Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.

BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

Systemic anticancer therapy for urothelial carcinoma: UK oncologists' perspective.

Urothelial carcinoma (UC) is a common cancer associated with a poor prognosis in patients with advanced disease. Platinum-based chemotherapy has remained the cornerstone of systemic anticancer treatment for many years, and recent developments in the treatment landscape have improved outcomes. In this review, we provide an overview of systemic treatment for UC, including clinical data supporting the current standard of care at each point in the treatment pathway and author interpretations from a UK perspective. Neoadjuvant cisplatin-based chemotherapy is recommended for eligible patients with muscle-invasive bladder cancer and is preferable to adjuvant treatment. For first-line treatment of advanced UC, platinum-eligible patients should receive cisplatin- or carboplatin-based chemotherapy, followed by avelumab maintenance in those without disease progression. Among patients unable to receive platinum-based chemotherapy, immune checkpoint inhibitor (ICI) treatment is an option for those with programmed death ligand 1 (PD-L1)-positive tumours. Second-line or later treatment options depend on prior treatment, and enfortumab vedotin is preferred after prior ICI and chemotherapy, although availability varies between countries. Additional options include rechallenge with platinum-based chemotherapy, an ICI, or non-platinum-based chemotherapy. Areas of uncertainty include the optimal number of first-line chemotherapy cycles for advanced UC and the value of PD-L1 testing for UC.

First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial.

Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population (N = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P < 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients. ClinicalTrials.gov Identifier: NCT03395197 .

Quantitative imaging of three-dimensional fiber orientation in the human brain via two illumination angles using polarization-sensitive optical coherence tomography.

The accurate measurement of three-dimensional (3D) fiber orientation in the brain is crucial for reconstructing fiber pathways and studying their involvement in neurological diseases. Optical imaging methods such as polarization-sensitive optical coherence tomography (PS-OCT) provide important tools to directly quantify fiber orientation at micrometer resolution. However, brain imaging based on the optic axis by PS-OCT so far has been limited to two-dimensional in-plane orientation, preventing the comprehensive study of connectivity in 3D. In this work, we present a novel method to obtain the 3D fiber orientation in full angular space with only two illumination angles. We measure the optic axis orientation and the apparent birefringence by PS-OCT from a normal and a 15 deg tilted illumination, and then apply a computational method yielding the 3D optic axis orientation and true birefringence. We verify that our method accurately recovers a large range of through-plane orientations from -85 deg to 85 deg with a high angular precision. We further present 3D fiber orientation maps of entire coronal sections of human cerebrum and brainstem with 10 µm in-plane resolution, revealing unprecedented details of fiber configurations. We envision that further development of our method will open a promising avenue towards large-scale 3D fiber axis mapping in the human brain and other complex fibrous tissues at microscopic level.

Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing. FINDINGS: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group. INTERPRETATION: Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. FUNDING: Pfizer.

Results from a Phase 1b/2 Study of Ibrutinib Combination Therapy in Advanced Urothelial Carcinoma.

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0-37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol.

BACKGROUND: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. METHODS: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). FINDINGS: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). INTERPRETATION: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Clinical testing of transcriptome-wide expression profiles in high-risk localized and metastatic prostate cancer starting androgen deprivation therapy: an ancillary study of the STAMPEDE abiraterone Phase 3 trial.

Metastatic and high-risk localized prostate cancer respond to hormone therapy but outcomes vary. Following a pre-specified statistical plan, we used Cox models adjusted for clinical variables to test associations with survival of multi-gene expression-based classifiers from 781 patients randomized to androgen deprivation with or without abiraterone in the STAMPEDE trial. Decipher score was strongly prognostic (p<2×10-5) and identified clinically-relevant differences in absolute benefit, especially for localized cancers. In metastatic disease, classifiers of proliferation, PTEN or TP53 loss and treatment-persistent cells were prognostic. In localized disease, androgen receptor activity was protective whilst interferon signaling (that strongly associated with tumor lymphocyte infiltration) was detrimental. Post-Operative Radiation-Therapy Outcomes Score was prognostic in localized but not metastatic disease (interaction p=0.0001) suggesting the impact of tumor biology on clinical outcome is context-dependent on metastatic state. Transcriptome-wide testing has clinical utility for advanced prostate cancer and identified worse outcomes for localized cancers with tumor-promoting inflammation.

