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Sacituzumab govitecan (SG), a novel antibody–drug conjugate (ADC) targeting TROP2, is approved for pre-treated metastatic triple-negative breast cancer (mTNBC). We conducted an investigator-initiated clinical trial evaluating neoadjuvant (NA) SG (NCT04230109), and report primary results. Participants with early-stage TNBC received NA SG for four cycles. The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) to SG. Secondary objectives included overall response rate (ORR), safety, event-free survival (EFS), and predictive biomarkers. A response-guided approach was utilized, and subsequent systemic therapy decisions were at the discretion of the treating physician. From July 2020 to August 2021, 50 participants were enrolled (median age = 48.5 years; 13 clinical stage I disease, 26 stage II, 11 stage III). Forty-nine (98%) completed four cycles of SG. Overall, the pCR rate with SG alone was 30% [ n = 15, 95% confidence interval (CI) 18% to 45%]. The ORR per RECIST V1.1 after SG alone was 64% (n = 32/50, 95% CI 77% to 98%). Higher Ki-67 and tumor-infiltrating lymphocytes (TILs) were predictive of pCR to SG (P = 0.007 for Ki-67 and 0.002 for TILs), while baseline TROP2 expression was not (P = 0.440). Common adverse events were nausea (82%), fatigue (76%), alopecia (76%), neutropenia (44%), and rash (48%). With a median follow-up time of 18.9 months (95% CI 16.3-21.9 months), the 2-year EFS for all participants was 95%. Among participants with a pCR with SG (n = 15), the 2-year EFS was 100%. In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed. • NA treatment with SG for localized TNBC is safe and feasible. • Approximately two-thirds of patients responded to NA SG alone, and 30% achieved pCR without additional chemotherapy. • Higher Ki-67 and TILs were predictive of pCR to SG, whereas TROP2 expression was not. [ABSTRACT FROM AUTHOR]

Residual disease after neoadjuvant therapy (NAT) is associated with higher risk of recurrence, including local failure (25%) in triple negative breast cancer (TNBC). Novel combinations that increase the efficacy of standard-of-care treatments on locoregional control are warranted. PARP inhibitors (PARPi) target the DNA damage repair pathway, which is often altered in TNBC, and show promise as radiosensitizers. The objective of this phase I trial (NCT03945721) was to determine the maximum tolerated dose (MTD) of a PARPi, niraparib, in pts with high risk TNBC receiving postoperative radiotherapy (RT). Eligible pts had stage I-III TNBC with residual invasive disease following NAT or primary tumor ≥1 cm after upfront surgery. A 3+3 escalation design was used to test 2 dose levels of QD niraparib (100mg, 200mg) with concurrent RT to the chest wall or breast +/- regional lymph nodes over 4-6 weeks. Dose expansion followed at the MTD. A boost was delivered in pts who had lumpectomy. 2 pts received proton beam RT. Bolus was administered in postmastectomy RT or in cases of dermal lymphatic invasion. Circulating tumor DNA (ctDNA) was collected at baseline, mid-RT, end of RT, and 30 days post-RT to assess the kinetics of ctDNA levels during RT and the association with clinical outcomes. Adverse events (AEs) were assessed using CTCAE v5.0. 21 pts were enrolled from July 2019 – October 2021. The median age was 49 (31-69). 19/21 pts had residual disease after NAT (6 RCB I, 7 RCB II, 6 RCB III); among them, 2 underwent adjuvant chemotherapy prior to enrolling. The remaining 2/21 pts (pT2N0; pT1cN0) received upfront breast conserving surgery followed by adjuvant chemotherapy. In dose escalation, 6 pts received 100mg niraparib + RT and 2 pts received 200mg niraparib + RT. One DLT in the 100mg cohort (G3 dermatitis) was attributed to RT. Two DLTs in the 200mg cohort (G3 thrombocytopenia) were attributed to niraparib and study drug was discontinued. In dose expansion, 13 pts received 100mg niraparib + RT. G3 AEs were dermatitis (4/21), hematologic (4/21), consisting of thrombocytopenia, anemia & lymphopenia, and elevated alkaline phosphatase (1/21). There was one G4 thrombocytopenia. All skin AEs were attributed to RT and were not exacerbated by niraparib. No pts in dose expansion discontinued treatment due to toxicity. 20/21 went on to standard-of-care capecitabine after completing RT. Results of ctDNA will be reported at the meeting. The MTD of niraparib + postop RT was determined to be 100mg QD and was associated with a 24% rate of G3-4 hematologic toxicities and 19% rate of G3 radiation dermatitis in pts with localized TNBC, which is within upper limits of normal for pts in whom chest wall/skin is targeted. These results will be informative for a future larger study testing the efficacy of niraparib + postop RT in high risk TNBC. [ABSTRACT FROM AUTHOR]