PARP inhibitors are making a big difference to cancer patients. Since they are administered orally, patients have the freedom to take them at home, and aren’t restricted by hospital visits for chemotherapy. Here’s Laurie McAndrews’s story.
In December 2014, Laurie McAndrews from Illinois was close to retiring when she felt something strange in her stomach. “The symptoms were so quiet, it's what I'd describe as a persistent twinge in my lower stomach,” said McAndrews. After consulting with a specialist at the UW’s Carbone Cancer Center, she was diagnosed with stage 3C ovarian cancer. McAndrews underwent surgery within a week after receiving a diagnosis of ovarian cancer, as well as a 4.5-month course of chemotherapy. “At the end of the 18-week treatment I was considered, 'no evidence of disease' so I was ecstatic. I was like 'this is it’,” said McAndrews.
Unfortunately, as in most cases of cancer patients with an advanced stage of ovarian cancer, there is the fear of recurrence. In Laurie’s case, the cancer came back a year and a half later. It was through performing a CA-125 blood test and a CT scan that revealed the cancer recurrence. “I fully expected to hear again 'no evidence of disease,' I figured 'Oh, I've beat it' Well ... it wasn't all gone but it's very small and manageable” said McAndrews. Still, the cancer’s small size made her qualified for maintenance therapy, in an effort to prevent relapse.
The promise of PARP inhibitors
During the same month as Laurie’s diagnosis of recurrence, cancer researchers received FDA approval for 3 new cancer-treating drugs: olaparib (marketed as Lynparza), rucaparib (marketed as Rubraca) and niraparib (marketed as Zejula). Known as PARP inhibitors, these drugs attack cancer cells without obstructing healthy surrounding cells. The first approved PARP inhibitor, olaparib, is designed for women with BRCA-mutated advanced ovarian cancer who have undergone 3 or more rounds of chemotherapy. The drug’s approval was based on a 55% response of cancer patients reporting being progression-free at 6 months. Rucaparib was the second PARP inhibitor to be approved and it is indicated for women with BRCA-positive advanced ovarian cancer, who have undergone at least 2 rounds of chemotherapy. The drug’s approval was based on data from clinical trials that proved proper detection of BRCA mutations in tumor tissue. The third and latest PARP inhibitor to be approved is known as niraparib. It is prescribed for maintenance therapy of women with non-BRCA mutated cancers of the ovaries, fallopian tubes, and primary peritoneal cancer, who demonstrated partial or complete response to platinum chemotherapy.
“Until recently, there have been few treatment advances for women with recurrent ovarian cancer and even fewer options available for women who do not harbor BRCA mutations. We are excited to have the opportunity to offer appropriate patients an oral, once-daily maintenance treatment that reduces the risk of cancer progression and extends the time between courses of chemotherapy for patients who have few treatment options” said Ursula Matulonis, professor of medicine at Harvard Medical School and director, gynecologic oncology at Dana-Farber Cancer Institute. Currently, more PARP inhibitors are underway in diverse phases of clinical trials.
“What's happened in ovarian cancer in the last three years is a huge insurgence of new medications that can be used both up front and in the recurrent setting. So when we use targeted therapy, we're successfully targeting the bad actors in the patient's body and allowing the rest of the body to go on business as usual. It's a revolution” said Dr. Lisa Barroilhet, Laurie’s doctor from the University of Wisconsin-Madison’s Carbone Cancer Center.
How PARP inhibitors can give patients freedom during treatment
While there are a few side effects that can be triggered with PARP inhibitors, their overall objective is to provide cancer patients with comfort during chemotherapy rounds. For Laurie, what made maintenance therapy with PARP inhibitors so tolerable is that they can be administered orally. Although she has not experienced any side effects so far, for some patients, this remains a challenge. “It's still chemotherapy; these drugs certainly still have side effects. But the idea that you can take that medication at home, and have the freedom in your day in your life to fit in your chemotherapy treatment that quickly, is totally different from anything we've been able to offer patients in the past,” said Dr. Barroilhet.
Living more than an hour and a half from the Cancer Center, these drugs have given Laurie freedom to live her life to the fullest and not give into the exhausting and lengthy chemotherapy treatments. “I've got eight grandchildren, so now I have time to go to their events, take them around, before it was like 'No, I have no energy'. Now I can get me out there and I'm feeling really good,” she said.
Dr. Barroilhet, a clinical caregiver and cancer researcher, feels that PARP inhibitors are making a big difference. “We have so much work to do. I don't want to make it sound like we've won this war, but I do feel and this is the first time I've felt this way in several years, that we've just won a major battle” she said.
Some of the details are still a mystery
PARP inhibitors are offering a promising option in place of targeted therapy in ovarian cancer. While they pose clear advantages to BRCA-gene carriers, questions still remain as to when the best time to use them is and whether they prove to be cost-effective for maintenance therapy. “Patients really want extension of life and also time off treatment, especially when that treatment involves significant side effects” said Dr. Elizabeth Swisher, director of the Breast and Ovarian Cancer Prevention Program at the Seattle Cancer Care Alliance. Therefore, maintenance therapy could be used as an alternative until additional chemotherapy is required. “I think we can all agree that delaying chemotherapy is an important clinical incentive” she added.
Still, PARP use in maintenance or actual time of relapse remains a mystery. Moreover, questions center on cost-effectiveness of maintenance therapy and whether PARP inhibitors can be combined with other therapies to target DNA repair. “We know that ovarian cancers that are proficient in homologous recombination are not sensitive to PARP inhibitors. Even BRCA-mutated ovarian cancers eventually develop resistance to PARP inhibitors, and much of that is through restoration of DNA repair and increase of homologous recombination. So new drugs that inhibit homologous recombination could be combined with PARP inhibitors” said Dr. Swisher. This, in turn, would render a PARP inhibitor ‘synthetically lethal’ to the cancer. “There is definitely a lot of potential to make PARP inhibitors even more effective” concluded Dr. Swisher.
To date, several doctors have stated that PARP inhibitors are showing great potential in their use not just in ovarian cancer, but eventually in several other types of cancers as well. When asked about the future of PARP inhibitors, Ruth Plummer, Professor of Experimental Cancer Medicine at Newcastle University, stated “I am quite an enthusiast for this class of agents and their potential. I think these drugs will eventually be used in a wide range of cancers, not just ovarian cancer with germline BRCA mutations. I am a bit wary about the adjuvant treatment, but if it is safe, this could be a way to avoid surgery for patients with germline mutations. I think this therapy is leading the field for other drugs that modulate DNA repair response pathways and is helping us understand how to develop better cancer treatments. I think PARP inhibitors have a bright future, even though it has been a varied path of clinical development over the last decade.”