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Music, Science, PARP And The Meaning Of A New Drug For Metastatic Breast Cancer With BRCA Mutations

This article is more than 6 years old.

Spark Media

A few months ago, I attended a N.E.D. concert in the Cutting Room, a Manhattan club. Previously I covered this band of talented gynecological oncologists. N.E.D. stands for “no evidence of disease,” a medical term denoting that a patient is in remission. The concert was good. The audience was exceptional! A good fraction of N.E.D. fans are women living with cancer. Several told me they are still alive—contrary to expectations—because they were taking a new kind of medication for ovarian cancer.

Last week, when the FDA approved Lynparza (olaparib, AstraZeneca) for some forms of metastatic breast cancer, I thought of those women at the N.E.D. concert.

Lynparza was first in a new class of drugs called PARP inhibitors to receive FDA approval for any condition. Since December 2014, when the agency OK’d this pill for women with refractory, metastatic ovarian cancer and probable BRCA mutations, the indications have expanded. In three years since, the FDA approved two other PARP drugs: Rubraca (rucaparib, Clovis Oncology), and Zejula (niraparib, Tesaro) for ovarian and related cancers. Last month, I reported on an experimental PARP inhibitor, talazoparib (Pfizer), for breast cancer, with promising results reported separately for the neoadjuvant setting and in metastatic disease.

You may have heard of PARP inhibitors from another source: Susan Gubar, an author and emeritus professor of English, has been writing about the experience of being a patient, and the topic of cancer, since she received a diagnosis of advanced ovarian cancer in November, 2008. In a New York Times “Living With Cancer” column last September (2017), she told of taking a PARP inhibitor in a clinical trial, for five years, “to keep my cancer in check.”

Historically, it’s primarily been gynecological oncologists—doctors typically trained in obstetrics and women’s health, who’ve further subspecialized in surgery to remove tumors from women’s reproductive organs, and to treat those—who care for patients with ovarian and fallopian tube cancers, the kinds of malignancy for which PARP inhibitors were first approved. That this kind of treatment is approved for breast cancer means that medical oncologists will need learn about these agents, and gain real-world experience with their activity and side effects.

I can attest to the interest: Last month in Texas during the 40th annual San Antonio Breast Cancer Symposium, on weeknights an attendee could choose among several free, “registration-required” off-site industry or Medscape-sponsored CME dinner events held in hotel ballrooms, focused on PARP inhibitors.

This type of medicine is moving forward, fast! PARP inhibitors have been on my radar since 2011, when I wrote a piece for Cure magazine about their experimental use in breast cancer. But my interest goes back further, to my lab’s work: when cells die, PARP gets activated and cleaved. I found it confusing, and maybe counterintuitive, that blocking an enzyme involved in cell death could be useful as cancer therapy.

As it turns out, PARP drugs are helpful probably because of what scientists call synthetic lethality.  In healthy cells, PARP gets turned on in response to DNA breaks. PARP enzymes repair single-strand gene nicks. The BRCA-1 and 2 molecules, while not identical, are involved with fixing errors in double-stranded DNA. If dividing cells are deficient in homologous recombination, which can happen due to BRCA abnormalities or failure of other DNA repair machinery components (such as PALB-2, ATM, or CHK2), they become extra death-prone when PARP also is impeded.

This combination of blocked DNA repair tools—what I might call “PARP plus”—promotes or enables cell death when genetic breaks occur, as tends to happen in cancer cells exposed to platinum-type and certain other chemotherapy agents, or to radiation. If the BRCA or BRCA-like defect in DNA repair is not inherited, or is inherited only on one chromosome (“heterozygous”), but is severe in a patient’s tumor cells, causing homologous recombination deficiency (HRD), there is reason to think that PARP inhibition could facilitate malignant cell death while leaving the relatively healthy, non-malignant cells alone.

That’s an oncologist’s dream, to kill the cancer cells but not the host, aka a person with cancer. Don’t get too excited, though. We’re not there yet. But I do think we’re closer than ever.

Back to the update on Lynparza, the first PARP drug approved for breast cancer: The FDA approved olaparib (Lynparza) for treatment of Her2 negative, metastatic disease in patients with confirmed BRCA mutations. For the time being, prescription depends on a companion diagnostic test (BRACAnalysis CDx, Myriad Genetics) finding a significant BRCA-1 or -2 abnormality in inherited (germline) DNA. The agency cited the OlympiAD trial results.

