Background: Despite significant progress, prostate cancer remains a leading cause of death. Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are already approved for the treatment of hormone receptor-positive breast cancer, are undergoing extensive testing as monotherapy and in various combinations as a potentially valuable treatment modality in prostate cancer patients. Thus far, a limited number of these studies have published results, which have been largely disappointing. Areas Covered: In this review, we describe the biologic rationale for the use of CDK4/6 inhibitors in prostate cancer, the existing clinical data describing their use in prostate cancer, and ongoing clinical trials of CDK4/6 inhibitors as monotherapy and in combination for the treatment of prostate cancer. In particular, we focus on possible resistance mechanisms that may be particularly relevant in prostate cancer patients, leading to de novo and acquired resistance, and we highlight novel strategies that can overcome this resistance. Conclusions: Current clinical trials are actively working to (1) refine the role of CDK4/6 inhibitors in prostate cancer patients; (2) develop new inhibitors of other cell-cycle targets, such as CDK2 and CDK7; and (3) explore novel combination therapies with inhibitors of other relevant pathways, such as PI3K or MAPK. Further genomic subtyping of advanced prostate cancer will likely shed light on the subsets of patients most likely to benefit from cell-cycle-targeted agents.

There is limited information on the long-term outcomes of ICDs in patients with inherited arrhythmia syndromes. Prospective registry study of inherited arrhythmia patients with an ICD. Incidence of therapies and complications were measured as 5-year cumulative incidence proportions and analyzed with the Kaplan-Meier method. Incidence was compared by device indication, diagnosis type and device type. Cox-regression analysis was used to identify predictors of appropriate shock and device complication. 123 patients with a mean follow up of 6.4 ± 4.8 years were included. The incidence of first appropriate shock was 56.52% vs 24.44%, p < 0.05 for cardiomyopathy and channelopathy patients, despite similar ejection fraction (61% vs 60%, p = 0.6). The incidence of first inappropriate shock was 13.46% vs 56.25%, p < 0.01 for single vs. multi-lead devices. The incidence of first lead complication was higher for multi-lead vs. single lead devices, 43.75% vs. 17.31%, p = 0.04. Patients with an ICD for secondary prevention were more likely to receive an appropriate shock than those with primary prevention indication (HR 2.21, CI 1.07–4.56, p = 0.03). Multi-lead devices were associated with higher risk of inappropriate shock (HR 3.99, CI 1.27–12.52, p = 0.02), with similar appropriate shock risk compared to single lead devices. In 26.5% of patients with dual chamber devices, atrial sensing or pacing was not utilized. The rate of appropriate therapies and ICD complications in patients with inherited arrhythmia is high, particularly in cardiomyopathies with multi-lead devices. Risk-benefit ratio should be carefully considered when assessing the indication and type of device in this population.

Metastatic androgen pathway modulation-resistant (mAPMR) prostate cancer subtypes harboring androgen receptor (AR) alterations have distinct AR biology that may impact response to therapy. We hypothesized that patients harboring AR T878A would have superior responses to AR pathway inhibitor (ARPI) therapy based on prior preclinical data. We utilized a large genomic-clinical database to identify mAPMR patients with AR T878A, AR L702H and AR amplification and performed a matched assessment of ARPI treatment outcomes using real-world surrogate endpoints for treatment response. Among AR T878A patients treated with enzalutamide, time to treatment discontinuation (TTD) was longer relative to patients with AR L702H (8 mo (95% CI 4.6–44 mo) vs. 3.5 mo (95% CI 2.3–5.5 mo) log-rank p < 0.0001) or AR amplification (7.7 mo (95% CI 4.7–15.8 mo) vs. 4.8 mo (95% CI 4–5.1 mo) (log-rank p = 0.0034). Among the AR T878A patients treated with abiraterone, TTD was not significantly different relative to patients with AR L702H, but longer relative to patients with AR amplification (7.1 mo (95% CI 5–8.5 mo) vs. 4.2 mo (95% CI 3.5–5.4 mo) (log-rank p = 0.037). This study provides hypothesis generating evidence that outcomes for patients with AR LBD mutations may differ by mutation subtype. AR T878A may be relatively more sensitive to ARPI treatment than AR L702H or amplified AR.