Neoadjuvant talazoparib induces pathologic complete response in breast cancer subset
Neoadjuvant talazoparib conferred pathologic complete response rates comparable with those of anthracycline- and taxane-based chemotherapy regimens among patients with germline BRCA1/BRCA2-mutated, HER2-negative early breast cancer.
Talazoparib (Talzenna, Pfizer), a poly(ADP)-ribose polymerase (PARP) inhibitor, also appeared generally well-tolerated, according to results of the nonrandomized, open-label, phase 2 NEOTALA study presented during the virtual ASCO Annual Meeting.
“When you have a strong biomarker to response, there may be a pathway to an easier therapy for patients,” Jennifer Keating Litton, MD, vice president of clinical research and professor of breast medical oncology and clinical cancer genetics at The University of Texas MD Anderson Cancer Center, told Healio.
Litton said the study began as a 2-month window trial but extended to 6 months of therapy prior to surgery because researchers at MD Anderson observed “significant tumor shrinkage in a short time” and several patients asked to stay on, which led to the multicenter trial.
“This ability to move from a window to a neoadjuvant trial may be a framework for future trials in this space as new therapies are being developed,” she said.
Germline BRCA1 and BRCA2 mutations occur in between 9% and 15% of patients with triple-negative breast cancer, according to study background. Talazoparib has been approved for patients with locally advanced or metastatic, HER2-negative breast cancer with deleterious or suspected deleterious germline BRCA mutations.
Litton and colleagues evaluated the efficacy and safety of the agent as neoadjuvant therapy among 61 women (mean age, 44.6 years; 77% white) with early-stage, germline BRCA1/BRCA2-mutated, triple-negative breast cancer. Treatment consisted of 1 mg oral talazoparib daily (0.75 mg/day for those with moderate renal impairment) for 24 weeks, followed by breast surgery.
Pathologic complete response by independent central review served as the study’s primary endpoint. Secondary endpoints included pathologic complete response by investigator assessment and residual cancer burden (RCB) by independent central review, as well as safety.
Sixty of the women had adenocarcinoma and one had squamous carcinoma with spindle cell. Twenty had stage I disease, 27 had stage II disease and 14 had stage III disease.
Mean duration since disease onset was 4.5 weeks, mean treatment duration was 23.3 weeks and mean overall relative dose intensity was 84.5%. Most women (90.2%) remained on talazoparib for at least 20 weeks, and 73.8% received talazoparib for 24 weeks or more.
The evaluable population included 48 women who received at least 80% of the initially prescribed talazoparib dose and underwent surgery and assessment for pathologic complete response, as well as those with progression before pathologic complete response could be assessed.
Results showed pathologic complete response rates by independent central review of 45.8% (95% CI, 32-60.6) in the evaluable population and 49.2% (95% CI, 36.7-61.6) in the overall intent-to-treat population. Researchers reported similar rates by investigator assessment (45.8% evaluable and 47.5% intent-to-treat).
“The trial was truncated due to business decisions by the sponsor, so we did not accrue to the full planned phase 2 accrual, but in this cohort, it did confirm that pathologic complete responses were reproduced in a multicenter trial,” Litton said.
In an analysis of RCB, Litton reported rates of zero in the evaluable population and 1.6% in the intent-to-treat population for RCB I (minimal burden); 31.3% and 27.9% for RCB II (moderate burden); zero for both populations for RCB III (extensive burden); and 22.9% and 21.3% for RCB “other,” which included those who experienced clinical progression during the study and moved to systemic therapy prior to surgery.
About half (50.9%) of women in the intent-to-treat population experienced grade 1 or grade 2 adverse events, 42.6% experienced grade 3 events and one patient experienced a grade 4 event (decreased neutrophil count). All-causality treatment-emergent serious adverse events occurred among 18% of women. Twenty-four women (39.3%) experienced grade 3 anemia, which was reported as a medically important event. Litton noted that anemia is a known adverse event of talazoparib.
“I think this is an example of potentially simplifying treatment for some patients and identifying groups of patients that may be able to de-escalate their therapy for early-stage breast cancer without compromising treatment outcomes,” Litton said.
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The results of Litton and colleagues’ work are exciting and in line with expectations. Prior, smaller studies of the use of PARP inhibitors in the neoadjuvant setting have demonstrated similar promising results.
In an initial 20-person study, neoadjuvant single-agent oral talazoparib once per day for 6 months without chemotherapy produced a substantial RCB-0 rate with manageable toxicity. Other PARP inhibitors have been examined in the neoadjuvant setting and similarly have shown high response rates among BRCA carriers, including niraparib (Zejula, GlaxoSmithKline).
The data here are compelling and suggest a chemotherapy-free regimen may become a reality for some patients with BRCA mutations. It will be important to study predictive biomarkers from this cohort to better understand which patients will have the most benefit from this approach.
The study results cannot be immediately adopted, as this was a single-arm study and this agent is not approved for the treatment of localized breast cancer. In the future, the role of neoadjuvant PARP inhibitors for patients with BRCA mutations will need to be considered in context of the exciting results for the use of olaparib (Lynparza, AstraZeneca) in the adjuvant setting.
References:
Han H, et al. Abstract P3-11-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019.
Litton JK, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.01304.
Tutt A, et al. Abstract LBA1. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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PARP inhibitors in a BRCA-deficient cancer result in synthetic lethality by trapping PARP1 on single-stranded DNA, breaking and converting it into double-stranded DNA breaks. PARP inhibitors alone have shown clinical benefit compared with chemotherapy in the metastatic setting for germline BRCA mutation-positive, HER2-negative breast cancer, but their efficacy in the neoadjuvant setting has been investigated for the first time in the single-arm, phase 2 NEOTALA study by Litton and colleagues.
The findings of this study, which investigates the role of neoadjuvant single-agent talazoparib without chemotherapy in patients with germline BRCA mutation-positive early triple-negative breast cancer, are exciting.
The researchers concluded that talazoparib is very active in neoadjuvant setting, with pathologic complete response rates comparable to polychemotherapy. This regimen could be especially useful in select patients for whom further chemotherapy may be contraindicated; for example, those exposed to prior chemotherapy for other cancers. Also, this may be considered for patients with germline BRCA mutation-positive, hormone receptor-positive lobular breast cancers who can safely forgo chemotherapy, given their low chemosensitivity.
Although the initial results are very interesting, they cannot be considered practice-changing and merit further study in future clinical trials. The role of adjuvant chemotherapy (especially among patients with pathologic complete response) on long-term outcomes remains unclear, because EFS and OS were not reached as the study was prematurely closed.
Whether or not myelosuppression from 6 months of neoadjuvant talazoparib makes it challenging to administer optimal adjuvant chemotherapy needs to be carefully evaluated. Longer follow-up to identify the risk for secondary myelodysplastic syndrome/acute myeloid leukemia is warranted.
Further studies are needed to ascertain if these results could be extended to patients with somatic BRCA and germline PALB2 mutations. The number of patients who progressed while on neoadjuvant talazoparib (16%) was higher than expected with chemotherapy alone, highlighting the fact that talazoparib is not appropriate for a subgroup of patients, and development of biomarkers would allow better identification of patients who would benefit from talazoparib.
The higher financial cost associated with use of PARP inhibitors vs. chemotherapy should be considered; future studies should be randomized and should also include patients with hormone receptor-positive breast cancer with germline BRCA mutations.
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Litton JK, et al. Abstract 505. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.