Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer

This single-arm pilot study (NCT03329937) evaluated neoadjuvant niraparib antitumor activity and safety in patients with localized HER2-negative, BRCA-mutated breast cancer. Twenty-one patients received niraparib 200 mg once daily in 28-day cycles. After 2 cycles, tumor response (≥30% reduction from baseline) by MRI was 90.5% and 40.0% (6 of 15) of patients who received only niraparib (2–6 cycles) had pathological complete response; no new safety signals were identified. High niraparib intratumoral concentration was observed.

Neoadjuvant niraparib was highly active in patients with localized HER2-negative, BRCA-mut BC. There were no new safety signals and no discontinuations due to TEAEs.
After 2 cycles, >90% of patients experienced a clinical response; 38% had pCR after neoadjuvant niraparib, most of whom received only niraparib. Intratumoral niraparib concentrations were >30-fold higher than in plasma. Tumor penetration may be associated with reduced tumor volume, warranting further investigation. This is consistent with preclinical data showing superior tumor penetration by niraparib (3.3-fold higher exposure than plasma) versus other PARP inhibitors (for example, olaparib: 0.6-to 0.7-fold plasma concentration) 7 . In addition, niraparib concentrates in tumor and other tissues rather than circulating in the plasma; dose-normalized niraparib exposure was 10-, 51-and 100-fold higher versus olaparib in plasma, tumor and brain, respectively 7 . This, combined with the low clearance and high volume of distribution of niraparib, further supports a higher tendency of niraparib to concentrate in the peripheral body compartment and solid tumors, rather than in plasma 7 .
A phase II pilot study of neoadjuvant talazoparib also demonstrated clinical activity. All patients with gBRCA-mut BC received 6 months of neoadjuvant talazoparib; 53% (10/19) had pCR (primary endpoint) and 9 patients had dose reductions due to TEAEs 5 .
In our study, physicians could make treatment decisions based on observed responses at the end of cycle 2 by MRI or ultrasound, before receipt of additional therapy. Of 15 patients, 6 (40.0%) who received niraparib only (no NACT) had pCR; these patients received 2-6 cycles of niraparib. Given that five of the six patients achieving pCR in our study received four or more cycles of niraparib (no NACT), the rate of pCR achieved in this population is consistent with that of the neoadjuvant talazoparib study 5 . Furthermore, the INFORM trial reported that 18-26% of patients with stage I-III, BRCA-mut, HER2-negative BC had pCR with NACT (cisplatin or doxorubicin-cyclophosphamide) 10 . These promising results, determined from imaging and pCR rates, highlight the efficacy of neoadjuvant niraparib in BRCA-mut BC and support the use of pCR as a primary endpoint for future studies using niraparib. In addition, these results also suggest that chemotherapy use could potentially be de-escalated, reducing toxicity.
Sensitivity to PARP inhibitors has also been shown in somatic BRCA-mut ovarian cancer and in patients with mutations in other HRd-related genes 11 . Up to 69% of patients with TNBC have HRd and PALB2 mutations are also associated with HRd 12 . A phase II trial of olaparib showed antitumor activity in metastatic BC with somatic BRCA1/2 and germline PALB2 mutations 13 . In addition, a phase II study of talazoparib monotherapy demonstrated activity of PARP inhibitors in patients with advanced HER2-negative BC and a HR pathway gene mutation, beyond BRCA1/2. RECIST response was seen in 3 of 12 BC patients who had a RECIST response (objective response rate 25%; 2 gPALB2, 1 gCHEK2/gFANCA/sPTEN) and 3 additional patients (gPALB2, sATR, sPTEN) had stable disease (SD) for ≥6 months 14 . Further investigations may identify additional genetic subgroups that are likely to respond to PARP inhibitors. Limitations of our study included small sample size and heterogeneity in treatment after neoadjuvant niraparib and the number of cycles of niraparib, limiting conclusions about pCR. However, this targeted, chemotherapy-sparing approach showed favorable pCR rates and tolerability, supporting future investigations.
In this pilot study, single-agent neoadjuvant niraparib demonstrated promising antitumor activity and high levels of tumor penetration in HER2-negative, BRCA-mut, localized BC. No new safety signals were identified.

Methods
The study was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines following approval by ethics committees and institutional review boards at each study site (Moffitt Cancer Center, Tampa The first subject was enrolled on 12 April 2018 and the last on 15 May 2019. All 24 patients were recruited from 7 of 11 active sites (site 1: 3 patients; site 2: 5 patients; site 3: 2 patients; site 4: 6 patients; site 5: 5 patients; site 6: 2 patients; and site 7: 1 patient). Eligible patients were female or male adults with: primary operable, histologically confirmed, HER2-negative, localized BC; deleterious/ suspected deleterious BRCA1/2 mutations (germline, may include somatic); primary tumor size ≥1 cm; and Eastern Cooperative Oncology Group performance status 0-1. Patients were excluded for previous therapy for current malignancy, previous PARP inhibitor use or distant metastases.
Niraparib 200 mg orally once daily was given in 28-day cycles. This dose was chosen to reduce the likelihood of dose interruptions due to AEs, which predominantly occurred within cycles 1-3 in a previous study 15 . Patients with progressive disease (increase in tumor volume >20% per ultrasound) after cycle 1 discontinued; patients with CR, PR or SD continued into cycle 2. The primary endpoint was tumor response rate (change in tumor volume by breast MRI by investigator after two cycles). A clinical response was defined as ≥30% reduction in tumor volume from baseline without new lesions (≥PR). After cycle 2, patients proceeded directly to surgery, received NACT and then surgery, or received up to 6 cycles of niraparib before surgery with or without subsequent NACT, at the physician's discretion.
Secondary endpoints were tumor response rate by breast ultrasound (≥30% reduction in tumor volume from baseline), change in tumor volume from baseline after cycle 2 by MRI and ultrasound, pCR at time of surgery (ypT0/Tis ypN0 by American Joint Committee on Cancer staging v.7.0) and safety/tolerability until 30 d after last niraparib dose. Niraparib intratumoral and plasma concentrations (via qualified liquid chromatography-tandem mass spectrometry at cycle 2) were exploratory endpoints.
Tumor volume was calculated as (length × width × height × π)/6 (ref. 16 ). If too small to measure, change from baseline was imputed as 99%. TEAEs were graded using Common Terminology Criteria for Adverse Events v.4.03. Differences between plasma and tumor niraparib concentrations were assessed using Wilcoxon's matched-pair, signed-rank test (significance level P < 0.05). Maximum concentration (C max ) was used to estimate niraparib tumor/plasma ratio when time-matched plasma samples were missing. Linear regression (GraphPad Prism v.8.0) assessed the correlation between response and niraparib tumor:plasma ratio. Spearman's rank correlation was also performed.
Statistics and reproducibility. All statistical analyses were performed using SAS statistical software v.9.3 or later unless otherwise noted; data distribution was assumed to be normal, but this was not formally tested. No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publications 17 . Data collection and analysis were not performed blind to the conditions of the experiments. Clinical exclusion criteria were pre-specified and patients were not eligible for the study if any of these were met; no data points were excluded from the analyses.
Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability
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