Leisha A. Emens, MD, PhD
Germline mutations in the breast cancer–susceptibility genes 1 and 2 (BRCA1/2) increase the risk for cancer due to an inability to repair DNA double-strand breaks, and about 5% of patients with unselected breast cancer carry a germline BRCA mutation.1 These DNA repair–deficient tumors are dependent on the enzyme poly ADP-ribose polymerase (PARP) to repair single-strand DNA breaks. Thus, inhibition of PARP in cancers with a BRCA1/2 mutation results in the accumulation of DNA damage that cannot be repaired, leading to tumor cell death.2
PARP inhibitors work in two major ways: (1) by inhibiting the enzymatic activity of PARP; and (2) by trapping PARP at the sites of DNA damage. Preclinical studies suggest that PARP trapping on DNA may induce cancer cell death more efficiently than catalytic inhibition of PARP.2
Of the PARP inhibitors currently either approved for clinical use or under clinical investigation (olaparib [Lynparza], talazoparib, niraparib [Zejula], rucaparib [Rubraca], and veliparib), talazoparib is the most potent in preclinical studies. It not only has strong catalytic inhibition, but it also traps PARP at levels 100-fold higher than other PARP inhibitors.2,3 Talazoparib showed promising evidence of safety and clinical activity in early trials, leading to its evaluation in the phase III EMBRACA study, conducted by Litton and colleagues4 and reviewed in this issue of The ASCO Post.
Closer Look at EMBRACA Findings
In the open-label trial, 431 patients with advanced triple-negative or hormone receptor–positive breast cancer and a centrally confirmed germline BRCA1/2 mutation were randomized 2:1 to receive talazoparib or protocol-defined standard single-agent chemotherapy (capecitabine, eribulin (Halaven), gemcitabine, or vinorelbine) or physician’s choice. Patients could have received up to 3 lines of prior cytotoxic therapy for advanced breast cancer and must have had a disease-free interval of at least 6 months from the last dose if they received a platinum in the neoadjuvant or adjuvant setting. The primary endpoint was progression-free survival in the intent-to-treat population, and secondary endpoints included overall survival, objective response rate, clinical benefit rate at 24 weeks, and duration of response. Safety and patient-reported outcomes were also evaluated.
PARP inhibitors represent an important addition to treatment options for patients with advanced breast cancer who have a deleterious germline BRCA mutation.— Leisha A. Emens, MD, PhD
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With a median duration of follow-up of 11.2 months, talazoparib improved progression-free survival by 3 months and reduced the risk of disease progression or death by 46%. This benefit was similar in all clinically relevant patient subgroups. Talazoparib also improved the objective response rate by 35.4%. Overall survival data remain immature. As expected, myelosuppression was more significant with talazoparib than with chemotherapy, with grade 3 or 4 hematologic adverse events at 55% vs 38%. Notably, these adverse events with talazoparib were mostly laboratory findings without significant clinical sequelae, and they were managed with dose reduction or delays, rather than drug discontinuation. Patient-related outcomes were significantly better with talazoparib than with chemotherapy.
These results are similar to those of the phase III OlympiAD study, which showed that olaparib improved progression-free survival by 2.8 months and reduced the risk of disease progression or death by 42%.5 Based on these OlympiAD data, in January 2018, the U.S. Food and Drug Administration approved olaparib for the treatment of patients with advanced HER2-negative breast cancers with a germline mutation in BRCA1/2 previously treated with chemotherapy.
Unanswered Questions: Selecting Patients and Sequencing Treatments
The EMBRACA and OlympiAD studies both required confirmation of a deleterious germline BRCA mutation by central testing, and olaparib is approved for breast cancer based on this predictive biomarker. Further refinement of biomarkers that predict the clinical activity of PARP inhibitors should identify patients who derive the most clinical benefit from them. Litton and colleagues noted that a subgroup of patients in the EMBRACA trial had durable responses to talazoparib that were not seen with standard chemotherapy. Studies of blood and tissues from these patients may identify biologic signatures associated with these exceptional responses. In addition, mutations in other proteins involved in DNA repair may create a “BRCA-like” phenotype that can predict response to PARP inhibition, expanding the use of PARP inhibitors to tumors that are deficient in DNA repair but do not carry a germline BRCA mutation.
Developing combination therapies that add PARP inhibitors to chemotherapy, other targeted agents, or immunotherapy to capitalize on potential therapeutic synergy is an area of active investigation.— Leisha A. Emens, MD, PhD
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As noted by Litton and colleagues, small clinical studies have reported response rates of 68% to 80% with single-agent platinum-based chemotherapy in patients with advanced breast cancer who have a germline BRCA mutation.6,7 The response rates for olaparib and talazoparib are similar, at 60% and 62.6%, respectively. About 28% of patients in the OlympiAD study and about 20% of patients in the EMBRACA study received platinum agents prior to trial participation, and about one-third of patients in both studies received platinum agents after trial participation.
The optimal sequencing of PARP inhibitors with platinum-based chemotherapy, and potentially with each other, remains an open question. Neither OlympiAD nor EMBRACA included platinum therapy as an option in the chemotherapy arm, and clinical trials directly comparing the clinical activity of PARP inhibitors and platinum-based chemotherapy are needed. In addition, developing combination therapies that add PARP inhibitors to chemotherapy, other targeted agents, or immunotherapy to capitalize on potential therapeutic synergy is an area of active investigation. Even with these open questions, it is clear that PARP inhibitors as a drug class represent an important addition to treatment options for patients with advanced breast cancer who have a deleterious germline BRCA mutation.■
Dr. Emens is Professor of Medicine at the UPMC Hillman Cancer Center in Pittsburgh.
DISCLOSURE: Dr. Emens has served as a consultant/advisor to Syndax, Molecuvax, Bayer, Peregrine Pharmaceuticals, etheRNA, Gritstone Oncology, AbbVie, MedImmune, Replimune, Macrogenics, and Novartis; has received research funding from Genentech, Roche, Maxcyte, Aduro Biotech, AstraZeneca, EMD Serono, Merck, and Corvus Pharmaceuticals; has received travel expenses from Bristol-Myers Squibb, Genentech, and Roche; and owns stock in Molecuvax.
Jennifer K. Litton, MD
As reported in The New England Journal of Medicine by Jennifer K. Litton, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, the phase III EMBRACA trial has shown significantly improved progression-free survival with the poly (ADP-ribose)...!-->!-->