The 'other' big complication: how chronic kidney disease impacts on cancer risks and outcomes.

Cancer is the second leading cause of death in people with chronic kidney disease (CKD) after cardiovascular disease. The incidence of CKD in patients with cancer is higher than in the non-cancer population. Across various populations, CKD is associated with an elevated risk of cancer incidence and cancer death compared with people without CKD, although the risks are cancer site-specific. Higher risk of cancer is detectable in mild CKD [estimated glomerular filtration rate (eGFR) 60-89 mL/min/1.73 m2], although this risk is more obvious if sensitive markers of kidney disease are used, such as cystatin C. Independent of eGFR, albuminuria is associated with increased risk of site-specific cancer incidence and death. Here, we explore the potential mechanisms for the increased risk of cancer observed in CKD, including patient factors (shared risks such as cardiometabolic disease, obesity, smoking, diet, lifestyle and environment), disease (genetic, inflammatory and infective) and treatment factors. In particular, we discuss the ways in which renal adverse events associated with conventional chemotherapies and newer systemic anti-cancer therapies (including targeted and immunotherapies) may contribute to worse cancer outcomes in people with CKD. Finally, we review the potential benefits of acknowledging increased risk of cancer in risk prediction tools used for the management of CKD.

A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma.

PURPOSE: A DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker-positive mUC. METHODS: DRD biomarker-positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model. RESULTS: Out of 248 patients, 74 (29.8%) were DRD biomarker-positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib. CONCLUSION: Maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.

Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial.

BACKGROUND: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival. METHODS: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression). RESULTS: Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity. CONCLUSIONS: There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.

Overall Survival Update for Patients with Metastatic Castration-resistant Prostate Cancer Treated with Capivasertib and Docetaxel in the Phase 2 ProCAID Clinical Trial.

The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47-1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36-0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63-3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor-targeted agents, which should be evaluated in prospective trials. PATIENT SUMMARY: The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor.

A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA).

BACKGROUND: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor. METHODS: NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity. RESULTS: In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype. CONCLUSIONS: NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery. CLINICAL TRIAL REGISTRATION: NCT03494816.

Mechanistic and Clinical Overview Cardiovascular Toxicity of BRAF and MEK Inhibitors: JACC: CardioOncology State-of-the-Art Review.

Rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors have revolutionized melanoma treatment. Approximately half of patients with melanoma harbor a BRAF gene mutation with subsequent dysregulation of the RAF-MEK-ERK signaling pathway. Targeting this pathway with BRAF and MEK blockade results in control of cell proliferation and, in most cases, disease control. These pathways also have cardioprotective effects and are necessary for normal vascular and cardiac physiology. BRAF and MEK inhibitors are associated with adverse cardiovascular effects including hypertension, left ventricular dysfunction, venous thromboembolism, atrial arrhythmia, and electrocardiographic QT interval prolongation. These effects may be underestimated in clinical trials. Baseline cardiovascular assessment and follow-up, including serial imaging and blood pressure assessment, are essential to balance optimal anti-cancer therapy while minimizing cardiovascular side effects. In this review, an overview of BRAF/MEK inhibitor-induced cardiovascular toxicity, the mechanisms underlying these, and strategies for surveillance, prevention, and treatment of these effects are provided.

Effects of metformin and statins on outcomes in men with castration-resistant metastatic prostate cancer: Secondary analysis of COU-AA-301 and COU-AA-302.

