A new type of cancer medication, called PARP inhibitors, is gaining traction in clinical practice. Already the FDA has approved several drugs in this class: Lynparza (olaparib, AstraZeneca), Rubraca (rucaparib, Clovis), and Zejula (niraparib, Tesaro). So far, these pills are approved only for women with particular genetic findings, and mainly for ovarian cancer and related tumors, such as Fallopian tube cancer.
Days ago, at the European Society of Medical Oncology (ESMO) conference in Madrid, investigators reported on a trial called ARIEL-3. The main finding is that Rubraca, as “maintenance” therapy, extends progression-free survival in platinum-sensitive ovarian cancer with or without BRCA mutations. This late-breaking abstract details the Clovis-sponsored randomized, placebo-controlled trial that enrolled 564 participants.
In this ARIEL-3 trial, Rubraca was most effective in delaying recurrence in patients with known BRCA mutations. But it also helped women with other markers of impaired DNA repair in the tumors, sometimes called genomic scarring or BRCA-ness, suggestive of homologous recombination deficiency (HRD). Overall, the drug was well-tolerated; 13% of participants receiving Rubraca withdrew due to toxicity. Based on these findings, Clovis Oncology plans to apply to the FDA, by October of this year, for a broader approval that would include maintenance treatment.
This is good news for women with platinum-sensitive ovarian cancer. It is not surprising. Already, this kind of drug has demonstrated activity as treatment of refractory, BRCA-linked ovarian tumors and, perhaps more so, as a maintenance therapy for platinum-responsive disease. The aim of maintenance therapy is not necessarily to cure an advanced malignancy, but to keep it under control, to delay recurrence.
What excites me about PARP inhibitors, including Rubraca, is their potential use in other cancer types, too. Patients may be unaware they’ve got a genetic disposition to develop tumors that could respond to these agents. Some cancers have acquired genetic changes that might render them sensitive to this type of treatment.
People who inherit deleterious mutations of either BRCA1 or BRCA2 are at increased risk for developing breast, ovarian, pancreatic, and prostate cancer. Other genes involved in DNA repair, such as PALB2, ATM and CHEK2 are also implicated in those malignancies. In general, there is reason to think that PARP inhibitors will be helpful in treating cancers in patients with BRCA mutations and other causes of DNA repair defects, which is why these agents have been tried first in these kinds of tumors.
Today I’ll focus on a trial of Rubraca in pancreatic cancer because it’s among those linked to BRCA mutations, a cancer for which chemotherapy tends to be inadequate, and for which targeted treatments are lacking. In families with unusually high incidence of pancreatic cancer, other genes have been implicated. Some studies suggest that mutations in BRCA2 or PALB2 confer the highest risk for developing pancreatic malignancy.
The NCI estimates that over 53,000 people will receive a pancreatic cancer diagnosis this year in the United States; over 43,000 will die from the condition. Adenocarcinoma is by far the most form, accounting for 95% of pancreatic tumors. Although it tends to affect older people, with median age 70 at diagnosis, over 11% of pancreatic cancer patients receive their diagnosis before age 55. Five-year survival remains shockingly low; the NCI suggests it’s only 8.2% (as of 2013) In the past ten and twenty years, there’s been comparatively little progress against this disease.
If you check all patients with pancreatic cancer, you’ll find between 3% and 7 % have inherited mutations in BRCA or related genes, said Dr. Kim Reiss Binder. She’s an oncologist and assistant professor at the University of Pennsylvania’s School of Medicine. Her clinical research, supported by the university’s Basser Center, focuses on BRCA and associated malignancies. We spoke by phone.
That’s an estimate, Reiss emphasized. Oncologists don’t yet know what fraction of patients have mutations, like BRCA, that may render tumors sensitive to PARP inhibition. Most pancreatic cancer patients don’t get checked. As NGS (next-generation sequencing) of cancer becomes more common, the number of patients who turn out to have acquired relevant changes in the malignant cells may turn out to be higher.
Reiss is running a clinical trial of rucaparib (Rubraca) as maintenance therapy in pancreatic cancer that has stabilized in response to a platinum-type chemotherapy. The phase 2, open-label study began recently. The study will enroll a total of 42 patients. Eligible participants have advanced pancreatic adenocarcinoma and a clinically significant mutation in BRCA1 or BRCA2, or in the PALB2 gene. To qualify for this trial, the relevant mutations can be either “germline” (inherited), or “somatic” changes detected within the cancer. Clovis Oncology, the drug’s manufacturer, is providing the medication and funds for the study.
