On June 3, 2017 Pfizer Inc. (NYSE:PFE) reported Phase 2 data showing that its investigational, dual-mechanism poly ADP ribose polymerase (PARP) inhibitor, talazoparib, demonstrated anti-tumor activity in patients with germline (inherited) BRCA1/2-positive (gBRCA+) advanced breast cancer (Press release, Pfizer, JUN 3, 2017, View Source [SID1234519408]). Results from the Phase 2 ABRAZO trial were presented during an oral session at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

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"Every day, I see the devastating effects of gBRCA+ advanced breast cancer – one of the most common forms of inherited breast cancer," said Nicholas C. Turner, MD, PhD, consultant medical oncologist at the Royal Marsden Hospital in London, United Kingdom. "As we learn more about the genetic drivers of cancer, mechanisms such as PARP inhibition are emerging as a potential therapeutic approach for this patient population."

ABRAZO is an open-label Phase 2, 2-stage, single arm, parallel cohort study that investigated the clinical efficacy and safety of single-agent talazoparib in 83 evaluable, heavily pretreated gBRCA+ advanced breast cancer patients. The primary endpoint was objective response rate (ORR) by independent radiology review.

Cohort 1 consisted of 49 patients who previously responded to platinum-based chemotherapy and subsequently developed disease progression. A 21% ORR (95% CI: 10-35) was observed in this group of patients. Cohort 2 consisted of 35 patients who developed disease progression following at least three lines of non-platinum-based therapy. This group of patients had a 37% ORR (95% CI: 22-55).

The most common adverse events (AEs) observed in at least 20% of patients consisted of anemia (51.8%), thrombocytopenia (32.5%), neutropenia (26.5%), fatigue (44.6%), nausea (42.2%), diarrhea (32.5%), decreased appetite (24.1%), dyspnea (24.1%), alopecia (21.7%), back pain (21.7%) and vomiting (20.5%). Grade 3 or 4 AEs observed in at least 10% of patients were anemia (34.9%), thrombocytopenia (19.3%) and neutropenia (14.5%). Hematological AEs were addressed with dose management. No clinically significant cardiovascular events were observed. Discontinuation rates due to drug-related AEs were low (4%).

"The activity observed in patients with gBRCA+ advanced breast cancer in the ABRAZO trial is highly encouraging. The Phase 3 EMBRACA trial was designed to build upon these results to determine whether talazoparib represents a potential treatment option in this type of breast cancer," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development.

Talazoparib is also being assessed in the open-label Phase 3 randomized, parallel, 2-arm EMBRACA trial. EMBRACA is evaluating talazoparib vs. protocol-specific physician’s choice of chemotherapy in patients with advanced and/or metastatic gBRCA+ breast cancer who have received zero to three prior chemotherapy regimens for advanced disease. The EMBRACA trial has completed enrollment and results will be made available at a future date.

About the ABRAZO Trial

Patients enrolled in the multicenter, open-label Phase 2, 2-stage, parallel cohort study received talazoparib once daily for 21 days in repeated 21-day cycles. Patients had triple negative breast cancer, hormone receptor-positive (HR+) breast cancer, or human epidermal growth factor 2 (HER2)-positive breast cancer that was refractory to HER2-targeted therapy. The median number of prior lines of chemotherapy for advanced breast cancer was two in Cohort 1 and four in Cohort 2. Investigators required at least five objective responses per cohort in ≤35 patients to progress from the first stage of the trial to the second stage. Both cohorts met the response criteria for advancement.

About Talazoparib

Talazoparib is an investigational anticancer compound called a PARP (poly ADP ribose polymerase) inhibitor, which is being evaluated in gBRCA+ breast cancer, as well as other cancer types with deficiencies in DNA damage repair (DDR). Preclinical studies suggest that talazoparib has a dual mechanism of action, with the potential to induce tumor cell death by blocking PARP enzyme activity and trapping PARP on the sites of DNA damage. Talazoparib has not been approved by any regulatory authorities for the treatment of any disease.

About Germline BRCA1/2-Positive Breast Cancer

BRCA1 and BRCA2 are human genes that produce proteins involved in DNA repair. When either of these genes is altered or mutated, DNA repair may not progress correctly. This can lead to the development of certain types of cancer – such as breast cancer.1,2,3 BRCA mutations can be hereditary (germline) or occur spontaneously (sporadic).1 BRCA mutations are the most common cause of hereditary breast cancers, and up to 65% of women who inherit a BRCA mutation will develop breast cancer by age 70.1,4 Epidemiologic studies indicate that individuals with gBRCA+ status are diagnosed with breast cancer at a median age of 40-45, which is approximately 20 years younger than the overall breast cancer population.5 Literature indicates that 5-10% of all breast cancer patients have a gBRCA mutation.6