In patients with breast cancer tumors harboring BRCA1 and BRCA2 mutations, inhibitors of poly (ADP-ribose) polymerase (PARP) have emerged as essential therapeutic agents. What more needs to be done to obtain even more benefit from these targeted agents? This question was tackled at the 2022 Miami Breast Cancer Conference, sponsored by PER, by Mark E. Robson, MD, Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York.1
“Although there was no overall survival advantage to olaparib, a benefit did emerge in women not previously treated for metastatic disease.”— Mark E. Robson, MD
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BRCA1- and BRCA2-mutated tumors are sensitive to PARP inhibitors and platinum agents because they are deficient in homologous recombination repair of DNA damage. The effectiveness of PARP inhibitors demonstrates proof of principle that targeting the DNA repair pathway is a productive treatment strategy, Dr. Robson said.
Initial proof of their benefit in breast cancer came from the OlympiAD trial.2 In patients with germline BRCA-mutated HER2-negative metastatic breast cancer, treatment with single-agent olaparib led to a 42% reduction in the risk of disease progression (7.0 vs 4.2 months) over chemotherapy. Subsequently, in the EMBRACA trial, talazoparib reduced the risk of disease progression by 46% (8.6 vs 5.6 months).3 Neither trial, however, showed an overall survival advantage for the PARP inhibitor in metastatic disease.
“These results were exciting because it was a true translational achievement to go from bench to bedside with these agents,” Dr. Robson said. “However, no one is going to get particularly excited about a 3-month improvement in progression-free survival with no improvement in overall survival in the metastatic setting. So, the question becomes, how can we make this better? What are the potential strategies for improving outcome?”
Maintenance in the Metastatic Setting
“One of the things that was first thought about in the metastatic setting was the idea of doing an induction/maintenance approach, which was a ‘riff’ on what we had already observed in the ovarian cancer space,” explained Dr. Robson.
In the SOLO-1 trial, in patients with newly diagnosed advanced ovarian cancer, maintenance therapy with olaparib after induction chemotherapy led to a 70% reduction in the risk for disease progression or death (P < .001),4 a “massively different improvement” compared with what had been seen in the metastatic setting,” he said. “The question was whether this might work in patients with metastatic breast cancer.”
A hint that maintenance PARP inhibition might, indeed, work in breast cancer came from the BROCADE 3 trial.5 Patients with advanced BRCA-mutated breast cancer were randomly assigned to receive veliparib plus chemotherapy, vs chemotherapy alone, with veliparib or placebo continued as maintenance. Veliparib is not a potent PARP inhibitor, but it is the only one that could be combined with conventional chemotherapy (carboplatin plus paclitaxel), he explained.
The veliparib arm demonstrated a 2-month improvement in median progression-free survival, and a landmark analysis showed roughly a doubling in progression-free survival at 24 and 36 months. The Kaplan-Meier curves began to separate around the time the chemotherapy was discontinued, and patients remained on veliparib or placebo.
“This suggests that at least in certain circumstances, an induction/maintenance approach might be a way to combine the benefits of platinum-based therapy with the benefits of oral PARP inhibition in the metastatic BRCA-mutant setting,” Dr. Robson proposed. “We haven’t been able to prove whether this is better than just single-agent PARP inhibition, but it’s an interesting idea.”
Earlier Treatment With PARP Inhibitors
Another approach could be to use PARP inhibitors earlier in treatment. This might avoid the negative consequences of the multiple mechanisms of PARP inhibitor resistance, much of which is aimed at restoring homologous repair proficiency in the tumor.
A suggestion of benefit with this approach comes from a post hoc subset analysis of the OlympiAD trial, which examined overall survival based on previous line of therapy.6 Although there was no overall survival advantage to olaparib, a benefit did emerge in women not previously treated for metastatic disease. In that subset of patients, median overall survival was 22.6 months with olaparib and 14.7 months with chemotherapy alone (hazard ratio = 0.51; P = .02).
“This is a very small unplanned subset analysis, not adjusted for multiple other factors, but, nonetheless, it certainly is a hint that maybe giving PARP inhibitors earlier would be better,” Dr. Robson suggested.
