Triple-negative breast cancer (TNBC) is a particularly aggressive breast cancer subtype, characterised by a higher incidence in younger women, rapid metastasis, and a generally poor prognosis. Patients with TNBC and BRCA mutations face additional therapeutic challenges due to the cancer’s intrinsic resistance to conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities in the homologous recombination repair (HRR) pathway. However, despite initial success, the efficacy of PARPis is often compromised by the development of resistance mechanisms, including HRR restoration, stabilisation of replication forks, reduced PARP1 trapping, and drug efflux. This review explores latest breakthroughs in overcoming PARPi resistance through combination therapies. These strategies include the integration of PARPis with chemotherapy, immunotherapy, antibody-drug conjugates, and PI3K/AKT pathway inhibitors. These combinations aim to enhance the therapeutic efficacy of PARPis by targeting multiple cancer progression pathways. The review also discusses the evolving role of PARPis within the broader treatment paradigm for BRCA-mutated TNBC, emphasising the need for ongoing research and clinical trials to optimise combination strategies. By tackling the challenges associated with PARPi resistance and exploring novel combination therapies, this review sheds light on the future possibilities for improving outcomes for patients with BRCA-mutated TNBC.

Introduction The aim of the study was to evaluate the efficacy and safety of fixed-dose combination (FDC) of dapagliflozin (10 mg) and linagliptin (5 mg) in comparison to linagliptin 5 mg (Trajenta) in patients with insufficiently controlled type 2 diabetes mellitus (T2DM) on metformin monotherapy. Methods The double-blind, randomized, multicentric, parallel-group phase III trial screened 287 adult patients with T2DM (age 18–65 years) from 16 sites across India. The recruited subjects were undergoing metformin monotherapy ≥ 1000 mg/day for at least 28 days. Patients with HbA1c of 7.5–10.5% (58–91 mmol/l) (n = 232) after 2 weeks of run-in period with linagliptin monotherapy and placebo dapagliflozin/linagliptin on metformin monotherapy were randomized (1:1) in parallel to once daily dapagliflozin/linagliptin 10/5 mg or linagliptin 5 mg for 16 weeks. Patients were stratified on the basis of HbA1c (≤ 9.0% and > 9.0%; ≤ 75 mmol/l and > 75 mmol/l)). A total of 225 subjects completed 16 weeks of treatment, 115 patients in the test group and 110 patients in the reference group. Results Dapagliflozin/linagliptin (p = 0.0003) exhibited a greater change in HbA1c from baseline than linagliptin (p < 0.0001) in 16 weeks (mean reduction, − 1.28% vs − 0.83%). Test group showed a significant decrease in fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and body weight compared to the reference group. The FDC was well tolerated with adverse events being more frequent in the reference group. No serious adverse events (SAEs) were reported in the study. Conclusion Dapagliflozin/linagliptin combination is a novel dipeptidyl peptidase 4 (DPP4)/sodium-glucose co-transporter 2 (SGLT2) inhibitor FDC approved in India for patients with T2DM. Potential limitations of this study are a small dose of dapagliflozin (10 mg) in the FDC, a short study duration (30 weeks) and a high minimum threshold for HbA1c (≤ 7.5%; ≤ 53 mmol/l). Results indicate the FDC to be a superior therapeutic option over linagliptin for patients with T2DM on metformin monotherapy. Trial Registration CTRI/2022/08/044563; 01/08/2022.

Understanding the relationship between the Objective Response Rate (ORR) and survival outcomes, notably Progression-Free Survival (PFS) and Overall Survival (OS), is relevant for assessing the efficacy of regimens in oncology. We evaluate the relationship between ORR, PFS and OS in immuno-oncology (IO) trials. Data from 68 clinical trials submitted to the FDA were evaluated, examining immunotherapy regimens, notably immune checkpoint inhibitors such as anti-programmed death (ligand)-1 [anti-PD-(L)1], cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors and combination therapies [e.g., IO + IO, anti-PD-L1 + chemotherapy, anti-PD-L1 + CTLA-4, anti-PD-L1 + TKI (tyrosine kinase inhibitors)]. Studies were included based on their reporting of ORR, PFS, and OS. Of the 68 clinical trials reviewed, 55 were included in the analysis. The correlation between ORR and PFS was moderate across most immunotherapy regimens, indicating that ORR can serve as a useful predictor of short-term disease control. However, the correlation between ORR and OS was weaker, especially in trials including combination therapies, indicating that ORR alone may not reliably predict long-term survival outcomes. ORR predicts PFS better in first-line treatment but declines in later lines and remains a weak OS predictor overall. Differing degrees of correlation between ORR and survival metrics, particularly across treatment lines and combinations, are observed. While ORR can serve as a surrogate marker for PFS in IO trials, its utility in predicting OS is restricted and the interpretation of the relationship between ORR and PFS or OS is a key limitation. Rather, a decline in PFS with increasing ORR may reflect trial differences rather than a direct relationship. Future analyses should adopt better methodologies to capture these dynamics and focus on improving surrogate endpoints for immunotherapy to improve clinical trial design and patient outcomes.