“Most of the clinical work on PARP inhibitors has been in ovarian, in triple-negative breast cancer and prostate cancer,” Reiss said. The potential applications of those drugs in other cancers is unknown. “If you look at pancreatic cancer patients with strong family histories, people of Ashkenazi Jewish ancestry, and some others, the proportion with BRCA and other mutations that might respond to PARP inhibitors goes up.”
As many as 14% of pancreatic cancers contain pathological evidence for homologous recombination deficiency, Reiss mentioned. This sort of problem—of impaired DNA repair—can be caused by inherited mutations in BRCA and other genes, like PALB2, ATM or CHK2. Sometimes, mutations in these genes are not inherited, but become evident only in the malignant cells. Whatever the cause, when cancer cells demonstrate features of unrepaired DNA, HRD or genomic “scarring,” they may be vulnerable to PARP inhibition.
In people who inherit PALB2 mutations, the cancer risk resembles that seen with BRCA2 mutations, Reiss said. “That’s why we’re including that group of patients in this trial.”
“Toxicity with PARP inhibitors is generally not too bad,” Reiss said. “People feel well with them. They like them a lot better than chemo. Mostly they experience a little nausea, and fatigue.” The main problem is suppression of the bone marrow, she said. “You have to watch the hemoglobin and the platelets, and check the blood.” That needs be done often at first, and then monthly, she suggested. “Also, you should keep an eye on patient’s kidney function,” she noted. “In general, people feel much more normal than they do on chemotherapy.”
The Rubraca study is not the only ongoing clinical trial of PARP inhibitors in pancreatic cancer with BRCA mutations, Reiss mentioned. For instance, the POLO study is testing AstraZeneca’s olaparib (vs. a placebo) in stable, platinum-sensitive pancreatic cancer. Other trials are exploring the safety and effectiveness of giving PARP inhibitors together with chemotherapy. “A major challenge of those regimens is toxicity,” she said. “The PARP inhibitors are generally myelosuppressive. If you give them together with chemo, you may need to drop the chemotherapy to ‘homeopathic’ doses, to a point that it’s sub-standard.”
“Our approach offers a new paradigm for treatment of pancreatic cancer in the setting of a BRCA or PALB2 mutation,” Reiss said. “The usual way of treating pancreatic cancer, once a patient begins chemotherapy, is that they stay on it for as long as they can tolerate it, or until the tumor breaks through,” she said. “There is no ‘maintenance’ mode in pancreatic cancer. That’s a problem,” she said. “Over time, given cumulative toxicities of chemotherapy, the treatment starts to become difficult if not impossible.”
Neuropathy from platinum-type chemotherapy reduces patients’ quality of life, Reiss emphasized. “It can be painful,” she said. “Some patients have trouble closing buttons, difficulty with walking, and falling.” Even with BRCA, most pancreatic cancer patients tend to be older, in their sixties or seventies. Toxicity from the chemo can be independence-limiting.
In the Rubraca trial, eligible patients need have stable disease on a platinum-type chemotherapy before they begin the PARP inhibitor. “In BRCA-positive patients with pancreatic cancer, the response to platinum tends to be strong and sustained,” Reiss said. “We’ll see if we can use chemotherapy as an ‘induction’ treatment, to shrink the tumor down, and then press back on the chemo,” she said. The idea is to give patients time off, after intravenous therapy, while keeping the cancer under control.
“It would be great if this works as maintenance therapy for patients with BRCA-associated pancreatic cancer,” Reiss said. “If the PARP inhibitor were approved for that setting, it would free some patients from the need for lifelong chemo,” she said. “We’re talking about people with incurable adenocarcinoma of the pancreas,” she considered. “This is a pill-as-maintenance strategy.”
I asked Reiss about trials of PARP inhibitors together with other drugs. “Combination therapy is the logical next step,” she said. “It could be a way to avoid resistance to medication, but we need studies to evaluate that possibility,” she said. “Down the road, we need to look at mechanisms of treatment resistance. It may be that dual inhibition, or combinations are the best approach,” she said.
“In the future, I think we need to far expand our definition of people who are sensitive to these types of agents,” Reiss said. “It may be not just for cancer patients with germline BRCA mutations. PARP inhibition could work with ATM, CHK2, and other changes,” she said. “We need to figure out the extent of the population for whom these drugs may be helpful.”
