Triple-negative breast cancer (TNBC) is a breast cancer subtype renowned for its capacity to affect younger women, metastasise early despite optimal adjuvant treatment and carry a poor prognosis. Neoadjuvant therapy has focused on combinations of systemic agents to optimise pathological complete response. Treatment algorithms now guide the management of patients with or without residual disease, but metastatic TNBC continues to harbour a poor prognosis. Innovative, multi-drug combination systemic therapies in the neoadjuvant and adjuvant settings have led to significant improvements in outcomes, particularly over the past decade. Recently published advances in the treatment of metastatic TNBC have shown impressive results with poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy agents. Immunotherapy agents in combination with traditional systemic chemotherapy have been shown to alter the natural history of this devastating condition, particularly in patients whose tumours are positive for programmed cell death ligand 1 (PD-L1).
Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0–8) were treated with daily tamoxifen (20 mg) and venetoclax (200–800 mg). Apart from uncomplicated “on-target” lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. Significance: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors. See related commentary by Drago et al., p. 323. This article is highlighted in the In This Issue feature, p. 305
Background The impact of regulatory approvals of new therapies for castration‐resistant prostate cancer (CRPC) in Australia is unclear. Aims To determine if changes in novel therapy access in Australia affected how clinicians initially managed men with newly diagnosed CRPC. Methods Data from patients diagnosed with CRPC from 2013 to 2016 across three Australian hospitals were retrospectively collected. Baseline clinicopathological factors and initial management decision at the time of CRPC development (early treatment (ET) vs deferred treatment (DT)) were recorded. Categorical variables between cohorts were compared by Chi‐squared analysis. Cox regression analysis was performed to assess the impact of CRPC diagnosis year on time to commencing life‐prolonging systemic treatment (TTT). Results Our study identified 137 CRPC patients, with 126 (92%) patients receiving life‐prolonging systemic treatment. The median age was 73 years. The initial management decision was DT in 71 (52%) patients and ET in 66 (48%) patients. There was a significant shift from DT to ET during the study period (2013–2014: DT 61% vs ET 33%; 2015–2016: DT 39% vs ET 67%; P = 0.004), with a rise in novel androgen receptor signalling inhibitor use and simultaneous reduction in first‐generation antiandrogen use at CRPC development. Each successive CRPC diagnosis year was associated with shorter TTT on univariate analysis (HR: 1.5, 95% CI: 1.3–1.7, P < 0.001). Conclusion Over time, clinicians are favouring earlier introduction of life‐prolonging systemic treatment at the development of CRPC. This trend is largely driven by substantial uptake of novel androgen receptor signalling inhibitors as the preferred initial treatment for CRPC patients.
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