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A randomized trial tested whether the addition of apalutamide, an androgen receptor blocker, to androgen-deprivation therapy might improve radiographic (including MRI-detected) progression–free survival and overall survival. Apalutamide was significantly more effective than placebo for both end points.

Key Points Many cell cycle proteins are overexpressed or overactive in human cancers, in particular, D-type and E-type cyclins, cyclin-dependent kinases (CDK4, CDK6 and CDK2), Polo-like kinase 1 (PLK1) and Aurora kinases (Aurora A and Aurora B). In transgenic mice, overexpression of several of these cell cycle proteins induces or contributes to tumorigenesis, revealing their prominent oncogenic roles. Some of these cell cycle proteins are also required for tumorigenesis, and their ablation in mice impairs tumour formation induced by specific genetic lesions or by carcinogen treatment, as demonstrated for several cyclins (D1, D2 and D3) and CDKs (CDK4, CDK6, CDK2 and CDK1), as well as for checkpoint kinase 1 (CHK1). Importantly, in some cases the continued presence of a cell cycle protein has also been shown to be required for tumour maintenance and progression, for example, for cyclin D1, cyclin D3 and CDK4, thereby providing a clear rationale for targeting these proteins in cancer treatment. Kinases involved in cell cycle checkpoint function such as CHK1 and WEE1 also constitute potential therapeutic targets. Their inhibition compromises checkpoint function, causes excessive DNA damage and eventually leads to apoptosis, particularly in cells with compromised p53 function. CDK4/6-selective inhibitors, such as palbociclib, ribociclib and abemaciclib, have shown significant benefits in clinical studies, particularly in breast cancer, but also in non-small-cell lung cancer, melanoma and head and neck squamous cell carcinoma. Importantly, following demonstration of a substantial improvement in progression-free survival, combination of palbociclib and letrozole received accelerated approval for first-line treatment of patients with advanced ER + HER2 − breast cancer. Inhibitors of PLK1, such as rigosertib and volasertib, have also shown encouraging results in clinical phase II/III studies for patients with myelodysplastic syndromes and acute myelogenous leukaemia, respectively, and several phase III trials are currently ongoing. Compounds targeting Aurora A, particularly alisertib, have been extensively studied in preclinical models and demonstrated synergy with many other targeted therapies, leading to tumour regression in various cancer models. Moreover, clinical studies revealed encouraging activity of alisertib in peripheral T cell lymphoma, non-Hodgkin lymphoma, non-small-cell lung cancer and breast cancer. Proteins regulating cell cycle progression are involved in the formation of most cancer types. This Review discusses the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment, results of clinical trials, as well as future therapeutic potential of various cell cycle inhibitors. Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. By contrast, many cancers are uniquely dependent on these proteins and hence are selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. In this Review, we focus on proteins that directly regulate cell cycle progression (such as cyclin-dependent kinases (CDKs)), as well as checkpoint kinases, Aurora kinases and Polo-like kinases (PLKs). We discuss the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors.

The addition of abiraterone, a drug that blocks endogenous androgen synthesis, to standard androgen-deprivation therapy in patients with newly diagnosed, metastatic prostate cancer significantly increased overall survival, with a low rate of adverse effects.

Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18–79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin modified release (4–8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (–8·70 mm Hg [95% CI −9·72 to −7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; −4·26 [–5·13 to −3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (–4·03 [–5·04 to −3·02]; p<0·0001) and versus bisoprolol (–4·48 [–5·50 to −3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. The British Heart Foundation and National Institute for Health Research.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment 1 , 2 , 3 , 4 , 5 , 6 – 7 . Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting 8 . All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74–1.03; P  = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients. The phase 3 SONIA trial challenges the benefits of using cyclin-dependent kinase 4 and 6 inhibitors as a first-line compared with second-line treatment.

Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor–neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF. In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker). The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30–0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37–0·67]), hospital admission for heart failure alone (0·32 [0·24–0·43]), and all-cause mortality (0·53 [0·40–0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy. Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard. None.

