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A New PARP Drug For Breast Cancer? I'm Thrilled!

This article is more than 6 years old.

Another day, another breast cancer drug with a long name and limited benefit. Or at least that’s how it might seem. Yet I am thrilled.

This month in San Antonio, Dr. Jennifer Litton presented initial findings from a randomized, open-label study of an experimental PARP inhibitor (talazoparib, Pfizer) in metastatic breast cancer. Litton is a breast cancer oncologist and clinical investigator at Houston’s MD Anderson Cancer Center. She receives research support from Astra-Zeneca, Pfizer and Genentech. She serves, without compensation, on advisory boards to both Pfizer and Astra-Zeneca. She spoke in a plenary session at SABCS, the world’s largest meeting on breast cancer.

The quick take is that talazoparib—a pill taken once daily—extends progression free survival (PFS) in patients with advanced breast cancer and inherited (germline) BRCA-1 or BRCA-2 mutations by 3 months. In the international, randomized open-label EMBRACA trial, patients taking talazoparib experienced relief of symptoms and improved quality of life, compared to chemotherapy. Although the data are not yet mature for demonstrating a benefit in overall survival (OS), the trend so far is favorable.

“I cannot compare this drug, talazoparib, to another PARP inhibitor,” Litton told me in an interview in San Antonio. “There is no head-to-head study. What I can tell you about this class of drugs is that I am impressed by how fast they work,” she said. “I’ve had patients who were so sick, and within a month, they felt better.”

The EMBRACA findings, however slight, are extremely important. What makes the report significant is, first, that it confirms the clinical usefulness of PARP inhibitors—a new type of anti-cancer medicine, so far approved only for ovarian and related tumors—in breast cancer. Last June at the ASCO meeting, Dr. Mark Robson of Memorial Sloan Kettering Cancer Center (MSKCC) presented findings from the AstraZeneca-funded OlympiAD trial of another PARP agent, Lynparza (olaparib), also in metastatic breast cancer. The drugs are not identical, but the big-picture findings are similar, so far: both pills, talazoparib and olaparib, extend PFS by 3 months and improve patients’ quality of life.

In October 2017, the FDA granted priority review to Lynparza for possible use in metastatic breast cancer in patients with inherited BRCA mutations and either triple-negative disease or hormone receptor (HR) positive, HER2 negative disease. AstraZeneca is developing Lynparza for possible use in breast cancer together with Merck, through a partnership announced last summer. Word from the FDA is expected early in 2018.

Before writing more, I should clarify that 3 months of PFS is not the reason why I am thrilled about using these drugs in breast cancer. Far from it; metastatic cancer patients need and want medicines that are curative or will keep them alive, and in good shape, for years and years. The value shown in both trials, EMBRACA and OlympiAD, is that either of these pills, taken as a single agent, caused tumors to shrink and staved off progression. One can only imagine the power of these medicines when tried, carefully, in combination with other agents, as is happening in trials ongoing and planned. This is just a start.

The other explanation for my enthusiasm is that these drugs will not only benefit patients who inherit BRCA mutations; the potential for PARP inhibitors to help is broader. Last March, a report in Nature Medicine suggested that as many as 22% of all breast tumors harbor genetic changes that render the cancers vulnerable to PARP inhibition. So we’re talking 1 in 5 metastatic breast cancer patients, ballpark, who might benefit from this kind of drug.

Because mutations in DNA repair genes, including BRCAPALB2ATM, and other molecules that confer sensitivity to PARP drugs can arise within tumors—apart from inherited DNA—these findings bear on the need to evaluate all advanced tumors by molecular profiling with next-generation sequencing, a topic now under consideration at the Centers for Medicare and Medicaid Services (CMS). Without access to that kind of information, many patients with PARP-sensitive cancers who lack known BRCA-associated risk, and their oncologists, will remain unaware that this kind of drug, less toxic than chemotherapy, might help.

Photo by © SABCS/Scott Morgan

Pfizer sponsors the EMBRACA trial. The study involves 431 patients, women and men, with stage 4, metastatic breast cancer and confirmed, germline BRCA-1 or BRCA-2 mutations. Eligible patients have either triple-negative or hormone receptor (HR) positive, HER2 negative pathology. Participants were randomized 2:1 to receive talazoparib pills, once daily, or a standard chemotherapy selected by the physician. The physicians’ treatment choice (PCT) could be any of these single-agent cytotoxic chemotherapies: capecitabine, eribulin, gemcitabine, or vinorelbine.

This EMBRACA trial includes a wide range of breast cancer patients. Median age was 46 years at enrollment (range 24-88 years). A nice detail is that this study includes patients with a history of brain metastases, a group sometimes excluded from clinical trials of experimental cancer drugs. The subgroup with brain metastases, approximately 15% of EMBRACA trial registrants, are being evaluated prospectively in a planned subgroup analysis. The study’s primary endpoint is PFS. Key secondary endpoints include overall survival (not yet mature), objective response rate (ORR), duration of responses, and quality-of-life (QoL) scores assessed by the EORTC QLQ-C30 and QLQ-BR23, a breast-cancer specific QoL questionnaire.

