1. Wolfgang, Kelly

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In the fight for improved treatments for patients with metastatic breast cancer, new research has thrown a powerful punch. A study has found that talazoparib, a PARP inhibitor, is effective in treating patients with PALB2 mutations, opening a new avenue of treatment that could benefit patients with breast cancer and beyond.

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In today's oncology treatment, talazoparib is active in germline BRCA1- and BRCA2-mutant advanced breast cancer treatment, but its use beyond was not previously well understood. The open-label Phase II Talazoparib Beyond BRCA trial evaluated 20 patients, 13 of whom had HER2-negative breast cancer, and seven who had other tumor types, including pancreatic cancer, parotid acinic cell carcinoma, colon cancer, testicular cancer, and mixed Mullerian uterine cancer.


Patients in the study had undergone either germline genetic testing or somatic tumor multiplex gene testing and had demonstrated a pathogenic or likely pathogenic mutation in a homologous recombination (HR)-associated gene, according to the research. All 20 participants had solid tumors with mutations in HR pathway genes other than BRCA1 and BRCA2. The majority of patients (75%) were female with a median age of 53.9 years and had received a median of two prior lines of therapy for advanced disease, including chemotherapy, hormonal therapy, and targeted agents. For 35 percent of patients, platinum-based therapies had been previously administered.


"We are interested in developing new treatments for patients with metastatic breast cancer and, in the case of our study, genetic testing was absolutely critical to identify patients that may benefit from these new drugs," noted Joshua Gruber, MD, PhD, Assistant Professor at Simmons Cancer Center at UT Southwestern Medical Center.


In the U.S., population-based studies have found that 24 percent of patients with breast cancer and 30.9 percent of patients with ovarian cancer have undergone germline DNA analysis for mutations associated with cancer onset, with that number expected to increase as DNA testing continues to expand into community-based oncology clinics, the study noted.


Similarly, somatic tumor genetics are expanding, most notably in the treatment of metastatic or advanced cancers, with a goal of enrolling patients in clinical trials of novel or expanded-access therapies and identifying mutations associated with FDA-approved agents for therapeutic benefit, the research stated. These testing methods have the potential to identify BRCA1/2 mutations or other germline HR-associated gene mutations that could be used to select PARP inhibitor therapy, including talazoparib, for patients with advanced disease.


Promising Results

Results of the study showed that, in patients with breast cancer, the overall response rate was 31 percent. Among those 13 patients, four (31%) achieved a partial response as best response, six patients (46%) had stable disease as best response (three with stable disease of more than 6 months and a clinical benefit rate of 54%), and three patients (23%) had progressive disease as their best response. Among patients with non-breast cancer disease, four patients (57%) had stable disease as their best response, and three patients (43%) had progressive disease as best response. All patients with germline mutations in PALB2 had treatment-associated tumor regression.


"We found that patients born with a mutation in the PALB2 gene who go on to develop breast cancer appear to benefit from the PARP inhibitor drug talazoparib," Gruber confirmed. "This tells us that breast cancers with PALB2 mutations behave similarly to breast cancers with BRCA1 or BRCA2 mutations in the sense that all three of these genes confer benefit to PARP inhibitors, which were originally developed only for patients with BRCA1/2 mutations. Our results allow this drug to also be used to for patients with PALB2 mutations."


The study also assessed whether HR-deficient (HRD) scores could serve as a biomarker of response to talazoparib therapy. Analysis yielded a positive correlation between continuous treatment response and HRD score, with higher HRD scores associated with better response to therapy. This showed another potential method to identify patients who may benefit from PARP inhibitor therapy.


In addition, researchers studied other germline pathogenic or likely pathogenic mutations in ATM, BRIP1, CHEK2, and FANCA, and somatic mutations in ATM, ATR, PTEN, and RAD50 as detected by any CLIA-approved next-generation sequencing assay performed on either germline tissue or tumor tissue, according to the study, though efficacy was not identified in those mutations.


"Outside of BRCA1 or BRCA2 mutations, it was unclear if other mutations could cause sensitivity to PARP inhibitors," Gruber said. "We designed our clinical trial to test a wide range of possible mutations in genes that we suspected were related to DNA repair, which is the primary function of BRCA1 and BRCA2. It was surprising that, of all the other genes we tested, only PALB2 actually conferred benefit."


Expanding Treatment

The findings offer a new therapy option for patients that could improve outcomes and diminish common chemotherapy-associated toxicity, the study found, urging further research on breast cancers with PALB2 mutations and the impact of PARP inhibitor monotherapy. By assessing more than BRCA1/2 status when performing genetic testing on patients, such as by performing an HRD assay, clinicians may identify further qualifying biomarkers for PARP inhibitor therapy, and thus treat a wider subset of patients than originally envisioned with drugs such as talazoparib.


Cohort A of the talazoparib Beyond BRCA study is currently investigating the use of an HRD score to select patients for PARP inhibitor therapy, specifically in patients with advanced or metastatic triple-negative breast cancer. Results from this study could be contemplated for other tumor types, further broadening the treatment potential, researchers indicated.


"This adds a new drug for patients with metastatic breast cancer, but someday this drug may also be used in early-stage breast cancer to help cure patients with the disease," Gruber said. "Additional clinical trials are going to confirm and extend these findings. We hope to pursue FDA authorization for this drug-gene combination."


Kelly Wolfgang is a contributing writer.