Tumor BRCA Dx Could ID More Responders to PARP Inhibitors; Myriad Expects Initial Launch in Europe

The gist: Breast cancer patients with BRCA mutations could potentially be treated with new drugs called PARP inhibitors. In many cases, BRCA mutations are inherited, and are therefore found in all cells in the body. But a patient who did not inherit a BRCA mutation might still develop a mutation in a small number of cells, which might grow into a breast cancer tumor. Indeed, patients with ovarian and breast cancers have been identified who have BRCA mutations in their tumors only, but not in normal cells. Testing for BRCA mutations in tumor tissues could help identify more people who might benefit from treatment with PARP inhibitors.

“A comparison of germline BRCA mutation testing against a new diagnostic developed by Myriad Genetics that can gauge somatic mutations revealed that the latter was able to pick up 44 percent more deleterious markers in women with ovarian cancer.

“In identifying additional mutation carriers, Myriad hopes its so-called Tumor BRACAnalysis CDx will be able to identify more responders PARP inhibitors. The company has long-term plans to launch somatic BRCA mutation testing as a companion diagnostic first in Europe and then in the US.

“Germline mutations show up in all cells of the body, but a blood test that gauges just these mutations can miss some patients who acquire mutations only in their tumor. Gauging somatic mutations usually requires a test that analyzes markers in tumor tissue samples.

“At the European Society for Medical Oncology’s annual meeting in Madrid, Spain this week, researchers from Myriad and MD Anderson Cancer Center described a study analyzing approximately 130 previously untreated, high-grade ovarian cancer patients for germline BRCA mutations in blood samples and somatic mutations in tissue samples. In the study, the researchers also tested patients undergoing surgery for both of these types of mutations, and they performed germline testing using a custom amplicon assay and next-generation sequencing.”

Sarah Cannon Research UK and BioMarin Collaborate on EMBRACA Clinical Study in Hereditary Breast Cancer With BRCA Mutation

The gist: Researchers are conducting a clinical trial with volunteer patients to test a new breast cancer treatment called BMN673. BMN673 is a “PARP inhibitor” drug that may benefit patients who have hereditary mutations in the BRCA genes. Patients involved in the trial must have locally advanced and/or metastatic breast cancer, and must have undergone no more than two prior chemotherapy treatments for metastatic disease.

” ‘We are excited to collaborate with BioMarin on this landmark trial to increase the treatment opportunities for patients with BRCA related breast cancer,’ said Dr Alison Jones, Consultant Medical Oncologist and Principal Investigator for the EMBRACA Phase 3 trial at Sarah Cannon Research Institute UK.

” ‘This study is an important milestone for both organizations to foster future collaborations,’ highlighted Dr Hendrik-Tobias Arkenau, FRCP, PhD, Medical Oncologist and Medical Director at Sarah Cannon Research Institute UK.

” ‘Sarah Cannon Research UK has a long history of pioneering significant advances in medical therapy, and we are thrilled to commence enrollment outside of the United States to evaluate the safety and efficacy of BMN 673 in patients with hereditary breast cancer,’ said Hank Fuchs, M.D., Chief Medical Officer of BioMarin. ‘Breast cancer patients with germline BRCA-associated tumors have no targeted treatment options. There is an unmet need for therapies that target specific molecular defects in tumors, and PARP inhibitors offer that potential in BRCA-related breast cancer.’

“The EMBRACA Phse 3 study began in the United states in the fall of 2013 and has expanded internationally. BioMarin plans to enroll patients from sites around the world and to work with partners outside of the United States. The EMBRACA Phase 3 study is an open-label, randomized, parallel, two-arm, multi-center study of BMN 673 versus physician’s choice in approximately 430 germline BRCA mutation patients with locally advanced and/or metastatic breast cancer, who have received no more than two prior chemotherapy regimens for metastatic disease. The primary objective of the study is to measure progression free survival (PFS). Secondary objectives include evaluating the objective response rate (ORR) and the overall survival (OS).”

Unique Study Focuses on Combined Treatment Approach for Locally Advanced Pancreatic Cancer

The gist: With the participation of volunteer patients, researchers are testing a potential new treatment approach for locally advanced pancreatic cancer, which is difficult to treat. The treatment combines radiation, chemotherapy, and a specific drug known as a PARP inhibitor, which keeps cancer cells from being able to undo the damage caused by radiation and chemotherapy. The treatment is being tested in a clinical trial. The researchers are also interested in investigating certain molecules, or “biomarkers,” found in patients’ tumors that could be used to predict how well the new treatment will work for different patients.