“Less is known about the acquired BRCA mutations,” Reiss said. “Even less is known about HRD without BRCA mutations.” We and others are looking into that, she said.
Last June, I met with Patrick Mahaffy, the CEO of Clovis Oncology and Dr. Lindsey Rolfe, the company’s Chief Medical Officer, in Chicago. Rolfe is a physician with expertise in pharmaceuticals.
I asked Rolfe if there is anything unique about ovarian cancer that makes it respond exceptionally well to PARP inhibition. “There are a couple of reasons,” she offered. “First, around 25% of high-grade serous ovarian cancer have BRCA mutations,” she said. “Around 10 to 15% of cases have germline mutations,” she said. “In another third of cases we find other evidence for HRD deficiency,” she said. The Foundation Medicine test picks up inherited and acquired mutations,” referring to this companion diagnostic test. “That’s really important, because 5-10% of cases will turn out to have BRCA mutations only in the tumors.”
Earlier this year, Clovis and Myriad Genetics announced an agreement that Myriad will submit a supplementary premarket approval application for its BRACAnalysis CDx to include Rubraca.
“Although BRCA mutations are particularly frequent in ovarian cancer, the clinical applicability may be broad,” she said. Clovis has ongoing trials of Rucaparib as a single agent in prostate cancer, such as the TRITON trial. “We’re looking at men with mutations in BRCA and other genes,” Rolfe said. There are over a dozen relevant mutations, she suggested. “Up to 20% of men with metastatic prostate might benefit.” The company is also sponsoring investigator-initiated studies of Rubraca in breast cancer, and Reiss’s trial of pancreatic cancer.
“Those studies are all single-agent,” she noted. “We have an ongoing of Rucaparib and Atezolizumab in gynecological cancers,” Rolfe said, referring to a combination being tested of Rubraca with Tecentriq, Roche’s immune-oncology anti-PDL1 checkpoint inhibitor. “We plan to extend studies of that combination to trials of triple-negative breast cancer,” she said.
Information on the use of PARP inhibitors in non-ovarian cancers is emerging from quite a few trials. Most recently, the New England Journal of Medicine published data from the OlympiAD trial, presented at the ASCO meeting, in which investigators found that olaparib, compared to a placebo, when taken together with chemotherapy, slightly extended progression-free survival in women with inherited BRCA mutations and advanced, HER2-negative breast cancer. That is an encouraging result, but the effect was small. One possible explanation is that the PARP inhibitors might more effectively control less bulky tumors, such as after cancer has been shrunk by more aggressive chemotherapy, along the lines of “maintenance” mode.
Earlier trials, beyond the scope of this article, have explored this and other PARP inhibitors in triple-negative breast cancer, particularly in BRCA-associated cases, as a single agent and in combination with other drugs. Olaparib is being tried in metastatic prostate cancer, too, with promising results reported in 2015.
I like the PARP inhibitors, in general, because they’re active against cancer in a way that can be anticipated. Overall, they seem to be well-tolerated. They do confer a risk of myelodysplastic syndrome due to damaged, unrepaired DNA in cells of the bone marrow. However, in 2017 that risk seems small in context of stage 4, incurable cancers for which these drugs are being given. That the FDA-approved PARP inhibitors come as pills can be problematic in terms of insurance and co-pays, but that should be a fixable-problem. From a patient’s point of view, taking a pill is far less of a hassle than getting intravenous infusions.
Other, investigational PARP inhibitors I’m keeping an eye on, because they may prove helpful, include talazoparib (by Medivation, now of Pfizer). Talazoparib has been tried in various solid tumors and is being evaluated in a phase 3 EMBRACA trial for BRCA-associated advanced breast cancer. Veliparib (AbbVie) has so far not yielded favorable results in trials of lung and breast cancer, but there’s not much information available about the veliparib studies and what exactly went wrong. Those details would be good to know, and should be published, as toxicity might be avoided in other trials, now ongoing, and future studies, being planned. (A search of the clinicaltrials.gov website on Sept 8, 2017 suggests there are over 4 dozen active studies with veliparib, mainly in combination with other oncology drugs. A similar search for talazoparib, upon checking “recruiting” or “active, not recruiting” yields 19 results.)
Unfortunately, there’s no way to readily compare the PARP inhibitors. I don’t know that Rubraca is more or less toxic, or more or less effective, than other drugs in its class. Ultimately, I suspect “big data” will reveal trends and differences among these agents. That will take a while.
