In a pilot, single-arm, phase II study, neoadjuvant treatment with single-agent niraparib demonstrated feasibility, promising antitumour activity and high levels of tumour penetration in patients with HER2-negative, BRCA-mutated, localised breast cancer. No new safety signals were identified. This targeted, chemotherapy-sparing approach showed favourable pathologic complete response (pCR) rates and tolerability, supporting future investigations. The findings are published by Dr. Steven J. Isakoff of the Massachusetts General Hospital and Harvard Medical School in Boston, MA, US and colleagues on 4 July 2022 in the Nature Cancer.
The authors wrote in the study background that preliminary pharmacokinetic data showed higher niraparib concentrations in tumours than in plasma, including in BRCA-mutated, triple-negative breast cancer (TNBC) and BRCA wild type ovarian xenograft models, which may facilitate primary tumour penetration in the neoadjuvant setting. This pilot study explored the antitumor activity of neoadjuvant niraparib for localised HER2-negative, BRCA-mutated breast cancer and assessed niraparib concentration in tumour versus plasma. Duration of niraparib treatment beyond cycle 2 was determined by clinician decision and based on observed patient responses.
As of 30 June 2020, efficacy-evaluable (2 or more cycles) and safety (1 or more niraparib dose) populations included 21 of 24 enroled patients with tumour BRCA mutations. One patient discontinued due to protocol non-compliance after completing two niraparib cycles. No patients received fewer than 2 cycles of niraparib, 19.0% received 2 cycles and 81.0% received more than 2 cycles. Six patients (28.6%) received post-niraparib neoadjuvant chemotherapy. All patients underwent surgery; 14 patients had BRCA1 mutation, 6 had BRCA2 mutation and 1 had BRCA1/2 mutation; 15 patients (71.4%) had TNBC, and 6 patients (28.6%) had hormone receptor (HR)-positive breast cancer.
Tumour response by magnetic resonance imaging (MRI) after 2 cycles which was study primary endpoint was 90.5% (95% confidence interval (CI) 69.6, 98.8%), with 2 CRs and 17 partial responses (PRs) (86.7% in TNBC, 100% in HR-positive tumours). By ultrasound, 81.0% (95% CI 58.1, 94.6%) of tumours responded (1 CR, 16 PRs) after 1 cycle of niraparib and 95.2% (95% CI 76.2, 99.9%) responded after 2 cycles (1 CR, 19 PRs). Median (range) decrease in tumour volume after 2 cycles was 86.4% (26–100%) by MRI and 87.2% (23–100%) by ultrasound; best response by ultrasound (≥2 cycles) was a 92.5% (23–100%) decrease.
Overall, 8 patients (38.1%; 95% CI 18.1, 61.6%) had pCR after neoadjuvant niraparib with niraparib duration of 1.9–5.9 months. Of 15 patients, 6 (40.0%; 95% CI 16.3, 67.7%; 5 TNBC, 1 HR-positive) who received only niraparib for 2–6 cycles had pCR; 2 of 6 patients (33.3%; 95% CI 4.3, 77.7%; 1 TNBC, 1 HR-positive) who received neoadjuvant chemotherapy after niraparib had pCR. Six patients with pCR had BRCA1 mutation; 2 had BRCA2 mutation. Of 15 patients, 6 (40.0%; 95% CI 16.3, 67.7%) with TNBC and 2 of 6 (33.3%; 95% CI 4.3, 77.7%) with HR-positive breast cancer had pCR.
Median (range) duration of niraparib exposure was 2.9 (1.8–5.9) months. Overall, 19 of 21 patients (90.5%) experienced any-grade, niraparib-related, treatment-emergent adverse events (TEAEs). Grade ≥3, niraparib-related TEAEs included anaemia in 3cases, neutropenia in 2 cases, decreased neutrophil count in 2 cases, hypertension in 1 cases and thrombocytopenia in 1 case. Two patients (9.5%) had a niraparib-related serious adverse event of which 1 was thrombocytopenia and 1 foetal ventricular septal defect of grade 2 in the foetus of a patient with approximately 3 weeks’ niraparib exposure during pregnancy identified at the end-of-treatment visit. TEAEs led to niraparib dose reduction in 4 patients (19.0%) of which neutropenia in 1 case, thrombocytopenia in 1 case and neutrophil count decreased in 2 cases. No patients discontinued treatment due to TEAEs and there were no deaths during the study.
In 10 patients with time-matched plasma/tumour samples collected after 2 cycles, mean (±s.d.) intratumoural niraparib concentrations were 35.2 ± 37.2-fold higher versus plasma (Wilcoxon’s matched-pairs signed ranks test, p = 0.002). A post-hoc analysis of the association of tumour/plasma niraparib concentration and tumour response was assessed by linear regression (R2 = 0.088; Spearman’s rank correlation ρ = −0.26, two-sided p = 0.36) including 95% confidence bands of best fit. Other parameters analyzed included total tumour niraparib concentration, which demonstrated a similar trend but was not statistically significant. However, due to the small sample size, conclusive statements cannot be drawn from these data.
The authors commented that after 2 cycles, >90% of patients experienced a clinical response; 38% had pCR after neoadjuvant niraparib, most of whom received only niraparib. Intratumoural niraparib concentrations were >30-fold higher than in plasma. This is consistent with preclinical data showing superior tumour penetration by niraparib versus other PARP inhibitors. Despite study limitations of small sample size, heterogeneity in treatment after neoadjuvant niraparib and the number of cycles of niraparib that limit conclusions about pCR, the study findings support future investigations.
The study was funded by GlaxoSmithKline.
Spring LM, Han H, Liu MC, et al. Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer. Nature Cancer; Published online 4 July 2022. DOI: https://doi.org/10.1038/s43018-022-00400-2