A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.

PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%. RESULTS: At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib. CONCLUSIONS: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.

Overall Survival and Exploratory Biomarker Analyses of Abemaciclib plus Trastuzumab with or without Fulvestrant versus Trastuzumab plus Chemotherapy in HR+, HER2+ Metastatic Breast Cancer Patients.

PURPOSE: The monarcHER trial has shown that abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, combined with fulvestrant and trastuzumab, improves progression-free survival (PFS) in hormone receptor-positive (HR+), HER2-positive (HER2+) advanced breast cancer (ABC) compared with standard-of-care (SOC) chemotherapy combined with trastuzumab. We report the final overall survival (OS) analysis, updated safety and efficacy data, and exploratory biomarker results from monarcHER. PATIENTS AND METHODS: monarcHER (NCT02675231), a randomized, multicenter, open-label, phase II trial, enrolled 237 patients across Arm A (abemaciclib, trastuzumab, fulvestrant), Arm B (abemaciclib, trastuzumab), and Arm C (SOC chemotherapy, trastuzumab). Following the statistical plan, OS and PFS were estimated in all arms. RNA sequencing (RNA-seq) was performed on archival tissue. RESULTS: Median OS was 31.1 months in Arm A, 29.2 months in Arm B, and 20.7 months in Arm C [A vs. C: HR, 0.71; 95% confidence interval (CI), 0.48-1.05; nominal two-sided P value 0.086; B vs. C: HR 0.83 (95% CI, 0.57-1.23); nominal two-sided P value 0.365]. Updated PFS and safety findings were consistent with previous results. The most frequently reported treatment-emergent adverse events included diarrhea, fatigue, nausea, neutrophil count decrease, and anemia. In exploratory RNA-seq analyses, Luminal subtypes were associated with longer PFS [8.6 vs. 5.4 months (HR, 0.54; 95% CI, 0.38-0.79)] and OS [31.7 vs. 19.7 months (HR, 0.68; 95% CI, 0.46-1.00)] compared with non-Luminal. CONCLUSIONS: In this phase II trial, abemaciclib + trastuzumab ± fulvestrant numerically improved median OS in women with HR+, HER2+ ABC compared with SOC chemotherapy + trastuzumab.

Concurrent Versus Sequential Chemoradiation for Low-grade Gliomas Meeting RTOG 9802 Criteria.

PURPOSE: Radiation Therapy Oncology Group (RTOG) 9802 has established postoperative radiation therapy (RT) and chemotherapy sequentially as the new standard of care for patients with high-risk low-grade glioma (LGG) meeting trial criteria. Although this trial investigated sequential chemoradiation therapy (sCRT) with RT followed by chemotherapy, it is unknown whether concurrent chemoradiation therapy (cCRT) may offer advantages over sCRT. MATERIALS AND METHODS: The National Cancer Database (NCDB) was queried for newly diagnosed World Health Organization (WHO) grade II glioma. Patients with unknown surgery, RT, or chemotherapy status were excluded, along with patients below 40 years old who underwent gross total resection to coincide with RTOG 9802 exclusion criteria. The χ, the Fisher exact, or Wilcoxon rank-sum tests evaluated differences in characteristics between groups. Kaplan-Meier analysis was used to evaluate overall survival (OS) between groups (sCRT vs. cCRT). Cox proportional hazards modeling determined variables associated with OS. RESULTS: In total, 496 patients were analyzed (n=416 [83.9%] cCRT, n=80 [16.1%] sCRT). Sequencing or concurrency of therapy did not independently influence survival on univariable/multivariable analysis. Factors associated with worse OS on multivariable analysis included advanced age (P<0.001), whereas mixed glioma (P=0.017) and oligodendroglioma (P=0.005) were associated with better OS than astrocytoma histologies. CONCLUSIONS: This is the only analysis of which we are aware of cCRT versus sCRT for LGG. There is no evidence that cCRT improves outcomes over sCRT.