Piecing Together the Next Chapter of PARP Inhibitors

Pairing PARP Inhibitors With Other Drugs

A core principle that underpins the evolution of PARP inhibitors is combination therapy — pairing two or more drugs that work in a complementary, even synergistic way. Efforts to identify powerful drug combinations are often guided by laboratory studies of patients' own cancer cells and their molecular vulnerabilities. By exploring the biology of ovarian cancer cells, Dana-Farber researchers can learn which DNA repair pathways the cells rely on and develop strategies to exploit those dependencies.

For example, patients whose tumors harbor mutations in the BRCA1 or BRCA2 genes can no longer deploy a type of DNA repair for mending breaks that span both strands of the double helix. As a result, the cells are even more dependent on other DNA repair pathways, such as the one controlled by poly (ADP-ribose) polymerase, or PARP. This form of DNA repair fixes breaks that affect just one DNA strand, and it is disabled by PARP inhibitors. When used to treat tumors with BRCA mutations, the drugs can deliver a mortal blow to the already crippled DNA repair network, killing the cancer cells. Such molecular insights spurred the early use of PARP inhibitors in patients with BRCA-deficient tumors.

Over the last several years, Dana-Farber scientists have followed a similar strategy to figure out why some tumors do not respond to PARP inhibitors. In some cases, the tumors have been previously exposed to the drugs and then devised ways to outsmart them; in others, the tumors were resistant to PARP inhibitors at the outset.

"There's now a large body of published research in this area and several clinical trials are underway to test potential combinations that might re-sensitize cells to PARP inhibitors, or to make cells that weren't originally going to respond to the drug now succumb to it," said Dr. Liu.

One such trial involves a drug that blocks ATR, a pivotal protein that helps cancer cells in their quest to relentlessly multiply. Before cells can divide, whether they are cancerous or not, they must duplicate their DNA. But even before that, they must repair any errors or gaps in the double helix. ATR behaves like a traffic cop, ensuring that the whole process pauses if there are lingering DNA breaks.

Early clinical trial data involving patients with ovarian cancer who had BRCA mutations and who had previously received treatment with a PARP inhibitor showed that nearly half responded to a combination of ceralasertib, an ATR inhibitor, together with olaparib, a PARP inhibitor. The findings were presented last June at the American Society of Clinical Oncology (ASCO) meeting. The trial, known as CAPRI, is a collaboration led by researchers from the University of Pennsylvania together with Dana-Farber and Johns Hopkins. This combination is also the focus of project 1 of a Dana-Farber/Harvard Cancer Center Ovarian Cancer Specialized Program in Research Excellence (SPORE) grant.

"There's a lot of interest in this work," said Dr. Liu. "We're continuing to enroll patients and are working to better understand the therapeutic activity we are seeing in women who have had prior treatment with PARP inhibitors."

Another drug combination Dr. Liu and her team are pursuing is a PARP inhibitor plus adavosertib, a drug that inhibits WEE1. WEE1 is a protein which acts similarly to ATR, providing a checkpoint for cells to ensure their DNA is fully intact and replicated before dividing.

In laboratory studies of PARP-inhibitor-resistant cancer cells, adavosertib, either on its own or paired with olaparib, could kill the cells. Now, Dr. Liu is leading a phase 2 clinical trial, together with researchers from MD Anderson Cancer Center and other organizations, involving patients with PARP-inhibitor-resistant forms of ovarian cancer. Initial results from a small cohort of patients were also presented at the ASCO meeting last June and showed that over 20% of patients responded to either adavosertib alone or a combination of adavosertib plus Olaparib. The researchers are continuing the trial and conducting laboratory analyses of tumors cells from clinical trial participants to better grasp which cells are responding and why.

"We're all driven to rapidly advance the pace of clinical development because we know our patients need treatments," said Dr. Liu. "At the same time, we need to be thoughtful and coordinate closely with basic, translational, and clinical researchers to understand which drugs work, why they work, and when they work."

Looking to the Future of PARP Inhibitors

Dr. Liu is also exploring the potential of other drugs to synergize with PARP inhibitors, including anti-angiogenic agents, like cediranib, which block the growth of blood vessels that feed tumors. Initial research conducted about a decade ago suggested that combining cediranib with a PARP inhibitor could help sensitize tumor cells to a PARP inhibitor. Since then, Dr. Liu has been studying the drug combination in ovarian cancer patients in a phase 2 clinical trial as well as two large phase 3 trials. Recent data suggests that combining the two drugs together does not improve survival beyond standard treatment with platinum-based chemotherapy.

