Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer.

Purpose: Adding ipatasertib to abiraterone and prednisone/prednisolone significantly improved radiographic progression-free survival for patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN-loss tumours by immunohistochemistry in the IPATential150 trial (NCT03072238). Here we characterise the safety of these agents in subpopulations and assess manageability of key adverse events (AEs).

Materials And Methods: In this randomised, double-blind, phase 3 trial, patients with previously untreated asymptomatic or mildly symptomatic mCRPC were randomised 1:1 to receive ipatasertib-abiraterone or placebo-abiraterone (all with prednisone/prednisolone).

Algorithmic considerations when analysing capture Hi-C data.

Chromosome conformation capture methodologies have provided insight into the effect of 3D genomic architecture on gene regulation. Capture Hi-C (CHi-C) is a recent extension of Hi-C that improves the effective resolution of chromatin interactions by enriching for defined regions of biological relevance. The varying targeting efficiency between capture regions, however, introduces bias not present in conventional Hi-C, making analysis more complicated.

A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer.

Purpose: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737.

Patients And Methods: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15.

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study.

Purpose: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented.

Methods: Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy.

Talazoparib, a Poly(ADP-ribose) Polymerase Inhibitor, for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses.

Background: The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib.

Patients And Methods: Men received talazoparib 1 mg/day (moderate renal impairment 0.

Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study.

Background: Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC).

Objective: To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC.

Design, Setting, And Participants: Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening.

Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound.

Purpose: Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes.

A phase space model of a Versa HD linear accelerator for application to Monte Carlo dose calculation in a real-time adaptive workflow.

Purpose: This study aims to develop and validate a simple geometric model of the accelerator head, from which a particle phase space can be calculated for application to fast Monte Carlo dose calculation in real-time adaptive photon radiotherapy. With this objective in view, the study investigates whether the phase space model can facilitate dose calculations which are compatible with those of a commercial treatment planning system, for convenient interoperability.

Materials And Methods: A dual-source model of the head of a Versa HD accelerator (Elekta AB, Stockholm, Sweden) was created.

Mapping Local Failure Following Bladder Radiotherapy According to Dose.

Aims: To determine the relationship between local relapse following radical radiotherapy for muscle-invasive bladder cancer (MIBC) and radiation dose.

Materials And Methods: Patients with T2-4N0-3M0 MIBC were recruited to a phase II study assessing the feasibility of intensity-modulated radiotherapy to the bladder and pelvic lymph nodes. Patients were planned to receive 64 Gy/32 fractions to the bladder tumour, 60 Gy/32 fractions to the involved pelvic nodes and 52 Gy/32 fractions to the uninvolved bladder and pelvic nodes.

Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER.

Background: Statins and metformin are commonly prescribed for patients, including those with prostate cancer. Preclinical and epidemiologic studies of each agent have suggested anti-cancer properties.

Methods: Patient data from three randomised, double-blind, placebo-controlled, phase III studies evaluating enzalutamide (AFFIRM, PREVAIL and PROSPER) in patients with castration-resistant prostate cancer were included in this analysis.

Feasibility of tumour-focused adaptive radiotherapy for bladder cancer on the MR-linac.

Bladder tumour-focused magnetic resonance image-guided adaptive radiotherapy using a 1.5 Tesla MR-linac is feasible. A full online workflow adapting to anatomy at each fraction is achievable in approximately 30 min.

A recurrent neural network for rapid detection of delivery errors during real-time portal dosimetry.

Background And Purpose: Real-time portal dosimetry compares measured images with predicted images to detect delivery errors as the radiotherapy treatment proceeds. This work aimed to investigate the performance of a recurrent neural network for processing image metrics so as to detect delivery errors as early as possible in the treatment.

Materials And Methods: Volumetric modulated arc therapy (VMAT) plans of six prostate patients were used to generate sequences of predicted portal images.

SEAFARER - A new concept for validating radiotherapy patient specific QA for clinical trials and clinical practice.

Background: The quality of radiotherapy delivery has been shown to significantly impact clinical outcomes including patient survival. To identify errors, institutions perform Patient Specific Quality Assurance (PSQA) assessing each individual radiotherapy plan prior to starting patient treatments. Externally administered Dosimetry Audits have found problems despite institutions passing their own PSQA.

Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma.

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.

Targeting radioresistance and replication fork stability in prostate cancer.

The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC).

Characterization of Acoustic, Cavitation, and Thermal Properties of Poly(vinyl alcohol) Hydrogels for Use as Therapeutic Ultrasound Tissue Mimics.

The thermal and mechanical effects induced in tissue by ultrasound can be exploited for therapeutic applications. Tissue-mimicking materials (TMMs), reflecting different soft tissue properties, are required for experimental evaluation of therapeutic potential. In the study described here, poly(vinyl alcohol) (PVA) hydrogels were characterized.

Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score.

Purpose: The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048.

Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist-Treated Prostate Cancers.

Unlabelled: Inhibiting androgen signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms, including the role of AR expressed in other cell types within the tumor microenvironment, will extend the clinical benefit of AR-targeted therapy.

Clinical Implementation of Robust Multi-isocentric Volumetric Modulated Arc Radiotherapy for Craniospinal Irradiation.

Aims: To determine if multi-isocentric volumetric modulated arc radiotherapy for craniospinal irradiation (CSI-VMAT) can be implemented safely and accurately using robust optimisation in a commercially available treatment planning system. Our initial clinical experience is reported for the first 20 patients treated with the technique.

Materials And Methods: Patients received between 23.

Interobserver variability in target volume delineation for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer.

Objectives: Quantify target volume delineation uncertainty for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer. Define optimal imaging sequences for target delineation.

Methods: Six experienced radiation oncologists delineated clinical target volumes (CTVs) on CT and 2D and 3D-MRI in three patients with rectal cancer, using consensus contouring guidelines.

Monte Carlo calculation of detector perturbation and quality correction factors in a 1.5 T magnetic resonance guided radiation therapy small photon beams.

With future advances in magnetic resonance imaging-guided radiation therapy, small photon beams are expected to be included regularly in clinical treatments. This study provides physical insights on detector dose-response to multiple megavoltage photon beam sizes coupled to magnetic fields and determines optimal orientations for measurements.Monte Carlo simulations determine small-cavity detector (solid-state: PTW60012 and PTW60019, ionization chambers: PTW31010, PTW31021, and PTW31022) dose-responses in water to an Elekta Unity 7 MV FFF photon beam.