Abstract S5-02: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL

Abstract

Background: I-SPY 2 is a multicenter, phase 2 screening trial using adaptive randomization within biomarker subtypes to evaluate a series of novel agents/combinations when added to standard neoadjuvant therapy (paclitaxel q wk x 12, doxorubicin & cyclophosphamide q 2-3 wk x 4, T/AC) vs. T/AC (control arm) for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. Our goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked Phase 3 neoadjuvant trial. Experimental regimens can "graduate" in at least 1 of 10 possible signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP), with a maximum number of 120 total patients enrolled. We report final efficacy results of the oral PARP inhibitor veliparib (V, ABT-888) in combination with carboplatin (carbo), 1 of 7 experimental regimens evaluated in the trial to date. Methods: Women with tumors ≥2.5 cm by clinical exam and ≥2 cm by imaging are eligible for screening. Tumors that are MP low/HR+/HER2-are ineligible for randomization. MRI scans (baseline, 3 weeks after start of therapy, at completion of weekly T, and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. V+carbo was assigned to HER2-tumors only, which limits its possible signatures to: all HER2-, HR+/HER2-, HR-/HER2-. For these 3 signatures we provide estimated pCR rates with associated 95% Bayesian probability intervals for V+carbo and concurrently randomized controls. Analysis is intent to treat with patients who switched to non-protocol therapy regarded as non-pCRs. For each signature we provide probabilities of superiority for V+carbo over control and Bayesian predictive probabilities of success in a neoadjuvant Phase 3 trial equally randomized between V+carbo and control. Results: When V+carbo met the 85% predictive probability criterion in HR-/HER2-and all HER2-, this regimen graduated and accrual to V+carbo was stopped. V+carbo was assigned to 72 patients, and there were 62 concurrently randomized controls (44 HER2-controls). The following table shows final results based on available pCR information. Two patients assigned to V+carbo withdrew consent during treatment and are not included in the table.

Concepts and targets in triple-negative breast cancer: recent results and clinical implications

“…The estimated pCR rate for this arm of the study was 52% [Rugo et al 2013]. These promising results led to the 'graduation' of the veliparib/carboplatin arm to a randomized phase III trial.…”

Targeted Therapies in Triple-Negative Breast Cancer

“…Trial statistics in a phase III trial predicted a probability of success of 90% for this combination [30]. Table 1 summarizes current phase III trials investigating PARP inhibitors in breast cancer.…”

Treating Triple-Negative Breast Cancer: Where Are We?

“…There was a 92% predictive probability (Bayesian) that the addition of V+C would be statistically superior to the standard anthracycline/taxane-based therapy alone based on the observed pCR rates: 52% (28%-67%) for V+C and 26% (9%-43%) in the control arm. 55 Finally, perturbation of the PI3K/ AKT and cell cycle pathways (eg, CDK1 inhibition) have been shown to sensitize cells to PARP inhibition even in BRCA-proficient tumors in preclinical models, and clinical studies of combination therapy with PARP and PI3K inhibitors are underway (ClinicalTrials.gov identifier: NCT01623349). 56 Other efforts to target DNA damage repair and cell cycle checkpoint mechanisms include use of histone deactylase (HDAC), heat-shock protein 90 (Hsp90), and Chk1 inhibition.…”