Even so, Dr. Liu believes that the idea of combining anti-angiogenics and PARP inhibitors still holds promise and has been studying combinations that introduce a third drug, such as immune checkpoint inhibitors. These drugs, which were first approved for use in melanoma, have had a remarkable impact on the treatment of certain forms of cancer. However, they have been less successful in ovarian tumors, in part because the tumors are "cold" — meaning the tumors have few, if any, signs of inflammation, such as T cells, limiting the usefulness of checkpoint inhibitors.

Dana-Farber's Panagiotis Konstantinopoulos, MD, PhD, director of translational research in the Division of Gynecologic Oncology and co-director of the Center for BRCA and Related Genes has been probing ways to render immunotherapy drugs more effective in ovarian cancer. Early laboratory studies in mice, led by Dana-Farber researcher Jean Zhao, PhD, showed that a PARP inhibitor and an immune checkpoint inhibitor can act synergistically through activation of the STING pathway. The researchers also revealed a biological explanation for this synergy: PARP inhibitors not only play a role in DNA repair but also help stoke the fires of the immune system. Dr. Konstantinopoulos is currently involved in clinical trials combining checkpoint inhibitors with PARP inhibitors.

Dr. Konstantinopoulos and his colleagues, including Dr. Matulonis, have spent several years studying another therapeutic combination, a PARP inhibitor plus a PI3-kinase inhibitor. Over a decade of laboratory and clinical research at Dana-Farber and other institutions indicates this pairing, too, could be synergistic, especially in ovarian cancer patients without BRCA mutations — a cohort that has been generally considered to be less responsive to PARP inhibitors alone. Now, Dr. Konstantinopoulos is leading an international multi-site phase 3 trial to investigate the drug combination of olaparib, a PARP inhibitor, and alpelisib, a PI3-kinase inhibitor, in non-BRCA-mutated forms of platinum resistant ovarian cancer.

"These are really exciting therapeutic strategies," Dr. Konstantinopoulos said. "We'll have to wait and see what the different trials tell us, but it's very gratifying to see the early pre-clinical and clinical research we've done here at Dana-Farber being carried forward to the next stage in service of our patients."

Alan D'Andrea, MD, director of Dana-Farber's Susan F. Smith Center for Women's Cancers and the Center for DNA Damage and Repair, is also pursuing a novel PARP inhibitor combination, pairing the drug with novobiocin, an antibiotic developed in the 1950's. Novobiocin is no longer prescribed for humans but is commonly used in animals. Dr. D'Andrea and his colleagues identified it in a screen for chemical compounds that could halt the growth of BRCA-deficient tumors while sparing healthy cells.

Now, Dana-Farber researchers are launching a clinical trial to study novobiocin in patients with BRCA-deficient cancers, including ovarian tumors, that have developed resistance to PARP inhibitors. "This strategy for overcoming PARP inhibitor resistance is deeply rooted in our research on the BRCA pathway," said Dr. D'Andrea. "It's exciting to see this work moving forward."

Novobiocin, together with the various other PARP inhibitor drug combinations now under development, mark the beginning of a new era in ovarian cancer treatment.

"The post-PARP-inhibitor age is here," said Dr. Liu. "We're learning more every day about what makes these drugs work or not work, and there are a variety of strategies now being pursued to overcome therapeutic resistance."

Dr. Matulonis added, "It's been so gratifying to see ovarian cancer treatment undergo such a fundamental shift with progress being made. There is a palpable sense of urgency for developing new treatment strategies for patients with ovarian cancer; the possibilities are truly endless."

Disclosure of Advisory Roles and Certain Industry Support

Dana-Farber is committed to ensuring the veracity of research conducted under its oversight and follows strict policies and procedures to ensure its research meets the highest ethical standards. Here are the significant board memberships, outside support, and advisory roles as reported by physicians and researchers in this article:

• Joyce Liu, MD, MPH, serves on advisory boards for AstraZeneca, Clovis, GlaxoSmithKline, Merck.
• Ursula Matulonis, MD, has served in a consulting role for AstraZeneca, GlaxoSmithKline, Merck, and Novartis.
• Panagiotis Konstantinopoulos, MD, PhD, served on an advisory board for the olaparib treatment and is a member of a scientific advisory board for AstraZeneca.