.


Key Findings

Median radiographic PFS was significantly improved with the combination versus enzalutamide alone (not reached vs. 21.9 months, HR: 0.63). In addition, radiographic PFS was 54 percent better in HRR-deficient patients for the talazoparib plus enzalutamide arm versus the placebo plus enzalutamide arm, and was 30 percent better in HRR-non-deficient tumors or tumors without a known homologous recombination repair status; radiographic PFS was 34 percent better based on tumor tissue testing. Results showed a trend toward improved overall survival (OS), with a median OS of 36.4 months versus not reached in the enzalutamide arm (HR: 0.89), but the data are not yet mature, Agarwal said.


The PFS appears to be the longest observed in a randomized clinical trial to date in this type of prostate cancer. ASCO discussant Elena Castro, MD, PhD, Clinical Scientist at the Instituto de Investigacion Biomedica de Malaga in Spain, noted that a benefit in radiographic PFS does not always translate into an OS benefit.


"We know that from other trials conducted in first-line mCRPC...[and] from other trials conducted with PARP inhibitors in ovarian cancer that initially showed a benefit in radiographic PFS but later did not translate into a benefit in OS," Castro stated. "TALAPRO-2 could mean that we start using PARP inhibitors in earlier mCRPC without the need for testing patients for HRR alterations," but she noted the benefit was greater in patients with HRR-altered disease.


In terms of side effects, Grade 3 or 4 treatment-emergent adverse events (TEAEs) were observed in 71.9 percent of patients in the combination arm and 40.6 percent in the enzalutamide arm. Side effects led to the discontinuation of talazoparib in 19.1 percent of patients compared to 12.2 percent for patients who received a placebo. The most common TEAEs leading to a dose reduction of talazoparib were anemia (43.2%), neutropenia (15.1%), and thrombocytopenia (5.5%). Median time to a decline in global health status and/or quality of life was significantly longer with talazoparib plus enzalutamide (30.8 months) versus placebo plus enzalutamide (25 months).


"Talazoparib plus enzalutamide demonstrated a statistically significant and clinically meaningful improvement in radiographic PFS over standard-of-care enzalutamide as first-line treatment in patients with mCRPC regardless of HRR status," Agarwal noted. "There were no new safety signals and toxicity was generally manageable." Talazoparib is under investigation in another trial including men with HRR-deficient metastatic castration-sensitive prostate cancer.


Sumanta Pal, MD, ASCO Expert in genitourinary cancers, as well as Professor in the Department of Medical Oncology & Therapeutics Research at the City of Hope, commented: "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 mCRPC 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."


Mark L. Fuerst is a contributing writer.