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AstraZeneca Outlines Precision Medicine Strategy for DNA Damage Response Portfolio

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CHICAGO (GenomeWeb) – Ovarian cancer patients with BRCA mutations lived nearly five months longer when they took AstraZeneca's Lynparaza (olaparib) as a means to stave off the disease and some of them have been on the drug for at least five years, researchers reported at the American Society of Clinical Oncology's annual meeting held here this week.

The data is part of AstraZeneca's strategy to expand the uses of Lynparza, as well as build an entire portfolio of products that target DNA damage response.

Mondher Mahjoubi, senior VP of AstraZeneca's global product strategy in oncology, said during a briefing at the meeting that the firm at one time was a leader in oncology, bringing to market targeted drugs such as Iressa (gefitinib) in 2003. Although the company shifted its priorities away from cancer for some years, AstraZeneca began building up its capabilities in this space four years ago when Pascal Soriot became CEO.

According to Mahjoubi, AstraZeneca is directing its development efforts in cancer across four areas: drugs that target the genetic drivers of resistance, treatments that interrogate DNA damage response, immunotherapeutics, and antibody drug conjugates. "A common pattern of our investment in oncology is through precision medicine and the development of companion diagnostics that can help identify the subset of diseases and the patients who will benefit the most from these treatments," he added.

AstraZeneca's first success toward this overarching strategy came with the US Food and Drug Administration's approval of Lynparza at the end of 2014 for advanced ovarian cancer patients who have received three or more prior chemotherapy agents, and have germline BRCA mutations. Simultaneously, the agency approved Myriad Genetics BRACAnalysis CDx to detect women who had BRCA mutations and are likely to benefit from treatment. 

The FDA granted accelerated approval for Lynparza after AstraZeneca submitted data from a single-arm, 137-participant trial, where 34 percent of heavily pretreated patients had an objective response to Lynparza that lasted for an average of 7.9 months. Myriad spokesperson Ron Rogers told GenomeWeb that using BRACAnalysis to identify best responders to Lynparza essentially rescued the entire PARP inhibitor class that had largely been "written off."

Since precision medicine is an important strategic focus at the company, AstraZeneca is also diversifying it CDx strategy. This week, AstraZeneca announced that it had inked a deal with Foundation Medicine to develop a next-generation sequencing based companion diagnostic for Lynparza that will detect alterations in a panel of genes associated with homologous recombination repair (HRR) pathways involved in fixing DNA double-stranded breaks. According to AstraZeneca, Foundation's test will help its efforts to expand Lynparza's indication into molecularly defined patient subpopulations beyond patients with germline BRCA mutations, as well as identify best responders to other DNA damage-response drugs and combination therapies it is exploring.

Lynparza expansion

Before the FDA approved Lynparza in 2014, AstraZeneca was seeking approval for it as maintenance therapy for BRCA mutation-positive ovarian cancer patients who responded to platinum-based chemotherapy. Earlier that year, however, based on the results of Study 19, the FDA's Oncologic Drugs Advisory Committee recommended the agency wait for mature overall survival data and not grant accelerated approval for the drug in this indication.

In Study 19, in the BRCA mutated population, median progression-free survival was 11.2 months and 4.3 months for those receiving Lynparza versus placebo. As of the November 2012 data cut off, there wasn't a significant difference in survival between the arms in the overall study population or in the BRCA mutated subpopulation.

At the meeting this week, researchers from AstraZeneca updated data from Study 19 after more than three-quarters of the clinical trial participants had died. Median overall survival was 29.8 months and 27.8 months for patients on Lynparza versus placebo in the overall study population, and 34.9 months versus 30.2 months in the BRCA-mutated population. Median overall survival was 24.5 months in the Lynparza-treated arm and 26.6 months in the placebo group in BRCA wild-type patients.

Study 19 wasn't designed to show statistical significance, said Jonathan Ledermann from the University College London Cancer Institute, who presented the data at the meeting. Importantly, he noted that as of September 2015, there were 15 patients still on Lynparza, approximately half of whom had BRCA mutations, and one patient on placebo who had a BRCA mutation. This represented "unprecedented long-term exposure" to Lynparza in the ovarian cancer maintenance setting, he noted.

Ovarian cancer is usually detected after it has metastasized, and therefore the five-year survival rate is 45 percent. The long-term survival data in this study "gives a sense of the benefit Lynparza can bring to women with ovarian cancer," Mahjoubi said. "There are patients who are on treatment for more than six years with Lynparza."

While this study represents only one step toward AstraZeneca's overall goal to expand Lynparza's indication into earlier ovarian cancer indications, as well as into breast, pancreatic, and prostate cancers, Mahjoubi highlighted during the briefing that the drugmaker has an entire portfolio of drugs that target DNA damage response mechanisms.

DNA damage normally occurs in the cells of our bodies thousands and thousands of times, and our bodies have various mechanisms that check for this damage and repair it to ensure cells continue to replicate and divide as they should. But DNA damage is often involved at the start of cancer, which takes out some of the pathways cancer cells use to check for damage and repair DNA. But these errors only cause further DNA errors that actually help tumor cells proliferate.

