In 2005, researchers in the U.K. struck upon a new way to kill cancer cells. A London-based team led by Alan Ashworth, currently head of the University of California, San Francisco’s cancer center, was working with cells harboring BRCA mutations—genetic perturbations that predispose humans to breast and other cancers. BRCA1 and BRCA2 proteins are part of the cell’s homologous recombination (HR) machinery, and help repair double-strand breaks in DNA. When they are dysfunctional, cells accumulate mutations.
Ashworth and his team wondered whether BRCA1 or BRCA2 (BRCA1/2) mutations, in addition to making a cell susceptible to cancer, also made that cell more vulnerable in the event of further damage to its DNA repair machinery. So the researchers tried targeting a different pathway in these cells—one that repairs single-strand DNA breaks, and is mediated by a family of enzymes called poly(ADP-ribose) polymerases (PARPs).
At the time, small-molecule inhibitors of PARP enzymes were being tested as a way to increase the sensitivity of cancer cells to chemotherapy and radiotherapy. But when the researchers blocked PARP proteins in cells harboring BRCA mutations, the results were striking: the cells died on the spot. “They found an exquisite sensitivity—as much as 1,000 times greater, in BRCA1/2-mutant cell lines and xenografts—to PARP inhibition, compared with BRCA wildtype cells,” says Timothy Yap, a cancer researcher at the University of Texas MD Anderson Cancer Center in Houston, who was not involved in the work, but receives funding from PARP inhibitor developers such as Pfizer and AstraZeneca.
PARP inhibitors have a clear benefit in BRCA-mutant disease.—Eileen Parkes, Queen’s University Belfast
This one-two punch—in which the loss of PARP and BRCA proteins, but not either one alone, is enough to kill the cell—is known as synthetic lethality, and its role in the 2005 findings “gave the impetus for PARP inhibitors to be tested in trials as single agents” in BRCA-mutated tumors, notes Christopher Lord, a cancer researcher specializing in genomics at the Institute of Cancer Research, London who holds patents on PARP inhibitors and has received payments for work with AstraZeneca and other drug developers. That same year, AstraZeneca began trials with a PARP inhibitor called olaparib (Lynparza); the drug was approved by the Food and Drug Administration (FDA) in late 2014 for advanced, pretreated BRCA-mutated ovarian cancer, and just this January, the same compound became the first drug to be approved for BRCA-mutated breast cancer.
A flurry of recent studies with PARP inhibitors have shown that the drugs can also kill cancer cells that harbor mutations in other genes involved in DNA repair processes. Such findings offer the hope of improving the prognoses of treatment-resistant cancers, including pancreatic and prostate cancer, and are changing the way researchers view these diseases.
Of course, it’s not been all successes. The recent failures of several Phase 3 clinical trials have revealed cracks in researchers’ understanding of PARP inhibitors’ exact mode of action. But with three PARP inhibitors FDA-approved, and at least four more in development, the sector is booming, and companies are jockeying for deals. Last July, Bristol-Myers Squibb announced plans to test Clovis Oncology’s PARP inhibitor rucaparib (Rubraca) in combination with one of its own anticancer drugs in Phase 2 and 3 trials in multiple tumor types in the U.S. and Europe. The same month, Japan-based Takeda agreed to pay US pharma company Tesaro $100 million for the rights to its PARP inhibitor, niraparib (Zejula), approved in the U.S. a few months previously. In short, says Yale University radiologist Ranjit Bindra, “the PARP inhibition era is unbelievably exciting.”
Beating back BRCA cancers
Ovarian cancer has historically proven stubbornly resistant to conventional treatment. But “recent trials are changing the landscape, and clinical practice, in ovarian cancer,” says Shannon Westin, a gynecologic oncologist at MD Anderson Cancer Center, who has consulted for AstraZeneca, Clovis, and other PARP drug developers. In a study published last year, for example, olaparib held advanced disease in check for more than 19 months in patients with BRCA1/2 mutations who had previously responded to platinum-based chemotherapy—more than three times longer than in patients taking a placebo (Lancet, 18:1274-84, 2017). The FDA approved olaparib last August for maintenance treatment to slow or prevent the return of disease in BRCA-mutated ovarian cancer. For women with BRCA mutations, who account for up to 15 percent of ovarian cancer patients, “the results are very impressive,” Westin says.