AstraZeneca sponsors this randomized, open-label study of 302 patients: women and a few men (7) with advanced, Her2 negative disease and inherited BRCA-1 or BRCA-2 mutations. They received either olaparib (Lynparza) pills or one of three standard chemotherapy drugs for breast cancer (“physician’s choice,” PC, as a comparator). The PC options were capecitabine (Xeloda), eribulin (Halaven), or vinorelbine (Navelbine). Never mind that those aren’t great drugs for comparison; the problem is, there are none. The point is to find better treatments!

As detailed in the paper, half of the OlympiAD participants had metastatic, triple negative breast cancer, a subtype for which there is no good chemotherapy. Median survival is less than 3 years. (The other participants had Her2 negative, hormone-sensitive breast cancer, and may also have received endocrine treatment.) 71% of the trial participants had previously received chemotherapy for metastatic disease. As I’ve said, these are patients who don’t have the luxury of waiting years for trials with bad drugs to pan out, or not pan out. The median age of participants in the OlympiAD trial was 44 - 45 years.

The OlympiAD study's primary endpoint is progression-free survival, PFS. Olaparib’s benefit, however slight, appeared early: the PARP inhibitor extended PFS to 7 months (vs. 4.2 months, with chemo) . Based on evaluation by a “blinded” central review, measurable responses to treatment were 59.9% with olaparib and 28.8% with PC (physician’s choice) chemotherapy. Another good sign, for olaparib, is that patients in the OlympiAD trial tended to stay longer on the olaparib arm, vs. chemo: 8.2 vs. 3.4 months (duration of treatment). There is no difference in overall survival reported, either way.

The term “remission” does not appear in the OlympiAD paper. Previously, I’ve discussed this trial with the first author, Dr. Mark Robson of Memorial Sloan Kettering Cancer Center. He’s mentioned that some patients with metastatic breast cancer have been doing very well, living while taking a PARP inhibitor, for quite a while, years. “There is a small but nonetheless measurable group of long-term survivors,” he told me by phone last October.

By email this week, Robson confirmed that “9% of olaparib-treated patients with measurable disease achieved a complete response.”

The main thing—apart from this drug, as a single agent, extending PFS and inducing some complete remissions, what sounds like N.E.D. in a nontrivial subset of metastatic cases—is how the patients felt while taking olaparib, compared to chemo. The PARP pills can be toxic but, for many people with advanced cancer, are preferable to the alternatives (chemo, or no treatment). In the OlympiAD trial, the rate of severe (grade 3 or 4) toxicity was 36.6% for olaparib vs. 50.5% for chemotherapy.

There’s also a lifestyle issue: olaparib is a pill. Who wants to go to doctors’ offices or hospitals for frequent infusions when, instead, they might take a pill to keep their cancer under control?

These drugs are expensive. GoodRx.com lists Lynparza for over $14,000 per month. And because they’re pills, many people wind up paying thousands of dollars more, out-of-pocket, for this kind of treatment than they would for chemotherapy infusions, which makes no sense. The lack of parity for insurance coverage of oral drugs, with laws varying by state, harms patients. It generates disparity in what kinds of treatments cancer patients receive. Another problem is that some doctors and hospitals have a financial incentive to give intravenous drugs, rather than pills.

PARP drug toxicity can be serious. Anemia was more problematic in patients taking olaparib on the OlympiAD trial. Low-grade nausea, vomiting and diarrhea were also more common in the olaparib group; presumably those kinds of symptoms can be optimized and better managed with medications, and possibly dietary adjustment (ES). The PARP inhibitors carry a theoretically significant risk of myelodysplastic syndrome (MDS, sometimes called “preleukemia”); so far, there have been no cases reported in the OlympiAD trial, but cases have been reported elsewhere. Chemotherapy can also cause MDS by damaging DNA. So the comparative data in clinical trials of PARP inhibitors vs. chemo, are hard to interpret due to confounding variables. Neutropenia (low white blood cells) and severe symptoms were generally higher among the chemotherapy-receiving patients. As discussed last June at ASCO, Quality-of-Life measures favored olaparib.

Still, Lynparza can’t be prescribed for most U.S. breast cancer patients; the FDA approval is narrow. But the potential application of this, and other PARP inhibitors, is huge. I think it’s likely the agency will expand approval to patients with BRCA mutations found by other CLIA-certified lab, and over time, to patients who have relevant changes found within the cancers. And I expect other PARP drugs to gain approval, for breast cancer and other conditions.  