AstraZeneca wants to take advantage of this biology and develop drugs that take out the remaining pathways cancer cells are relying on for DNA repair and disable their ability to check for damage, so they are overwhelmed by DNA damage and die. These drugs theoretically would limit toxicities by sparing non-tumor cells with normally functioning DNA repair mechanisms.

AstraZeneca estimates that up to 50 percent of common cancers have errors in one of their DNA repair pathways. "Despite the fact Lynparza has been approved and everyone's very excited about it, when people think about the commercial potential or medical potential, [they believe that] germline BRCA defects are relatively infrequent, so this is going to be a relatively small opportunity," Susan Galbraith, VP of oncology at AstraZeneca, said at the briefing. "That's not true."

The firm is developing AZD1775, which inhibits WEE1, a kinase that regulates cell cycle. Overexpression of this protein pauses cell cycle so tumor cells can repair DNA damage and continue to thrive. Other drugs in AstraZeneca's DNA damage response program include an ATM kinase inhibitor AZD0156, an ATR kinase inhibitor AZD6738, and an aurora B kinase inhibitor AZD2811 that it is developing in collaboration with Bind Therapeutics.

The drug firm is betting there is much potential in combining DNA damage response-targeting drugs with each other, with targeted agents, and with immunotherapies. For example, AstraZeneca is studying Lynparza with its WEE1 inhibitor, and with its anti-PD-L1 immunotherapy durvalumab.

"Germline BRCA is just the starting point, a proof of principle if you like," Galbraith said. "It is not the limit to the potential for such drugs."

Universal companion diagnostic

In Study 19, researchers used Myriad's BRACAnalysis to determine BRCA mutations in the germline and Foundation Medicine's NGS test to determine BRCA mutation status in tumors for 96 percent of 265 patients. In the study, researchers are continuing to investigate the responses of patients who didn't have BRCA mutations to see if other mutations in the homologous recombination repair pathway are impacting response to Lynparza.

Lynparza's approval in 2014 was important for the treatment of ovarian cancer, said Gordon Mills, co-director of the Zayed Institute for Personalized Cancer Therapy at MD Anderson Cancer Center, because the last approved drug that made a difference for patients was in 1992. "But we need to go beyond that," and develop companion diagnostics to identify patients who are likely to respond to newly available treatment options, said Mills, who is on AstraZeneca's scientific advisory board.

Toward this end, Galbraith told GenomeWeb that AstraZeneca is collaborating with Foundation Medicine to develop a companion diagnostic that could potentially identify best responders to drugs in its entire DNA damage response portfolio.

As a first step, Galbraith said AstraZeneca wants to use Foundation's test to identify patients who will benefit from Lynparza beyond the subpopulation with BRCA mutations. Though the same panel of homologous recombination repair genes could identify patients who will benefit from other DNA damage response-targeting drugs AstraZeneca is developing, the panel may need to be expanded in the future to address other biological mechanisms that might be important, she noted.

AstraZeneca and Foundation plan to take Lynparza and the companion test through FDA approval. "The principle of getting a next-generation sequencing companion diagnostic approved by the FDA is exciting," she said. "It opens up the potential."

The drugmaker decided to move ahead with Foundation's test as a CDx based on input from its collaboration partners and the FDA. However, its choice naturally raises questions about why AstraZeneca didn't pick Myriad's myChoice HRD, which includes tissue-based BRCA1 and BRCA2 sequencing, and measures "genomic scars" through loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) in cancer cells, which reflect the extent to which a tumor has lost DNA repair abilities

Galbraith explained to GenomeWeb that when DNA repair pathways are debilitated, there are chunks of DNA that get rearranged across the genome. With Myriad's test focused on measuring genomic scars, "what you're looking at there is the result of the deficiency; what you're detecting with [Foundation's] HRR panel is the cause of the deficiency," she said.

Myriad was quick to claim the superiority of its test, however. "We have demonstrated in multiple studies that you need [to assess] all three [LOH, TAI, and LST] to identify the most number of patients who are candidates for PARP inhibitors," said Rogers.

Myriad is conducting further studies to demonstrate that its HRD test can predict treatment benefit in patients without BRCA mutations. One study presented last year at the San Antonio Breast Cancer Symposium by Roisin Connolly from Johns Hopkins School of Medicine looked at the ability of myChoice HRD to predict pathologic complete response in early-stage breast cancer patients who had received preoperative carboplatin and paclitaxel, plus or minus Zolinza (vorinostat). In that study, even when researchers considered 40 patients without BRCA mutations, 64 percent of those with a high myChoice HRD score had pathologic complete response compared to 8 percent of those with a low score. 

The definitive study demonstrating the HRD test's utility in non-BRCA cancers will come from a study called NOVA that Tesaro is conducting in ovarian cancer patients treated with its PARP inhibitor niraparib. This study will report soon, Rogers said. 

Although AstraZeneca has decided to go with Foundation's test to expand Lynparaz beyond patients with BRCA mutations, the drug firm is still using Myriad's BRACAnalysis CDx in five Phase III studies of Lynparza as first-line maintenance therapy for ovarian cancer, in metastatic and adjuvant breast cancers, as salvage therapy in ovarian cancer, and in metastatic pancreatic cancer.

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