West Cancer Center and Research Institute
Chief Medical Director
Lee Schwartzberg, MD, FACP, has disclosed that he has served as a scientific advisor for Bristol-Myers Squibb and has received consulting fees/honoraria from Genentech, Genomic Health, and Pfizer.
Two poly ADP-ribose polymerase (PARP) inhibitors, olaparib and talazoparib, are currently approved in multiple countries for similar indications for patients with advanced HER2-negative breast cancer and germline BRCA1/2 mutations. At the 2019 ASCO annual meeting, we saw some intriguing presentations touching on new strategies with the potential to further define and perhaps expand the role of PARP inhibitors in the management of patients with breast cancer. In this commentary, I briefly share my thoughts on a few of these new strategies and the associated studies that I found of interest.
The first interesting study was the GeparOLA neoadjuvant phase II trial, which was reported by Fasching and colleagues from the German Breast Cancer Group and the German Gynecological Oncology Working Group—Breast (AGO-B). Previous data suggested that carboplatin improved pathologic CR (pCR) as neoadjuvant therapy in patients with triple-negative breast cancer (TNBC) with the highest pCR rates among patients with either germline BRCA1/2 mutations or homologous recombination deficiency defined as a high HRD score.
The GeparOLA trial randomized patients with HER2-negative breast cancer and homologous recombination deficiency (defined as a high HRD score or a germline or somatic BRCA1/2 mutation; n = 102) to either 12 cycles of paclitaxel plus olaparib or paclitaxel plus carboplatin, each followed by epirubicin/cyclophosphamide, as neoadjuvant therapy before surgery. The pCR rate seen in patients who received paclitaxel plus olaparib was 55%, which I think is a promising result even though it did not meet the preplanned level of statistical significance. Of interest, in prespecified exploratory analyses, patients who were hormone receptor positive or women younger than 40 years of age appeared to do better if they received paclitaxel plus olaparib, whereas in every other patient subgroup examined, paclitaxel plus olaparib did at least as well as paclitaxel plus carboplatin. Although this is a relatively small phase II study, I think it suggests that olaparib does have additive effects with chemotherapy in the neoadjuvant setting in terms of pCR rate for patients with breast cancer harboring homologous repair deficiencies, a hypothesis that I think should be further explored.
Talazoparib Beyond BRCA Trial
Gruber and colleagues reported results from cohort B of the Talazoparib Beyond BRCA trial that investigated the efficacy and safety of talazoparib in previously treated patients with metastatic/recurrent HER2-negative breast cancer and other metastatic solid tumor types with a germline or somatic mutation in one of several homologous repair pathway genes other than BRCA1/2. Among 13 patients with HER2-negative metastatic breast cancer (MBC) and homologous repair pathway mutations, the ORR was 31% (all PRs) and the clinical benefit rate was 54% (included patients with stable disease for at least 6 months). Of interest, all of the patients with HER2-negative MBC and a germline PALB2 mutation (n = 6) experienced tumor regression and had high HRD scores. This trial highlights the need for further study of the utility of PARP inhibitors in the setting of defective homologous repair pathway genes other than BRCA1/2.
Mechanisms of Resistance to PARP Inhibitors
We also gained a little more insight into the mechanisms of resistance to PARP inhibitors at ASCO 2019. Waks and colleagues reported on an in-depth genetic analysis of biopsy samples obtained from patients with BRCA1/2-mutated MBC before and after they developed resistance to a PARP inhibitor or platinum chemotherapy. Reversion mutations that restored functional BRCA1 or BRCA2 reading frames were identified in 4 of 8 patients who developed resistance whereas 2 other patients showed evidence of increased DNA end resection, suggesting it as a potential mechanism of resistance to these therapies. Similarly, Zhu and colleagues reported data from patients with breast cancer and other tumor types showing secondary mutations that restored the BRCA1/2 open reading frame in 7 patients, all of whom had been treated with platinum-based chemotherapy or a PARP inhibitor. Although the mechanisms of resistance to PARP inhibitors are only beginning to be explored, in the future, therapeutic strategies will be needed to prevent or overcome resistance due to reversion and nonreversion resistance mechanisms, with the latter potentially being targeted by the addition of another drug.
Combination Therapy: PARP Inhibitors Plus Immune Checkpoint Inhibitors
An emerging therapeutic strategy that I find interesting is the potential to combine PARP inhibitors with immune checkpoint inhibitors, a combination that has been shown in preclinical studies to have potential synergy via stimulation of the immune system by PARP inhibitors. In the phase I/II TOPACIO trial that enrolled previously treated patients with advanced triple-negative breast cancer (TNBC) or with recurrent ovarian carcinoma, Vinayak and colleagues reported an ORR of 28% and a disease control rate of 50% among 46 evaluable patients with advanced TNBC who were treated with niraparib plus pembrolizumab regardless of BRCA1/2 mutation status. The efficacy and safety results in patients with recurrent ovarian carcinoma from this study were recently published in JAMA Oncology. Similarly, the combination of olaparib plus durvalumab is being evaluated in the ongoing phase I/II MEDIOLA trial with preliminary results showing promise in patients with HER2-negative MBC and germline BRCA1/2 mutations.
At ASCO 2019, there were also a few trials in progress presentations on studies evaluating this combination strategy that are actively enrolling patients and that I will be watching. The international, randomized phase II DORA trial is evaluating olaparib with or without durvalumab as maintenance therapy in patients with advanced TNBC who achieve at least stable disease after 3 cycles of platinum-based chemotherapy (NCT03167619). Another single-arm phase II trial is evaluating olaparib plus durvalumab in previously treated patients with metastatic TNBC and wild-type BRCA1/2 (NCT03801369). Finally, the phase II JAVELIN BRCA/ATM trial is evaluating avelumab plus talazoparib in patients with advanced solid tumors and either BRCA1/2 or ATM mutations (NCT03565991).
Have you started using PARP inhibitors in the treatment of your patients with breast cancer? Share your experiences in the comment box below.
To see what 5 experts would recommend for patients with MBC in different clinical scenarios, visit the Interactive Decision Support Tool: Treatment for Metastatic Breast Cancer.