The requirement for BRCA testing by Myriad may be a source of contention, as other companies perform and sell BRCA evaluations at lower prices. On Twitter, Grazia DeMichele (“L’Amazzone Furiosa”), a breast cancer advocate and PhD student, asked why Myriad’s diagnostic test, BRACAnalysis CDx, is necessary. It’s a good question, and a potential sticking point.

Perhaps the quality of genomic testing is the issue; if different companies get different results for BRCA, the researchers, and FDA, may rightfully be choosy about who does BRCA analyses. In the OlympiAD trial, participants’ inherited BRCA status was checked or confirmed by that company (Myriad Genetics) in all but a handful of cases. Myriad is listed as a collaborator in the OlympiAD trial. Some of the OlympiAD investigators receive support from Myriad, besides AstraZeneca and other, competing companies.

Meanwhile, Merck announced its involvement in developing Lynparza for breast cancer, with trials of immune-oncology drugs, for instance. There’s lots of money at stake, obviously, possible conflicts of interest, and concerns that extend beyond this column.

A bigger deal might be how cancer patients without inherited BRCA mutations might benefit from PARP inhibitors . Of note, Rubraca has been approved for ovarian cancer patients who don’t necessarily have inherited BRCA mutations, but who have BRCA changes in the cancerous cells as determined by a companion diagnostic, Foundation Focus CDx BRCA. And Zejula, the third approved PARP drug for advanced ovarian and related tumors, does not require any BRCA testing.

The reason these PARP drugs work in some patients who lack known BRCA mutations is that their cancerous cells contain mutations leading to PARP vulnerability (considered above), or because they’ve inherited other mutations, such as in PALB-2, affecting DNA repair. To find HRD changes requires molecular evaluation of the tumors, which can be accomplished in a CLIA-certified lab.  The FDA recently approved one such diagnostic test, and will be evaluating more.

So far in the U.S., nearly 4,000 patients with advanced ovarian cancers have received Lynparza. That's according to an email I received from AstraZeneca this week. That number falls below what I would have guessed. I’m biased by my interest and exposure to information about PARP inhibitors. I don’t have the figures for prescriptions of more-recently approved Rubraca or Zejula.

The NCI estimates that 154,000 people are living with metastatic breast cancer in the United States. The proportion with metastatic disease likely differs for patients with and without BRCA mutations, and the number of metastatic cases with Her2 is unknown. For a ballpark estimate, consider: 5-10% of breast cancers arise in people with germline BRCA mutations. Very roughly, if the proportion holds (a big if): 7700 – 15,000 metastatic cases are associated with inherited BRCA mutations. Call it 10K. Another estimate: 15-20% of breast cancers are Her2+ (the proportion of metastatic cases is likely to differ). But for purposes of approximating: if 80% of metastatic cases are Her2 negative, and there’s no relationship between Her2 in tumors and BRCA status (another assumption), then around 8,000 metastatic breast cancer patients might be eligible for Lynparza, today.

One can ponder the potential application of these kinds of drugs in breast cancer, prostate cancer, pancreatic cancer, and other malignancies, and how these agents might be combined with immune-oncology and other agents. It’ll be hard (impossible) testing all of the possible permutations in conventional clinical trials.

Perhaps the PARP (and precision oncology) skeptics should see Wit, a Pulitzer-winning play by Margaret Edson about a college professor who has ovarian cancer and dies after lots of awful treatment. There’s a film version, too. Either way, that drama reveals what it’s like to get chemotherapy and feel terrible most of the time, and the pointlessness of giving toxic care that doesn’t help.

Back to the music: The Cutting Room is a small venue on East 32nd Street. While I enjoyed the N.E.D. concert, I was a bit disappointed. After I’d watched a documentary about the group, in a theater, seen every clip on YouTube, interviewed band members, and listened to some of their songs over and over, the performance wasn’t so amazing as I expected. Hype can let you down.

But it was good! The vocalist, Dr. Joanie Hope, impressed me by the strength of her voice and physicality, on-stage, in person. As did the other musicians. That night’s version of “Turn it Around,” my favorite of their songs, was fantastic. I had fun. And I wonder, if this new drug—and others—turns out to be helpful in many more cancer types, attending a concert in a giant stadium ten years from now…where thousands of cancer patients are in remission. Maybe not cured, but N.E.D.

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