In a multicenter placebo-controlled study, patiromer, a nonabsorbable potassium binder, led to a reduction in serum potassium levels in patients with chronic kidney disease and hyperkalemia who were receiving renin–angiotensin–aldosterone system (RAAS) inhibitors. Hyperkalemia is associated with life-threatening cardiac arrhythmias and increased mortality. 1 Patients at the highest risk for hyperkalemia are those with stage 3 or higher chronic kidney disease, with or without diabetes or heart failure, who are being treated with drugs that inhibit renal potassium excretion, particularly inhibitors of the renin–angiotensin–aldosterone system (RAAS). 1 – 4 Outpatient treatment of hyperkalemia is limited by the lack of effective agents. 4 Sodium polystyrene sulfonate and calcium polystyrene sulfonate may cause serious gastrointestinal adverse events 5 – 8 as well as less serious gastrointestinal side effects that may be difficult for patients to tolerate, which together typically limit their . . .

Standard therapy for metastatic, hormone-sensitive prostate cancer is androgen-deprivation therapy, usually with docetaxel. A large, multinational, phase 3 trial assessed the addition of the androgen-receptor blocker darolutamide to standard therapy. At 4 years, survival was higher with darolutamide than with placebo (62.7% vs. 50.4%), with no major differences in the frequency of adverse events.

The proliferation of targeted anticancer agents over the last two decades has revolutionized cancer treatment and improved survival in many previously refractory malignancies. However, many agents are associated with characteristic ophthalmic adverse effects. It is important that ophthalmologists recognize and maintain a high index of suspicion for these side effects in patients on targeted therapy. Most ophthalmic adverse effects can be treated with specific ocular therapy without discontinuation of cancer treatment, although it is important to be aware of the life-threatening and vision-threatening circumstances that would require therapy cessation in conjunction with the patient’s oncologist. This review aims to summarize the ophthalmic adverse effects of targeted and hormonal anticancer agents and briefly describe their management.

Chronic heart failure has high morbidity and mortality, with approximately half of the patients dying within 5 years of diagnosis. Recent additions to the armamentarium of anti-heart failure therapies include angiotensin receptor-neprilysin inhibitors (ARNIs) and sodium/glucose cotransporter 2 inhibitors (SGLT2is). Both classes have demonstrated mortality and morbidity benefits. Although these new therapies have morbidity and mortality benefits, it is not known whether rapid initiation is beneficial when compared with the conventional, slower-stepped approach. Many clinicians have been taught that starting with low-dose therapies and gradually increasing the dose is a safe way of intensifying treatment regimens. Pharmacologically, it is rational to use a combination of drugs that target multiple pathological mechanisms, as there is potential synergism and better therapeutic outcomes. Theoretically, the quicker the right combinations are used, the more likely the beneficial effects will be experienced. However, rapid up-titration must be balanced with patient safety and tolerability. This study aims to determine if early addition of ARNIs, SGLT2is, β-blockers, and mineralocorticoid receptor antagonists (within 4 weeks), when compared with the same therapies initiated slower (within 6 months), will reduce all-cause mortality and hospitalizations for heart failure in patients with stable heart failure with reduced ejection fraction. This is a single-center, randomized controlled, double-arm, assessor-blinded, active control, and pragmatic clinical trial. Adults with stable heart failure with reduced ejection fraction and idiopathic dilated cardiomyopathy will be randomized to conventional sequencing (the control arm; over 6 months) of anti-heart failure therapies, and a second arm will receive rapid sequencing (over 4 weeks). Study participants will be followed for 5 years to assess the safety, efficacy, and tolerability of the 2 types of sequencing. Posttrial access and care will be provided to all study participants throughout their lifespan. We are currently in the process of obtaining ethical clearance and funding. We envisage that this study will help support evidence-based medicine and inform clinical practice guidelines on the optimal rate of sequencing of anti-heart failure therapies. A third placebo arm was considered, but costs would be too much and not providing study participants with therapies with known morbidity and mortality benefits may be unethical, in our opinion. Given the post-COVID-19 economic downturn and posttrial access to interventions, a major challenge will be acquiring funding for this study. PRR1-10.2196/44027.