Other PARP inhibitors are making gains against ovarian cancer, too. Following promising results across two Phase 2 trials, rucaparib received approval in December 2016 for patients with germline or somatic BRCA mutations who had received two or more previous chemotherapy treatment regimens. And last year’s results from Clovis’s Phase 3 trial found that, compared to a placebo, the drug more than tripled progression-free survival in women with BRCA-mutated tumors. “Rucaparib has really been a breakthrough in treatment for ovarian cancer,” says Eileen Parkes, a clinical lecturer at the Centre for Cancer Research and Cell Biology at Queen’s University Belfast, who was not involved in either study. Just last March, the FDA approved niraparib for maintenance treatment for multiple types of ovarian cancer in patients who had responded to platinum-based chemotherapy, making it the third PARP inhibitor to get the green light for that indication.
PARP inhibitors are also showing progress in the fight against BRCA-mutated breast cancers. At last summer’s American Society of Clinical Oncology meeting, researchers from the University of Pennsylvania presented the results of a Phase 3 trial showing that, compared to chemotherapy, olaparib nearly doubled progression-free survival—to seven months—in patients with HER2-negative breast cancer with BRCA mutations (NEJM, 377:523-33, 2017). In light of these findings, the FDA extended olaparib’s approval at the beginning of 2018 to include germline BRCA-positive, HER2-negative metastatic breast cancer for patients who have previously received chemotherapy—making the drug the first PARP inhibitor approved for breast cancer, and the first breast cancer therapy to target a germline BRCA mutation.
There are signs of more progress on the horizon. Pfizer is currently developing a “second generation” PARP inhibitor, talazoparib, which has shown much higher cancer cytotoxicity than rucaparib and olaparib in preclinical research. In a recent Phase 3 trial for multiple BRCA-mutated breast cancers, the drug significantly extended the time until relapse compared with standard chemotherapy. Patients also reported substantial improvements in their quality of life. Although there are some concerns about small (less than 2 percent) increases in the risk for complications such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with certain PARP inhibitors, overall, “PARP inhibitors have a clear benefit in BRCA-mutant disease,” says Parkes, “and their toxicity profiles are much kinder than other currently available treatments.”
From BRCA to BRCAness
Cancer cells harboring damage in other genes involved in DNA repair also appear to be vulnerable to the drugs. Scientists call this genetic vulnerability of certain tumors BRCAness. From a therapeutic perspective, “cancers that have BRCAness may also respond to similar therapeutic approaches as BRCA-mutated tumors,” says Lord.
BASED ON NEJM, 361:189-91, 2009/THE SCIENTIST STAFF
Exploiting BRCAness could significantly expand the range of patients treatable with PARP inhibitors. For example, while a little more than 20 percent of patients with high-grade serous ovarian carcinoma—the most common and most aggressive subtype of ovarian cancer—carry BRCA mutations, a further 30 percent have defects in other genes involved in the HR pathway, such as PALB2, FANCD2, and RAD51. All told, “we now have a broad population, about 40 percent of ovarian cancer patients, who will respond to these drugs,” Westin says. Tumors with defects in yet other DNA repair genes such as PTEN, which is often mutated in brain, breast, and prostate cancers, are also considered to display BRCAness, opening up the possibility of treating these cancers with PARP inhibitors as well.
Recent clinical research suggests the strategy may be successful. Results from niraparib’s 2016 Phase 3 trial signaled a watershed moment in PARP inhibitor development because it showed efficacy in all patients, regardless of BRCA status, indicating they likely had damage in other, unidentified DNA repair pathways. And following its 2017 trial, Clovis announced that rucaparib worked almost as well in BRCA-wildtype ovarian cancer patients as it did in women with BRCA mutations.
Some researchers hypothesize that, to be clinically effective, PARP inhibitors must have dual mechanisms of action.
Preclinical results show similar promise for other PARP inhibitors in targeting non-BRCA DNA-repair mutations. In patient-derived mouse xenografts with triple-negative breast cancer (TNBC), researchers at MD Anderson discovered that talazoparib produced shrinkage not only in tumors with BRCA mutations, but also in BRCA-wildtype tumors that had mutations in other HR genes such as ATM (Clin Cancer Res, 23:6468-77, 2017). For the study, Funda Meric-Bernstam and colleagues tested a number of anticancer drug types, including inhibitors of the mTOR pathway that regulates the cell cycle, but found that only talazoparib produced significant tumor regression. Meric-Bernstam, whose research is partly funded by AstraZeneca and other PARP inhibitor developers, tells The Scientist that the team is now developing newer models to home in on PARP inhibitor sensitivity in these and other cancers that might display BRCAness.