“Investigators at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute are developing a novel, multistep investigational treatment for one of the most complex and difficult-to-treat forms of the disease, locally advanced pancreatic cancer.

“Locally advanced pancreatic cancer has the lowest survival rate of any solid tumor, with a cumulative five-year survival rate of only 4 percent for all stages of disease. Surgery is rarely an option for patients because tumors often involve vital blood vessels. Chemotherapy and radiotherapy given concurrently remain the mainstay treatment, yet to-date, no treatment has had a significant impact on improving outcomes.

” ‘To move the needle forward toward prolonged survival and better treatment outcomes, our research team created a combined investigational regimen for patients with locally advanced pancreatic cancer,’ said Richard Tuli, MD, PhD, a radiation oncologist in the Department of Radiation Oncology and a member of the Samuel Oschin Comprehensive Cancer Institute. ‘Coupled with this research treatment, we are also looking to identify patient biomarkers, or molecular signatures, that may provide clues to how, and why, some patients respond better than others.’ “

Experimental Breast Cancer Drug to be Trialled in Lung Cancer Patients

“A clinical trial using an experimental drug originally designed to treat breast cancer launches for patients with advanced lung cancer.

“The drug, called olaparib – a type of treatment called a PARP inhibitor – will be given after chemotherapy to patients with non-small cell lung cancer (NSCLC) to see if it delays the growth of their tumour.

“The phase II trial will recruit over 100 people with advanced non-small cell lung cancer at 25 hospitals around the UK. It is funded by Cancer Research UK and AstraZeneca through a National Cancer Research Network initiative and is being co-ordinated by Cancer Research UK’s Wales Cancer Trials Unit at Cardiff University and Velindre NHS Trust in Cardiff.”

Editor’s Note: More and more, scientists are finding that different types of cancer (breast and lung cancer, for instance) can sometimes have similarities, meaning that a treatment that works for one type might also work for another type. This study is exploring once such treatment.

Proteomic Markers of DNA Repair and PI3K Pathway Activation Predict Response to the PARP Inhibitor BMN 673 in Small Cell Lung Cancer

 Here, we evaluate activity of a novel, potent PARP inhibitor, BMN 673, and identify markers of response as a basis for developing predictive markers for clinical application.

Elevated expression of multiple DNA repair proteins, as well as a corresponding “DNA repair protein score,” predict response to BMN 673 in in vitro SCLC models. These observations complement recent work in which PI3K inhibition sensitizes breast cancer models to PARP inhibition, suggesting cooperation between DNA repair and PI3K pathways.

BMN 673, a Novel and Highly Potent PARP1/2 Inhibitor for the Treatment of Human Cancers with DNA Repair Deficiency

PARP1/2 inhibitors are a class of anticancer agents that target tumor-specific defects in DNA repair. Here, we describe BMN 673, a novel, highly potent PARP1/2 inhibitor with favorable metabolic stability, oral bioavailability, and pharmacokinetic properties. BMN 673 is currently in early-phase clinical development.

Breast Cancer Drugs May Also Be Effective Against Some Lung Cancers

A class of drugs already in clinical trials for breast and ovarian cancer, so-called PARP inhibitors, may also be effective against some forms of non-small cell lung cancer (NSCLC). Around half of all NSCLC tumors have low levels of ERCC1, a protein that helps repair damaged DNA. PARP inhibitors act by blocking a different DNA repair mechanism. This creates a one-two punch that kills the NSCLC tumor cells that are low in ERCC1, while healthy cells remain relatively unharmed. A recent cell culture study showed that PARP inhibitors like olaparib, niraparib, and BMN 673 killed ERCC1-deficient NSCLC cells, but not cells with normal ERCC1 levels.

PARP Inhibitors May Offer New Option in Lung Cancer Treatment

A new class of drugs called PARP inhibitors could help patients with non-small cell lung cancer (NSCLC) who have become resistant to cisplatin (Platinol), a study suggests. Researchers found that Platinol-resistant NSCLC cells contain high levels of a protein called PARP1 in an unusually hyperactive form. PARP1 inhibitors killed these cancer cells and slowed the growth of Platinol-resistant NSCLC tumors implanted into mice. High levels of a protein called PAR predicted greater effectiveness of PARP inhibitors and may be a future biomarker for identifying patients who would benefit from the treatment.

Cisplatin-Resistant Cancer Cells Sensitive To Experimental Anticancer Drugs Called PARP Inhibitors

Cisplatin-resistant non-small cell lung cancer cells expressed high levels of hyperactivated PARP1. Cells succumbed to PARP inhibitors in vitro. PARP inhibitor slowed cisplatin-resistant tumor