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SAN FRANCISCO -- Treatment with the PARP inhibitor talazoparib (Talzenna) plus enzalutamide (Xtandi) significantly improved radiographic progression-free survival (rPFS) compared with enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer (mCRPC), the phase III TALAPRO-2 trial showed.

Among 805 randomized patients, rPFS assessed by blinded independent central review was not reached in those who received the combination versus 21.9 months in the enzalutamide arm (HR 0.63, 95% CI 0.51-0.78, P<0.001), reported Neeraj Agarwal, MD, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City, during the Genitourinary Cancers Symposium.

Patients with homologous recombination repair (HRR)-deficient mCRPC treated with the combination had an rPFS of 27.9 months compared with 16.4 months in the enzalutamide arm (HR 0.46, 95% CI 0.30-0.70, P<0.001), while those who didn't have HRR-deficient tumors or whose status was unknown had a median rPFS that was not reached versus 22.5 months, respectively (HR 0.70, 95% CI 0.54-0.89, P=0.004).

In HRR-deficient men detected by prospective tumor tissue testing, rPFS was not reached in the combination arm versus 22.1 months in the enzalutamide arm (HR 0.66, 95% CI 0.49-0.91, P=0.009).

"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," Agarwal said.

The combination also prolonged time to prostate-specific antigen progression compared with enzalutamide (26.7 vs 17.5 months; HR 0.72, 95% CI 0.58-0.89, P=0.002), and led to higher rates of complete response (37.5% vs 18.2%), "suggesting a cooperative effect of talazoparib plus enzalutamide."

However, discussant Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga in Spain, suggested that Agarwal's conclusion that results of the study support the combination as a first-line treatment for this population of patients may be a bit premature.

"I think we need to better understand the benefit of combining ARPIs [androgen receptor pathway inhibitors] and PARP inhibitors, because the balance between the potential benefit and the side effects depends on the HRR status, and may also depend on other factors," she said.

While overall survival (OS) results were immature at the time of data cutoff, an interim analysis showed a trend towards a survival benefit with talazoparib plus enzalutamide, with a median OS of 36.4 months versus not reached in the enzalutamide arm (HR 0.89, 95% CI 0.69-1.14, P=0.35).

Castro noted that a benefit in rPFS does not always translate into an OS benefit.

"We know that from other trials conducted in first-line mCRPC, but, we also know that from other trials conducted with PARP inhibitors in ovarian cancer that initially showed a benefit in rPFS but later did not translate into a benefit in overall survival," she said.

For this study, Agarwal and colleagues randomized 805 patients (median age 71) 1:1 to talazoparib 0.5 mg or placebo plus enzalutamide 160 mg once daily. Patients were stratified by prior abiraterone (Zytiga) or docetaxel therapy in the castration-sensitive setting and HRR gene alteration status.

All men had mildly or asymptomatic mCRPC with disease progression at study entry, an Eastern Cooperative Oncology Group performance status score of 0 or 1, ongoing androgen deprivation therapy, and no prior life-prolonging therapy for CRPC.

Grade 3 or 4 treatment-emergent adverse events (TEAEs) were observed in 71.9% of patients in the combination arm and 40.6% in the enzalutamide arm. Grade 5 TEAEs occurred in 3.3% and 4.5%, respectively.

One case of myelodysplastic syndrome and one case of acute myeloid leukemia were reported in the combination arm, and pulmonary embolism was reported in 2.5% of patients in the combination arm and 0.7% in the enzalutamide arm.

The most common TEAEs leading to a dose reduction of talazoparib were anemia (43.2%), neutropenia (15.1%), and thrombocytopenia (5.5%).

Grade 3 or 4 anemia was reported in 46.5% of men in the talazoparib arm, and 8.3% discontinued the PARP inhibitor due to anemia.

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