Furthermore, a study from the MD Anderson Cancer Center examined the benefit of daily talazoparib given neoadjuvantly in 20 patients with BRCA mutations not previously treated for invasive cancer.7 More than 50% of those patients achieved a residual cancer burden (RCB) score of 0, and 60% achieved an RCB score of 0 to 1. Patients in this setting with triple-negative breast cancer, the most common subtype in BRCA1-mutation carriers, are likely now to receive checkpoint inhibitors. There are studies, however, looking at combining checkpoint inhibitors with PARP inhibitors in early-stage disease. “This might be an interesting, “chemo-free” de-escalation strategy in some patients,” he commented.
As adjuvant therapy, he continued, “the study that really hit the airwaves” was the OlympiA trial, which evaluated olaparib in 1,836 women with HER2-negative germline BRCA-mutated early breast cancer considered at high risk for disease progression.8 Patients received six cycles of conventional neoadjuvant or adjuvant chemotherapy, radiation therapy if warranted, and surgery; they then were randomly assigned to 1 year of olaparib or placebo.
The 3-year invasive disease–free survival rate was 85.9% in the olaparib group and 77.1% in the placebo group (HR = 0.58; P < .001), and the 3-year distant disease–free survival rate was 87.5% and 80.4%, respectively (HR = 0.57; P < .001). Olaparib was associated with fewer deaths than placebo—59 and 86, respectively (HR = 0.68; P = .02); however, the difference did not initially meet the statistical threshold for significance. This changed with an updated analysis presented at the ESMO Virtual Plenary, in which adjuvant olaparib was associated with a statistically significant 3.8% improvement in overall survival at 36 months.
Subgroup analyses showed that maintenance olaparib “benefits everybody,” Dr. Robson added, including patients with either estrogen receptor–positive or –negative tumors and those with prior platinum use or not. Treatment was generally well tolerated, although nausea was fairly common early in treatment. Anemia and fatigue were also more common than with placebo. Fortunately, there was no increase in myelodysplastic syndrome or acute myeloid leukemia (unlike what is seen in heavily pretreated patients in the metastatic setting) or pneumonitis. This safety profile is important in a “healthy, curative population,” he said.
The study also provided “at least a hint” that this strategy may result in less risk for contralateral cancer and perhaps even ovarian cancer, “like what we first saw with tamoxifen as adjuvant therapy for breast cancer,” he added.
As a result of OlympiA, the U.S. Food and Drug Administration recently approved adjuvant olaparib for patients with BRCA-mutated HER2-negative high-risk early breast cancer who have undergone chemotherapy prior to or following surgery.
Other Strategies Under Study
Besides induction/maintenance in the metastatic setting and the adjuvant use of PARP inhibitors, combination strategies also hold promise. Studies are evaluating PARP inhibitors given with other chemotherapies; PIK3CA inhibitors (alpelisib); vascular endothelial growth factor (VEGF) inhibitors (cediranib); checkpoint inhibitors; selective estrogen receptor degraders; and novel inhibitors of other pathways. Research is also advancing on more selective PARP1 inhibitors, which may be associated with less hematologic toxicity and may be combined more effectively with other agents.
Finally, the hope is that these agents will expand into “small but nonetheless important” subsets of patients beyond germline BRCA carriers (with promise shown for germline PALB2 carriers) and even to patients with somatic (not just germline) BRCA mutations, where there is a “strong suggestion” of benefit, Dr. Robson stated. “We need to do more to extend benefit in all these populations.”
DISCLOSURE: Dr. Robson disclosed uncompensated advisory relationships with Artios Pharma, AstraZeneca, Daiichi Sankyo, Epic Sciences, Merck, Pfizer, Tempus Labs, and Zenith Pharma; research funding from AstraZeneca, Merck, and Pfizer; editorial support from AstraZeneca and Pfizer; and honoraria from Change Healthcare, Clinical Education Alliance, Genome Quebec, MJH Associates, myMedEd, and Physicians’ Education Resource.
REFERENCES
1. Robson ME: PARP inhibitor update 2022. 2022 Miami Breast Cancer Conference. Presented March 4, 2022.
2. Robson M, Im SA, Senkus E, et al: Metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017.
3. Litton JK, Rugo HS, Ettl J, et al: Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379:753-763, 2018.
4. Moore K, Colombo N, Scambia G, et al: Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379:2495-2505, 2018.
5. Diéras V, Han HS, Kaufman B, et al: Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21:1269-1282, 2020.
6. Robson ME, Tung N, Conte P, et al: OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 30:558-566, 2019.
7. Litton JK, Scoggins ME, Hess KR, et al: Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol 38:388-394, 2020.
8. Tut ANJ, Garber JE, Kaufman B, et al: Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021.