Bindra’s group, meanwhile, recently uncovered an unexpected sensitivity to PARP inhibition in tumors harboring mutations in IDH1 or IDH2, genes that code for enzymes involved in processing lipids and other molecules in the cell cytoplasm. Although the proteins are not directly involved in DNA repair, the team found that defective IDH enzymes produce a compound called 2-hydroxyglutarate that inhibits HR, conferring BRCAness on those cells. While IDH inhibitors have not been effective in IDH-mutated cancers such as glioma and acute myeloid leukemia, Bindra found in murine xenografts that these cancers did respond to treatment with olaparib (Sci Transl Med, 375:eaal2463, 2017). The findings offer a new path to treatment for these cancers using PARP inhibitors, he tells The Scientist. “Exploiting this DNA repair deficiency, rather than inhibiting the function of mutant IDH proteins, may be a better strategy for treating brain and other tumors with these mutations.”
Mixing and matching
Cancer treatment almost always involves combining therapies to block multiple pathways and reduce resistance (see “Make Me a Match” here). But combining PARP inhibitors with chemotherapy—usually the first-line treatment against cancer—has proven to be problematic, producing mixed results, with varying side effects, including bone marrow toxicity, says Westin. Instead of broad-effect chemotherapy drugs, “combinations with targeted drugs are most exciting,” she says.
Last year, the University of Pennsylvania’s Susan Domchek presented results of a Phase 2 trial on the combination of olaparib and the programmed death ligand-1 (PD-L1) inhibitor durvalumab, an immunotherapy. Around 80 percent of patients with pretreated germline BRCA- and HER2-negative metastatic breast cancer responded to the drugs, and 70 percent remained progression-free at 12 weeks. A Phase 2 trial is planned to test this same combination in TNBC patients. And Fatima Karzai of the National Cancer Institute (NCI) and colleagues reported a 50 percent response rate with the same two drugs in patients with castration-resistant metastatic prostate cancer. All patients with this type of cancer produce abundant amounts of PD-L1, and about 30 percent have germline or somatic mutations in DNA-repair genes, making the drug duo a logical choice.
Another Phase 2 trial sponsored by the NCI found that olaparib showed better antitumor activity in combination with the angiogenesis inhibitor cediranib than it did by itself. The pair is being tested in a larger study now, says James Doroshow, director of the Division of Cancer Treatment and Diagnosis at the NCI’s Center for Cancer Research. Despite this progress, the combination of PARP inhibitors with other drugs is still in early stages, says Doroshow. “There is a lot of additional biology that needs to be explored before we can figure out which combinations will be best.”
Focusing on efficacy
Researchers are working on better understanding that biology, but just what makes an effective PARP inhibitor is still an open question. Initially, the drugs were thought only to work by blocking PARP enzymes’ catalytic activity. However, in 2012, Yves Pommier, chief of the developmental therapeutics branch at the NCI’s Center for Cancer Research and colleagues discovered a second mechanism of action, in which the inhibitors cause PARP enzymes to physically clump together on DNA and prevent repair (Cancer Res, 72:5588-99, 2012). Pommier and his colleagues found that this mechanism, which they named PARP trapping, was more deadly to cells than catalytic inhibition, and that different PARP inhibitors trap PARP-DNA complexes to different extents.
Some researchers hypothesize that, to be clinically effective, PARP inhibitors must have strong, dual mechanisms of action—that is, both catalytic and trapping activity. Pfizer’s talazoparib, for example, is thought to derive its greater potency compared to previous PARP inhibitors by more successfully trapping PARP-DNA complexes than its predecessors, while simultaneously inhibiting the enzymes’ catalytic activity. This argument was bolstered by the failure last spring of Phase 3 trials in TNBC and lung cancer patients of AbbVie’s veliparib—a PARP inhibitor now known to only weakly trap DNA. The hypothesis is controversial, however, and ignores other benefits of “weaker” PARP inhibitors, says Doroshow. “The upside of veliparib’s apparent ‘weakness’ is that it can be combined with chemotherapy and other drugs with less toxicity,” he says. Indeed, in one trial, combining veliparib with chemotherapy drugs resulted in improved response rates in TNBC (NEJM, 375:23-34, 2016).
Results such as these have highlighted questions about this still-evolving drug class, and some of the wrinkles to be ironed out in the future. For example, one key challenge researchers are now focusing on is finding effective biomarkers to identify which patients will benefit from which therapies and combinations. Nevertheless, the rapidly expanding number of trials using PARP inhibitors suggests that the drugs are therapeutically promising, leaving researchers hopeful that PARP inhibitors will change outcomes in additional patients with hard-to-treat cancers, notes Ohio State University cancer researcher David O’Malley, who has consulted for Clovis, AstraZeneca, and other drug developers. “We are starting to identify more and more patients who will markedly benefit from these drugs.”
Vicki Brower is a New York City–based freelance writer specializing in biotechnology and medicine.