Potent PARP Inhibitor Moves Ahead in BRCA-Mutated Breast Cancer


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“PARP inhibitors inhibit PARP catalytic activity and trap PARP at the sites of DNA damage. Cancers with mutations in BRCA1/2 are unable to repair trapped PARP, resulting in cell death.”
— Nicholas C. Turner, MD

TALAZOPARIB, a novel inhibitor of poly (ADP-ribose) polymerase (PARP), showed encouraging efficacy in breast cancer patients with BRCA1/2 mutations in the phase II ABRAZO trial, presented at the 2017 ASCO Annual Meeting by Nicholas C. Turner, MD, of the Royal Marsden Hospital and The Institute of Cancer Research in London.1 

In patients who had responded to prior platinum therapy, 21% responded to talazoparib, as did 37% of patients who had received three or more prior lines of chemotherapy but not a platinum agent, Dr. Turner reported. 

Rationale for PARP Inhibition 

BRCA MUTATIONS render cancers deficient in the ability to repair DNA double-strand breaks. These cancers depend on PARP for DNA repair; therefore, inhibition of PARP further suppresses these tumors. 

“PARP inhibitors inhibit PARP catalytic activity and trap PARP at the sites of DNA damage. Cancers with mutations in BRCA1/2 are unable to repair trapped PARP, resulting in cell death,” he explained. 

In terms of the potency of PARP inhibition, talazoparib surpasses veliparib, olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula). In a phase I trial of 18 patients with germline BRCA-mutated breast cancer, the response rate was 50%.

TALAZOPARIB IN BRCA-MUTATED BREAST CANCER

  • Talazoparib, a potent new PARP inhibitor, showed strong activity in the phase II ABRAZO trial of advanced breast cancer with BRCA1/2 mutations.
  • The study included two cohorts, based on prior therapy.
  • Response rates were 21% among patients who had responded to prior platinum therapy and 37% among patients who had received 3 or more prior lines of chemotherapy but not a platinum agent.
  • Median overall survival exceeded 1 year in both groups.

ABRAZO Details 

THE PHASE II ABRAZO STUDY included patients with advanced breast cancer harboring a BRCA1/2 mutation (by central laboratory or local report approved by the sponsor). Cohort 1 included 49 patients who had responded to the last platinum-containing regimen for metastatic disease and had disease progression more than 8 weeks after the last platinum dose. Cohort 2 included 35 patients with 3 or more prior nonplatinum cytotoxic regimens for metastatic disease (ie, no prior platinum). One-third had triple-negative breast cancer, half had hormone receptor–positive tumors, and only a few patients had HER2-positive disease. The mean number of prior cytotoxic regimens was three. 

The primary endpoint was objective response rate and was 28% across the two cohorts. Cohort 1 had an objective response rate of 21% (with 4 patients being complete responders), and cohort 2 had an objective response rate of 37%. Objective responses were observed in 23% of patients with BRCA1 mutations and in 33% of patients with BRCA2 mutations. Additionally, 26% of patients with triple-negative disease responded, as did 29% of those with hormone receptor–positive disease (with any HER2 status). 

“We saw similar responses in BRCA1/2 mutation carriers as well as in triple-negative and non–triple-negative breast cancer,” Dr. Turner said. 

Stable disease was achieved in 36% of talazoparib-treated patients (18% of each cohort). The clinical benefit rate was 41% overall (stable disease for at least 24 weeks). Median duration of response was 4.9 months. Survival rates are shown in Table 1. 

TABLE 1: Outcomes for Talazoparib in BRCA-Mutated Breast Cancer 

Endpoint

Cohort 1

(Prior Platinum Responder)

Cohort 2

(≥ 3 Prior Cytotoxic Regimens, No Platinum) 

Objective Response Rate 21% 37%
Complete Responses 2% 0%
Stable Disease 18% 18%
Median Duration of Response 5.8 months 3.8 months
Median Progression-Free Survival 4.0 months 5.6 months
Median Overall Survival 12.7 months 14.7 months

In cohort 1, patients with the longest platinum-free interval (> 6 months) were the most likely to respond (47%) and also had the longest progression-free survival (6.9 months). “We saw increased activity with longer platinum-free intervals in an exploratory, hypothesis-generating analysis,” he said. 

Treatment-emergent adverse events leading to study drug dose reductions occurred in 18% overall (and were more likely in patients with prior platinum therapy), and 4% led to permanent discontinuation of treatment. The most common reason for dose reduction was anemia. Nonhematologic toxicity was uncommon. ■

DISCLOSURE: Dr. Turner reported no conflicts of interest. 

REFERENCES 

1. Turner NC, Telli ML, Rugo HS, et al: Final results of a phase 2 study of talazoparib following platinum or multiple cytotoxic regimens in advanced breast cancer patients with germline BRCA1/2 mutations (ABRAZO). 2017 ASCO Annual Meeting. Abstract 1007. Presented June 3, 2017. 

2. de Bono J, Ramanathan RK, Mina L, et al: Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov 7:620-629, 2017.


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