More research needed to realize true benefit of PARP inhibitors in breast cancer
NEW YORK — The effectiveness of PARP inhibitors demonstrate a proof of principle that targeting DNA repair pathways can be a productive treatment strategy, but more research is necessary to extend their benefit, according to a presenter at Chemotherapy Foundation Symposium.
“Single-agent therapy benefit so far has only been demonstrated in patients with germline BRCA mutations. We don’t have data yet regarding somatic BRCA mutations in breast cancer,” Mark Robson, MD, chief of the breast medicine service at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Cornell Medicine, said during a presentation. “We have to do a lot more work to extend the benefit both in the germline population and in other populations.”
Several PARP inhibitors are in clinical development, with most research focusing on their use in breast, ovarian and prostate cancers.
Two of these agents — olaparib (Lynparza, AstraZeneca) and talazoparib (Pfizer) — are most relevant for breast cancer.
“These have different pharmacokinetic and pharmacodynamic properties, particularly with regard to potency and potentially regarding mechanisms relevant to activity, but whether there are any clinically relevant differences remains unclear,” Robson said.
OlympiAD was the first phase 3 study to establish the benefit of PARP inhibition in in breast cancer.
The trial included women with HER2-negative metastatic breast cancer who had pathogenic or likely pathogenic germline mutations in BRCA1 or BRCA2 and underwent prior treatment with anthracyclines and taxanes.
Researchers randomly assigned women to the olaparib tablet formulation dosed at 300 mg twice daily or physician’s choice of chemotherapy.
PFS served as the primary endpoint. Secondary endpoints included time to second progression or death, OS, objective response rate, safety and tolerability, and global health-related quality of life.
Results presented at ASCO Annual Meeting in 2017 showed olaparib conferred a statistically significant PFS benefit, which translated to an absolute benefit of approximately 2.8 months. However, interim analysis showed no statistically significant OS benefit with olaparib.
A final OS analysis, conducted at about 63% data maturity, continued to show no statistically significant improvement in OS in the overall cohort.
Preplanned subset analyses suggested a potential OS advantage for women who had not received prior chemotherapy for metastatic disease.
“These data certainly are hypothesis generating rather than definitive,” Robson said.
Olaparib appeared relatively well tolerated, with the “most differentiating” toxicities being gastrointestinal events, Robson said. These primarily consisted of grade 1 or grade 2 nausea and vomiting.
Grade 3 adverse events were uncommon. The most significant in the olaparib group was anemia (16%), with 18% of patients requiring transfusions. Neutropenia and febrile neutropenia “were quite rare,” Robson said.
The phase 3 EMBRACA included 431 patients with advanced breast cancer with a germline mutation in BRCA1 and BRCA2.
Researchers randomly assigned patients 2:1 to talazoparib 1 mg once daily (n = 287; median age, 45 years) or physician’s choice standard single-agent chemotherapy (n = 144; median age, 50 years) — which included capecitabine (44%), eribulin (40%; Halaven, Eisai), gemcitabine (10%) or vinorelbine (7%) — in continuous 21-day cycles.
All patients previously received no more than three cytotoxic regimens for the treatment of advanced breast cancer.
Results showed a statistically significant improvement in PFS — the study’s primary endpoint — with talazoparib, but no improvement in OS at interim analysis.
“You might think perhaps there seems like some separation in the curves occurring later on, so we will wait for the final overall survival analysis. That could be interesting,” Robson said.
Both the OlympiAD and EMBRACA studies showed benefit in terms of time to deterioration of health-related quality of life, which is “highly relevant” in the metastatic setting, Robson said.
“An interesting question becomes: What are the differences between these two studies,” Robson said. “There really isn’t much difference between the two.”
PFS and tolerability were comparable in the PARP inhibitor groups in both trials, as were response rates.
“I would emphasize that the response rates are high with single-agent PARP inhibition at around 60%,” Robson said. “Perhaps there might be a difference in overall survival but that remains to be seen and, of course, neither of these studies were tremendously powered for that particular endpoint.”
Importantly, researchers observed no cases of myelodysplasia or acute myeloid leukemia in the PARP inhibitor groups in either trial.
“This has been something of considerable concern, particularly in ovarian cancer studies where there have been a couple cases reported,” Robson said.
An important clinical question to emerge in the past year is whether to use PARP inhibition or platinum.
The randomized TNT trial compared carboplatin with docetaxel as first-line treatment for patients with triple-negative breast cancer. A preplanned analysis of patients with germline mutations in BRCA1 or BRCA2 showed longer PFS and higher ORR with carboplatin.
However, a comparison of outcomes among patients with BRCA-mutated disease in the OlympiAD, EMBRACA and TNT trials revealed comparable PFS and ORR.
“Cross-trial comparisons, of course, are always dangerous, so we have to take this with a grain of salt,” Robson said. “Nonetheless, there are no obvious differences. The response rates are perhaps a little bit better with platinum but, again, we’re talking about the first-line setting vs. a mixed group of first and second line.”
Robson also addressed another key question: Why don’t PARP inhibitors work better?
“There is an extremely strong biologic rationale for why these drugs should be effective in a BRCA-deficient [setting],” Robson said. “And yet, we don’t have anything close to 100% response rates. The durations of response and PFS are not what we would hope for them to be. This, unfortunately, is not Gleevec for breast cancer.”
There has been considerable research into PARP resistance, and that must continue, Robson said.
“We need to be able to identify biomarkers, both for initial intrinsic resistance and for developed resistance,” Robson added. “[We also] potentially should look into other combination strategies to try to mitigate the development of resistance so we can realize the true benefit of these compounds.” – by Mark Leiser
For more information:
Robson ME. Putting PARP inhibitors into practice in breast cancer. Presented at: Chemotherapy Foundation Symposium; Nov. 7-9, 2018; New York.
Robson reports consultant/advisory board roles with AstraZeneca and McKesson; honoraria/travel from AstraZeneca and Pfizer; research funding to his institution from AbbVie, AstraZeneca, Medivation and Tesaro; and in-kind research support from Invitae and Myriad.