NEW YORK – While Merck and AstraZeneca's PARP inhibitor Lynparza (olaparib) is already part of the standard-of-care maintenance treatment for advanced ovarian cancer, its known benefit has historically been limited to patients with ovarian cancers harboring BRCA1 or BRCA2 mutations or with genomic instability characteristic of homologous recombination repair deficiency (HRD).
Now, interim progression-free survival results from the Phase III DUO-O clinical trial, presented at the American Society of Clinical Oncology's annual meeting on Saturday, have demonstrated that patients whose tumors do not harbor BRCA1/2 mutations could also benefit from Lynparza and AstraZeneca's immunotherapy Imfinzi (durvalumab) added to standard-of-care chemotherapy and Genentech's VEGF inhibitor Avastin (bevacizumab).
The 1,130 patients enrolled in DUO-O trial were from around the world, newly diagnosed with stage III to IV high-grade epithelial ovarian cancer, and scheduled to undergo debulking surgery. Patients were prospectively enrolled based on their tumor biomarker status and randomized only if their tumors did not harbor BRCA1/2 mutations — a notable shift from many historical ovarian cancer PARP inhibitor studies.
"Previous Phase III trials have focused solely on the BRCA-mutated group or a combination of BRCA-mutated and non-BRCA-mutated advanced ovarian cancer," Carol Aghajanian, a DUO-O investigator and the chief of gynecologic medical oncology at Memorial Sloan Kettering Cancer Center, said while presenting the results at a press briefing earlier in the week before the ASCO annual meeting.
Patients enrolled in DUO-O were randomized to one of three treatment arms: standard-of-care platinum-based chemotherapy plus Avastin and a placebo followed by maintenance Avastin and two placebos; chemotherapy plus Avastin and Imfinzi followed by maintenance Avastin plus Imfinzi and a placebo; or chemotherapy, Avastin, and Imfinzi followed by maintenance Avastin, Imfinzi, and Lynparza. In all three arms, the maintenance-phase Avastin was administered for 15 months or until patients progressed. The maintenance Imfinzi and Lynparza — or their respective placebos, depending on the arm — were administered for two years or until patients progressed.
Researchers compared patients' progression-free survival in arm 3 versus arm 1, both in the non-BRCA-mutated HRD-positive patient population and then in the non-BRCA-mutant intent-to-treat population. Investigators also tracked progression-free survival in arm 2 versus arm 1 in the intent-to-treat population and assessed patients' overall survival and safety.
Among 140 patients with non-BRCA-mutant, HRD-positive tumors who received chemotherapy plus Avastin followed by Avastin-Imfinzi-Lynparza, median progression-free survival was 37.3 months, whereas among 143 patients with the same biomarker status in arm 1 who received chemotherapy plus Avastin and placebo followed by Avastin and two placebos, median progression-free survival was 23 months.
In the non-BRCA-mutant intent-to-treat cohort, which included patients regardless of HRD status, the addition of Imfinzi and Lynparza also improved progression-free survival. Among 378 patients in arm 3 who received chemotherapy and Avastin plus Imfinzi followed by Avastin-Imfinzi-Lynparza, median progression-free survival was 24.2 months. Meanwhile, in arm 1, patients who received chemotherapy plus Avastin and placebo followed by Avastin and two placebos, had median progression-free survival of 19.3 months. For patients in arm 2, who received chemotherapy plus Avastin and Imfinzi followed by Avastin and Imfinzi plus a placebo instead of Lynparza, Aghajanian noted a numeric improvement in progression-free survival versus arm 1. However, this improvement wasn't statistically significant. Patients in arm 2 lived a median of 20.6 months without their cancers progressing.
The researchers also conducted an exploratory subgroup analysis, in which they assessed outcomes among patients who didn't have BRCA1/2 mutations and were HRD negative. Here, too, there was an improvement in progression-free survival in arm 3 versus arm 1. For patients whose tumors were HRD-negative and who received chemotherapy plus Avastin followed by Avastin-Imfinzi-Lynparza, median progression-free survival was 20.9 months, versus 17.4 months among the HRD-negative patients who received chemotherapy plus Avastin and placebo followed by Avastin and two placebos.
According to Aghajanian, the treatment combination's safety profile was in line with what was expected, though slightly more patients discontinued treatment due to any adverse events in the Lynparza-containing arm 3 versus in arms 1 and 2.