BACKGROUND: The associations of metformin and statins with overall survival (OS) and prostate specific antigen response rate (PSA-RR) in trials in metastatic castration-resistant prostate cancer remain unclear. OBJECTIVE: To determine whether metformin or statins ± abiraterone acetate plus prednisone/prednisolone (AAP) influence OS and PSA-RR. DESIGN, SETTING AND PARTICIPANT: COU-AA-301 and COU-AA-302 patients were stratified by metformin and statin use. Cox proportional hazards models were used to estimate hazards ratio (HR) stratified by concomitant medications, and a random effects model was used to pool HR. We compared PSA-RR using Chi χ2 test. RESULTS: In COU-AA-301-AAP, metformin was associated with improved PSA-RR (41.1% versus 28.6%) but not prolonged OS. In COU-AA-301-placebo-P, there was no association between metformin and prolonged OS or PSA-RR. In COU-AA-302-AAP, metformin was associated with prolonged OS (adjHR 0.69, 95% CI 0.48-0.98) and improved PSA-RR (72.7% versus 60.0%). In COU-AA-302-P, metformin was associated with prolonged OS (adjHR 0.66, 95% CI 0.47-0.93). In pooled analysis, OS was prolonged among those treated with metformin (pooled HR 0.77, 95% CI 0.62-0.95).In COU-AA-301-AAP, statins were associated with an improved OS (adjHR 0.76, 95% CI 0.62-0.93), while there was no difference in COU-AA-301-P. There was no association with statins and OS in either COU-AA-302 groups. When pooling HR, OS was prolonged among those treated with statins (pooled HR 0.78, 95% CI 0.68-0.88). CONCLUSION: Within the limitations of post-hoc sub-analyses, metformin and statins are associated with a prolonged OS and increased PSA-RR, particularly in combination with AAP.

Addition of nintedanib or placebo to neoadjuvant gemcitabine and cisplatin in locally advanced muscle-invasive bladder cancer (NEOBLADE): a double-blind, randomised, phase 2 trial.

BACKGROUND: Recurrence is common after neoadjuvant chemotherapy and radical treatment for muscle-invasive bladder cancer. We investigated the effect of adding nintedanib to neoadjuvant chemotherapy on response and survival in muscle-invasive bladder cancer. METHODS: NEOBLADE was a parallel-arm, double-blind, randomised, placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin chemotherapy with nintedanib or placebo in locally advanced muscle-invasive bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 15 hospitals in the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using permuted blocks with random block sizes of two or four, stratified by centre and glomerular filtration rate. Treatments were allocated using an interactive web-based system, and patients and investigators were masked to treatment allocation throughout the study. Patients received oral nintedanib (150 mg or 200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant chemotherapy with intravenous gemcitabine 1000 mg/m2 on days 1 and 8 and intravenous cisplatin 70 mg/m2 on day 1 of a 3-weekly cycle. The primary endpoint was pathological complete response rate, assessed at cystectomy or at day 8 of cyclde 3 (plus or minus 7 days) if cystectomy did not occur. Primary analyses were done in the intention-to-treat population. The trial is registered with EudraCT, 2012-004895-01, and ISRCTN, 56349930, and has completed planned recruitment. FINDINGS: Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The median follow-up for the study was 33·5 months (IQR 14·0-44·0). Pathological complete response in the intention-to-treat population was reached in 21 (37%) of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group (odds ratio [OR] 1·25, 70% CI 0·84-1·87; p=0·28). Grade 3 or worse toxicities were observed in 53 (93%) of 57 participants who received nintedanib and 50 (79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74-3·65; p=0·24). The most common grade 3 or worse adverse events were thromboembolic events (17 [30%] of 57 patients in the nintedanib group vs 13 [21%] of 63 patients in the placebo group [OR 1·63, 95% CI 0·71-3·76; p=0·29]) and decreased neutrophil count (22 [39%] in the nintedanib group vs seven [11%] in the placebo group [5·03, 1·95-13·00; p=0·0006]). 45 treatment-related serious adverse events occurred in the nintedanib group and 43 occurred in the placebo group. One treatment-related death occurred in the placebo group, which was due to myocardial infarction. INTERPRETATION: The addition of nintedanib to chemotherapy was safe but did not improve the rate of pathological complete response in muscle-invasive bladder cancer. FUNDING: Boehringer Ingelheim.

Refractive-index matching enhanced polarization sensitive optical coherence tomography quantification in human brain tissue.

