When Two Drugs Are Better Than One - Advances in Ovarian Cancer Treatment

From Turning Point 2015

by Elizabeth Dougherty

When Donna Gregory's ovarian cancer came back for the third time, she began looking for alternatives to chemotherapy. She'd been diagnosed, during an unrelated surgical procedure, with stage III ovarian cancer in 2003, at age 58. After having surgery to remove the tumors, she tried platinum-based chemotherapy, but her cancer did not respond. Another chemotherapy drug worked, though. And then another. "Everything was fine," she says. "Until last summer."

Gregory had already defied the odds. The five-year survival rate for women with similar disease is about 39 percent, according to the American Cancer Society. "You're absolutely thrilled to be alive after five years of ovarian cancer," she says.

Having run out of traditional therapeutic options, Gregory searched online for experimental alternatives and found news of a clinical trial under way at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). The trial was open to women with recurrent ovarian cancer, and wasn't restricted to BRCA mutation carriers or platinum-sensitive cancers. "I thought, oh, this is perfect for me!" she says.

The trial offered Gregory a new approach to ovarian cancer therapy that takes two targeted drugs (agents that interfere with the biological machinery that drives tumor cell growth), and teams them up as a unified, potentially synergistic force. Gregory immediately flew to Boston from her home in Miami, Fla., and enrolled.

A New Strategy

When Joyce Liu, MD, MPH, a gynecologic oncologist at the Susan F. Smith Center for Women's Cancers at Dana-Farber, first proposed combining two targeted drugs, the reaction from colleagues was lukewarm. Previous efforts to combine chemotherapy drugs for ovarian cancer patients had not produced profoundly better results, and targeted drugs were showing only modest benefits as single agents.

But Dr. Liu persevered. She had science on her side, with evidence from the National Cancer Institute that the combination she was proposing had promise. She also had a clear purpose. Each year in the United States, approximately 22,000 women are diagnosed with ovarian cancer. While many women respond to initial chemotherapy, the cancer often comes back. "There's a definite unmet need for new therapies and new approaches to attacking this disease," says Dr. Liu.

While Dr. Liu's trial was the first of its kind for ovarian cancer, it was certainly not the last. Since then, Dana-Farber clinical researchers have begun several other trials of novel combinations in women with recurrent ovarian cancer.

"We're here to expand the options for our patients and provide options that are based on the genomic abnormalities of their particular cancers," says Ursula Matulonis, MD, medical director for Gynecologic Oncology at the Susan F. Smith Center. "We really need to think about a multi-pronged, multi-drug approach."

Molecular Mixology

Dr. Liu's trial combines two drugs that target specific aspects of ovarian tumor biology. One is olaparib, a PARP inhibitor that compromises the way cells repair broken strands of DNA, thereby making them more vulnerable to death. The other is cediranib, an antiangiogenic drug that interferes with the machinery that builds new blood vessels.

In early results reported in 2014, the combination showed exciting results in women with recurrent ovarian cancer. One patient's cancer vanished. In almost half of the patients enrolled in the trial, tumors shrank by more than a third, and several patients have remained stable. Dr. Liu is now leading additional trials that will enroll more women and compare the drug combination in a head-to-head test with the current standard of care.

It isn't clear yet how the drugs synergize to support or amplify one another's effects, but Dr. Liu has a hypothesis. PARP inhibitors typically work best in women with BRCA mutations because they help deliver a DNA repair double-whammy. The BRCA gene mutation knocks out one form of DNA repair, leaving only the PARP mechanism to do the work. This mechanism helps BRCA mutation carriers stave off cancer for a time, but once cancer has begun to grow, it also helps tumor cells stay alive. Disabling it with a PARP inhibitor pushes tumor cells a step closer to death.

In Dr. Liu's trial, women without BRCA mutations, like Gregory, are responding to PARP inhibitors plus antiangiogenics. Dr. Liu speculates that the antiangiogenic drugs are mimicking the effects of BRCA mutations by starving the tumor of blood and oxygen. In this state, DNA repair falters, making the cells more vulnerable to the PARP inhibitor. In upcoming clinical trials, Dr. Liu is planning to collect tissue samples from patients so she can test this theory more thoroughly.

Selection Science

Finding new combinations that are as complementary as the two Dr. Liu is testing is a challenge. There are many molecular agents, immunological agents, and other biologically-based targeted drugs available, so the number of potential combinations is enormous and growing.

One way to narrow down the options is to test large numbers of different combinations on models of ovarian cancer to see which ones show promise. Drs. Liu and Matulonis are collaborating with colleagues at Dana-Farber on a project to screen a host of drug combinations in cultured ovarian cancer cells.

From there, the most promising combinations will be tested — in a much more labor-intensive and expensive process — in mouse models of ovarian cancer. The mouse models Drs. Liu and Matulonis are using are sometimes called mouse "avatars" because they are derived from tumor samples of real patients and implanted in mice. These cancers more closely resemble those of real patients than cultured cells.

The avatars also allow more detailed scrutiny of the response to new therapies. "We can learn which cancer types respond well and why; and if the cancer does not respond, we can also begin to understand the mechanisms of resistance," says Dr. Matulonis.

For example, a drug combination now being tested in patients — an experimental PI3K inhibitor plus olaparib, a PARP inhibitor — was first studied in mouse avatars representing triple-negative breast cancer at Beth Israel Deaconess Hospital. The researchers learned that the PI3K inhibitor impairs DNA repair and, in turn, amplifies the effects of the PARP inhibitor.

Because high-grade serous ovarian cancers genetically resemble triple-negative breast cancers, Dr. Matulonis launched a trial of this combination in women with these types of breast and ovarian cancers.

Based on promising early results, she recently expanded the trial to offer two options: olaparib plus one of two different experimental PI3K inhibitors. Results are expected in 2016. Trials of drug combinations are also under way for other gynecologic cancers including cervical.

Combination Caveats

While these novel drug combinations show promise, they also present challenges. Just as two drugs may benefit patients more than either one alone, they may also result in additional side effects.

"We are learning that there can be synergistic toxicities," says Sara Tolaney, MD, MPH, a breast oncologist at the Susan F. Smith Center's Breast Oncology Program who is also involved in the Early Drug Development Center (EDDC) at DF/BWCC. "We need to figure out which patients will benefit, and prevent patients who are not going to respond to the treatment from getting toxicities with no gain."

Gregory, for instance, has found a good match. After just eight weeks on the drugs, a twice-daily set of pills, her tumor shrank by 57 percent and the side effects have been tolerable. Dr. Liu lowered Gregory's dose of cediranib to manage her blood pressure, which had been high and had increased on the drug.

The biggest hardship has been the weekly flights to Boston. "You never know how your body is going to respond," she says. "You plan for all the variables and get an aisle seat in back near the bathroom."

Gregory has been on the treatment regimen long enough that her check-ups at Dana-Farber are now monthly, rather than weekly, giving her time for one of her favorite activities: attending art fairs.

Turning Point 2015 Table of Contents