The early results are extremely encouraging, Litton told me in San Antonio. “I’m excited that we met the study’s primary endpoint of progression-free survival. But I’m excited about the possibility for an overall survival benefit too.” That remains to be seen, she clarified. “This is just an interim look. But the PFS curves separate early and ‘quite a bit,’” she observed. “Quite a few patients are still on talazoparib, alone. There’s a tail on the curve.”

In the paper Litton presented in San Antonio (abstract GS6-07), the difference in PFS with talazoparib emerged early, after just 11.2 months of median follow-up. The PARP inhibitor nearly halved the chances of breast cancer’s progression, compared to chemotherapy. Objective, measurable tumor responses were 62.6% for patients on talazoparib vs. 27.2% for chemotherapy. The most frequent toxicity of talazoparib is blood-related, and primarily anemia; over a third of patients experienced grade 3 anemia. Alopecia (hair loss) affected 25% of those on talazoparib, but was reportedly mild in all cases. The study is ongoing.

“Overall toxicity was higher for patients taking chemo,” Litton said. Fatigue (tiredness) was similar for patients in both arms of the trial. “Neutropenia (low white blood cells> was actually higher in the chemotherapy arm,” she said. “Gastrointestinal problems and ‘hand-foot syndrome,’ which is painful, were more common among patients receiving chemotherapy, she said. “The concern with PARP inhibitors is the risk of myelodysplastic syndrome or AML <acute myelogenous leukemia>, which we did not see in the talazoparib arm,” she said. “But it would be too early see that,” she acknowledged.

“I think the paradigm for using chemo first to treat advanced disease may change, as we gain experience with these drugs,” Litton told me in San Antonio. “We should be thinking of talazoparib as an excellent option for patients with advanced disease,” she said. The advantages are obvious, she stated: “Patients are not sitting in the chemo chair. Instead, they’re taking the pill once a day. That’s a big difference.”

Lynparza (olaparib) was the first of three PARP inhibitors to receive FDA approval so far, and for that reason is probably most familiar to clinicians. It was originally approved in December 2014 for advanced and refractory ovarian tumors in women with known or suspected BRCA mutations. The indications have since expanded. Rubraca (rucaparib, Clovis Oncology) was next approved, in December 2016, and has demonstrated activity as maintenance treatment. It is approved for treatment of advanced and refractory ovarian tumors with germline or acquired BRCA mutations (as assessed by a Foundation Medicine test for aberrations within the tumor). Zejula (niraparib, Tesaro) was the third entry in this market, approved in March 2017 for relapsed and recurrent ovarian, fallopian tube & related cancers “that have demonstrated sensitivity to platinum-type chemotherapy.” Its prescription does not require BRCA abnormalities.

Pfizer asserts that talazoparib differs from the other PARP inhibitors based on a “highly potent dual-mechanism” of inhibition; based on preclinical data, this agent is said to block PARP enzymatic activity and also to trap PARP on single-strand DNA breaks. Whether or not that difference is true, the clinical advantage or disadvantage relative to other PARP inhibitors cannot be inferred. What is clear from the EMBRACA study, reported, is that the drug helps keep some advanced breast tumors in check.

Also this month, Litton and colleagues published an early-phase study on talazoparib as a single agent in the neoadjuvant setting for patients with BRCA mutations and relevant breast pathology. “Decreases in tumor volume occurred in all patients following 2 months of talazoparib,” for the first 13 patients who enrolled. The median drop in tumor volume was 88% (range 30-98%). “Given the rapid rate of accrual, profound response and favorable toxicity profile, the feasibility study was modified into a phase II study to determine pathologic complete response rates after 4-6 months of single-agent talazoparib,” the authors concluded. The drug’s activity, as a single agent, seems evident.

In late October 2017, I spoke with Dr. Mark Robson about the potential use of olaparib (Lynparza) in breast cancer.  Robson is a medical oncologist who leads the breast cancer service and directs the clinical genetics service at MSKCC in New York. He has received consulting fees and honoraria from AstraZeneca, grant support to his institution from AbbVie and Biomarin/Medivation (the company from which Pfizer purchased talazoparib), and research support paid to his institution from Myriad Genetics and Invitae. We discussed the OlympiAD trial results, which he and colleagues reported in the NEJM, and whether an extra 3 months of PFS represents a meaningful benefit for advanced cancer patients.

“These drugs do have a cost,” Robson said. “Progression free survival is not a cure,” he considered. “But I would argue that freedom from progression with limited toxicity is a worthwhile outcome for cancer patients, such as we’re seeing with PARP inhibitors used in ovarian cancer.”

“When you’re a physician taking care of a patient, and you think they’re going to benefit, it’s a little hard to say oh it’s too expensive," Robson said. "My responsibility is to do the best thing I can for the person who’s sitting in front of me.”

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Broadly considered—and in context of other agents discussed at the San Antonio conference, such as the CDK4/6 inhibitors about which I wrote last week—the findings raise general questions about doctors’ prescriptions, and if patients with metastatic breast cancer still need jump through the toxic hoops and costs of chemotherapy, of taking standard old drugs that are ineffective, and instead might skip all that and go directly to targeted pills like these, if the tumor characteristics match.

All of this will require more careful testing of patients’ tumor pathology, for BRCA and other aberrations, and more education of doctors, so that they might know and understand what kind of drugs will help their patients. The field is moving forward quickly, though not fast enough.

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