Breast, ovarian cancer trials find targeted therapies provide benefit over chemotherapy
Clayton Boldt, Ph.D.
Results from two The University of Texas MD Anderson Cancer Center-led clinical trials indicate that targeted therapies led to significant improvements in progression-free survival (PFS) and response rates compared to the standard of care for women with certain types of breast and ovarian cancers. These studies were presented today in Barcelona as late-breaking abstracts at the European Society for Medical Oncology Congress 2019. As the data matures, the investigators suggest the trials should change the standard of care and improve outcomes for these patients going forward.
MEK inhibitor trametinib yields improved response rate and PFS for women with recurrent low-grade serous ovarian cancer
Low-grade serous carcinoma of the ovary or peritoneum represents a rare subtype of ovarian cancer, accounting for just 5%-10% of all cases, and typically has better outcomes than the more common high-grade cancers. However, as these cancers are relatively resistant to available chemotherapies, new ovarian cancer treatment approaches are needed.
Many of these cancers are marked by mutations in the MAPK molecular pathway, a key signaling mechanism for the cell. Trametinib targets the MEK protein, an important piece of the pathway, and was, therefore, investigated as a therapeutic option in these patients. The Phase II/III study randomized 260 patients with recurrent cancer to receive either trametinib or physician’s choice of five standard-of-care options. The study’s primary endpoint was PFS, with additional analyses of overall survival (OS) and overall response rate (ORR).
Trametinib treatment resulted in a median PFS of 13 months and a 26.2% ORR, compared to 7.2 months and 6.2% for the standard of care, both of which were statistically significant improvements. Trametinib also achieved a median OS of 37 months relative to 29.2 months on standard of care, though this was not statistically significant. Preliminary quality-of-life analyses show no significant or clinically meaningful differences in toxicities between the groups.
“This is a practice-changing finding that will enhance our treatment options and make a difference in the lives of women with recurrent low-grade serous carcinoma,” said lead author David Gershenson, M.D., professor of Gynecologic Oncology and Reproductive Medicine. “Based on these findings, trametinib will hopefully soon be included as a treatment option in NCCN Ovarian Cancer guidelines and will undoubtedly be investigated in future combination clinical trials.”
PARP inhibitor veliparib achieves significant PFS increase relative to chemotherapy for breast cancer patients with germline BRCA mutations
Inherited mutations in the BRCA1/2 genes significantly increase an individual’s risk of developing breast cancer, as well as several other cancer types. Mutations in these genes are responsible for an estimated 5%-10% of all breast cancers and 10%-25% of triple-negative breast cancers, a more aggressive type of the disease.
Mutations in BRCAgenes cause deficiencies in normal DNA damage repair, therefore, making them susceptible to a class of drugs known as PARP inhibitors, which target a compensatory DNA repair pathway. PARP inhibitors have proven effective as single agents in treating BRCA-positive breast cancers, but they have previously not been investigated in combination with standard chemotherapy.
This international Phase III trial tested the use of the PARP inhibitor veliparib in combination with two chemotherapies, carboplatin and paclitaxel. For the trial, 513 patients with metastatic breast cancer and inherited BRCA mutations were randomized to receive either veliparib with carboplatin/paclitaxel or carboplatin/paclitaxel with placebo. The study’s primary endpoint was PFS, with secondary endpoints of OS, clinical benefit rate and ORR.
Veliparib treatment resulted in a median PFS of 14.2 months, compared to 12.6 months for placebo, a statistically significant improvement. At the current analyses, median OS was 33.5 months for veliparib and 28.2 months for placebo, although these data are not yet mature. The toxicity profiles were not substantially different between the two treatment groups.
“This is the first and largest international study showing that the addition of veliparib to chemotherapy prolongs progression-free survival compared to chemotherapy alone for these patients,” said senior author Banu Arun, M.D., professor of Breast Medical Oncology. “This combination of PARP inhibitor plus chemotherapy is the new standard of care for metastatic BRCA-associated breast cancers.”