Although the interim analysis reported at ASCO demonstrated a progression-free survival benefit with the PARP inhibitor and immunotherapy combination, investigators are still treating patients in the trial and tracking their overall survival and other outcomes.
Even so, Merry Jennifer Markham, the chief of the division of hematology and oncology within University of Florida Health's department of medicine, noted that in the absence of a known overall survival benefit, the progression-free survival benefit represents progress for this patient population.
"This is a huge step forward. Progress has really not been quick enough for our patients with advanced ovarian cancer," Markham said during the press briefing, adding that ovarian cancer patients are typically diagnosed in advanced stages and are told that their tumors will progress at some point. "While progression-free survival may not necessarily mean overall survival, we hope it does … [and] progression-free survival is very important to our patients," Markham said.
With regard to the focus on non-BRCA1/2-mutated patients in this trial, Markham took a moment to recognize that the results are meaningful to a population that has historically been thought of as not benefiting from PARP inhibitors.
"Women are often disappointed when they don't have a BRCA mutation, or their tumor doesn't have a BRCA mutation, because they know that that may limit some of their treatment options," she said. "To be able to have options for all-comers with advanced ovarian cancer is very meaningful. … This is something that physicians can take into the exam room when we're counseling our patients with this disease. Even though you may not have a BRCA mutation, and your tumor may not be HRD-positive, there is still hope, and there's still progress being made."
Aghajanian explained that even though BRCA1/2 mutations have often served as a proxy for HRD positivity, mutations in other genes can also cause HRD, making it difficult for cells to repair double-strand DNA breaks.
In this trial, Aghajanian highlighted that Myriad Genetics' MyChoice CDx test was used to test tumors that are BRCA1/2 wild type, and then investigators looked at whether patients' tumors behaved "like" they were BRCA1/2 mutated, indicating that they have HRD based on a different mechanism than an alteration in one of these two genes. Patients with "BRCA1 and BRCA2 mutations who receive PARP inhibitors … have a profound benefit with PARP inhibitor maintenance [therapy], and then the HRD population has a benefit but not as profound; in the HRD-negative group, you still see a benefit that's meaningful … and we think this is because our tests are imperfect," Aghajanian said.
In light of these findings, Aghajanian felt that HRD testing could help patients understand the magnitude of benefit they can hope to have with a PARP inhibitor, but it shouldn't be used to rule out whether to give patients these drugs. Even so, she was adamant that every patient diagnosed with advanced ovarian cancer should still undergo testing for BRCA1/2 germline mutations.
Concerns over Imfinzi's role, treatment costs
Although the DUO-O trial showed a benefit with Imfinzi and Lynparza, Aghajanian underscored that the complicated trial design doesn't make it possible to discern whether Imfinzi added any benefit, or if Lynparza was driving the progression-free survival improvements. Given when the trial began in early 2019 and when Lynparza was approved with Avastin as part of standard-of-care maintenance therapy for HRD-positive ovarian cancer patients the following year, the investigators couldn't answer this question.
"If we had to do [it] over again, of course we would have a fourth arm that had Avastin and Lynparza maintenance so that we could do a comparison of the relative contribution [of Imfinzi]," she said.
Both Aghajanian and Markham acknowledged that it would be valuable to answer this question, not just for the sake of better understanding why the regimen is benefiting patients but also because of the financial burden that comes with adding another expensive therapy to an already costly regimen.
"We've got expensive drugs here," Aghajanian said. The average retail price for Imfinzi is $3,889.90 per 500 mg dose, and patients on the DUO-O trial received 1,120 mg every three weeks. Lynparza's list price is $15,886.80 for a 30-day supply. Aghajanian is hopeful insurers would cover these therapies recognizing their benefit, but Markham countered that even so, the out-of-pocket cost would be prohibitive for many patients, particularly those who are uninsured or underinsured.
"I may be a little less optimistic in terms of what this looks like from an access perspective," Markham said. "I practice in the southern US, and … we run into a lot of issues with people not being able to afford their copays."
Both Aghajanian and Markham acknowledged that even before patients face high treatment costs, they can face barriers accessing biomarker testing. "Getting those BRCA1 and BRCA2 tests done and getting the HRD tests done … we do have disparities with genetic and genomic testing that need to be solved," Aghajanian said, underscoring that addressing these barriers is becoming more and more important, not just for patients with advanced ovarian cancers but also for patients with all types of cancers.