The importance of polarization-sensitive optical coherence tomography (PS-OCT) has been increasingly recognized in human brain imaging. Despite the recent progress of PS-OCT in revealing white matter architecture and orientation, quantification of fine-scale fiber tracts in the human brain cortex has been a challenging problem, due to a low birefringence in the gray matter. In this study, we investigated the effect of refractive index matching by 2,2'-thiodiethanol (TDE) immersion on the improvement of PS-OCT measurements in ex vivo human brain tissue. We show that we can obtain fiber orientation maps of U-fibers that underlie sulci, as well as cortical fibers in the gray matter, including radial fibers in gyri and distinct layers of fibers exhibiting laminar organization. Further analysis shows that index matching reduces the noise in axis orientation measurements by 56% and 39%, in white and gray matter, respectively. Index matching also enables precise measurements of apparent birefringence, which was underestimated in the white matter by 82% but overestimated in the gray matter by 16% prior to TDE immersion. Mathematical simulations show that the improvements are primarily attributed to the reduction in the tissue scattering coefficient, leading to an enhanced signal-to-noise ratio in deeper tissue regions, which could not be achieved by conventional noise reduction methods.

Healthcare Costs for Metastatic Castration-Resistant Prostate Cancer Patients Treated with Abiraterone or Enzalutamide.

OBJECTIVE: The aim was to assess the real-world healthcare resource use and direct medical costs for metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide, in whom chemotherapy is not yet indicated (pre-chemotherapy) or who had previously received docetaxel-based chemotherapy (post-chemotherapy), before commencing these medicines. METHODS: A retrospective cost analysis of mCRPC patients who commenced abiraterone or enzalutamide between 2012 and 2015 was conducted. Routinely collected datasets from the largest health board in Scotland and the UK, Greater Glasgow and Clyde, were linked. They contained information on patient demographics, diagnosis, outpatient consultations, hospital admissions, treatments (abiraterone and enzalutamide), and supportive medicines. Unit costs were obtained from the Scottish Health Service Costs, Personal Social Services Research Unit, and British National Formulary. Generalised linear model-based regression was used to estimate total mean direct costs, and two-part models were used to estimate separate cost components. All models were adjusted for propensity score and key variables. Sensitivity analysis was conducted to explore the impact of hypothetical patient access scheme discounts. RESULTS: Estimated total mean direct medical costs of treating mCRPC patients were similar, albeit with wide and overlapping confidence intervals. Across both treatments, patients who received abiraterone or enzalutamide in a pre-chemotherapy setting incurred the highest total mean direct medical costs. However, post-chemotherapy patients were associated with higher outpatient clinic visits, inpatient hospital admissions, and supportive medicines. Regarding relative contribution to the total mean direct medical cost, the treatment costs were the main contributor, followed by inpatient admissions, outpatient clinic visits, and supportive medicines. CONCLUSION: The total mean direct medical costs were similar for abiraterone and enzalutamide patients. The costs were not driven by the choice of treatment regimen, but treatment setting (pre-chemotherapy or post-chemotherapy indications) and related healthcare resource utilisation. Future studies should focus on economic evaluations, such as cost-effectiveness analyses, using real-world data.

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.

BACKGROUND: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544. FINDINGS: Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63-73) and median PSA 34 ng/ml (14·7-47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60-84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]-NE) than in the control groups (not reached, 97-NE; hazard ratio [HR] 0·53, 95% CI 0·44-0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79-85) in the combination-therapy group and 69% (66-72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70-1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached [IQR NE-NE] in the combination-therapy groups vs not reached [103-NE] in the control groups; HR 0·60, 95% CI 0·48-0·73, p<0·0001), prostate cancer-specific survival (not reached [NE-NE] vs not reached [NE-NE]; 0·49, 0·37-0·65, p<0·0001), biochemical failure-free-survival (not reached [NE-NE] vs 86 months [83-NE]; 0·39, 0·33-0·47, p<0·0001), and progression-free-survival (not reached [NE-NE] vs not reached [103-NE]; 0·44, 0·36-0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death). INTERPRETATION: Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.