ABSTRACT
BACKGROUND: Taxane- based chemotherapy is widely used in patients with platinum- and immunotherapy refractory, metastatic urothelial carcinoma (mUC). Outcomes are poor and biomarkers associated with outcome are lacking. We aim to identify cancer hallmarks associated with survival in patients receiving paclitaxel. METHODS: Whole-transcriptome profiles were generated for a subset of patients enrolled in a randomised phase II study investigating paclitaxel and pazopanib in platinum refractory mUC (PLUTO, EudraCT 2011-001841-34). Estimates of gene expression were calculated and input into the Almac proprietary analysis pipeline and signature scores were calculated using ClaraT V3.0.0. Ten key gene signatures were assessed: Immuno-Oncology, Epithelial to Mesenchymal Transition, Angiogenesis, Proliferation, Cell Death, Genome Instability, Energetics, Inflammation, Immortality and Evading Growth. Hazard ratios were calculated using Cox regression model and Kaplan-Meier methods were used to estimate progression free survival (PFS) and overall survival (OS). RESULTS: 38 and 45 patients treated with paclitaxel or pazopanib were included. Patients with high genome instability expression treated with paclitaxel had significantly improved survival with a HR of 0.29 (95% CI: 0.14-0.61, p=0.001) and HR 0.34 (95% CI: 0.17-0.69, p=0.003) for PFS and OS, respectively. Similarly, patients with high evading growth suppressor expression treated with paclitaxel had improved PFS and OS with a HR of 0.35 (95% CI: 0.19-0.77, p=0.007) and HR 0.46 (95% CI: 0.23-0.91, p=0.026), respectively. No other gene signatures had significant impact on outcome. In both paclitaxel and pazopanib cohorts, angiogenesis activation was associated with worse PFS and OS, and VEGF targeted therapy did not improve outcomes. CONCLUSION: High Genome-instability and Evading-growth suppressor biologies are associated with improved survival in patients with platinum refractory mUC receiving paclitaxel. These may refine mUC risk stratification and guide treatment decision in the future.
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BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).
Subject(s)
Chemoradiotherapy , Uterine Cervical Neoplasms , Adult , Female , Humans , Chemoradiotherapy/methods , Cisplatin/administration & dosage , Cisplatin/therapeutic use , United Kingdom , Uterine Cervical Neoplasms/therapy , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/pathology , Clinical Trials, Phase I as Topic , Multicenter Studies as TopicABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzamides , Docetaxel , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant , Pyrimidines , Humans , Male , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/therapeutic use , Phenylthiohydantoin/adverse effects , Docetaxel/administration & dosage , Docetaxel/therapeutic use , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Middle Aged , Double-Blind Method , Pyrimidines/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Androstenes/therapeutic use , Androstenes/administration & dosage , Aged, 80 and over , PyrrolesABSTRACT
BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Adjuvants, Immunologic , Platinum , Retrospective StudiesABSTRACT
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.
Subject(s)
Antineoplastic Agents, Immunological , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/pathology , Cisplatin , B7-H1 Antigen , Platinum/therapeutic use , United Kingdom , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Aim: The cost-effectiveness of avelumab first-line maintenance treatment for locally advanced or metastatic urothelial carcinoma in Scotland was assessed. Materials & methods: A partitioned survival model was developed comparing avelumab plus best supportive care (BSC) versus BSC alone, incorporating JAVELIN Bladder 100 trial data, costs from national databases and published literature and clinical expert validation of assumptions. Incremental cost-effectiveness ratio (ICER) was estimated using lifetime costs and quality-adjusted life-years (QALY). Results: Avelumab plus BSC had incremental costs of £9446 and a QALY gain of 0.63, leading to a base-case (deterministic) ICER of £15,046 per QALY gained, supported by robust sensitivity analyses. Conclusion: Avelumab first-line maintenance is likely to be a cost-effective treatment for locally advanced or metastatic urothelial carcinoma in Scotland.
What is this article about? This study looked at the costs of avelumab when given as maintenance treatment for people in Scotland with advanced urothelial carcinoma, compared with the longer survival and other benefits that it provides. How was this done? Researchers estimated the costs and treatment benefits expected with avelumab using data from a clinical trial called JAVELIN Bladder 100, national databases, data from previously published studies and expert opinions. What were the results? Costs associated with using avelumab maintenance treatment for people with advanced urothelial carcinoma in Scotland were considered to be acceptable based on the benefits it provides. What do the results of the study mean? These results support the use of avelumab first-line maintenance as a standard treatment for people with advanced urothelial carcinoma in Scotland.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Carcinoma, Transitional Cell/drug therapy , Cost-Effectiveness Analysis , Urinary Bladder Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Cost-Benefit Analysis , Quality-Adjusted Life YearsABSTRACT
BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.
Subject(s)
Carcinoma, Transitional Cell , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Metformin , Urinary Bladder Neoplasms , Humans , Proton Pump Inhibitors , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Metformin/therapeutic use , Retrospective StudiesABSTRACT
BACKGROUND: Bladder and urinary tract cancers account for approximately 21,000 new diagnoses and 5,000 deaths annually in the UK. Approximately 90% are transitional cell carcinomas where advanced disease is treated with platinum based chemotherapy and PD-1/PD-L1 directed immunotherapy. Urinary tract squamous cell carcinoma (UTSCC) accounts for about 5% of urinary tract cancers overall making this a rare disease. We have yet to establish definitive systemic treatment options for advanced UTSCC. Preliminary translational data, from UTSCC patient tumour samples, indicate high PD-L1 expression and tumour infiltrating lymphocytes in a proportion of cases. Both of these features are associated with differential gene expression consistent with a tumour/immune microenvironment predicted to be susceptible to immune checkpoint directed immunotherapy which we will evaluate in the AURORA trial. METHODS: AURORA is a single arm, open-label, multicentre,UK phase II clinical trial. 33 patients will be recruited from UK secondary care sites. Patients with UTSCC, suitable for treatment with palliative intent, will receive atezolizumab PD-L1 directed immunotherapy (IV infusion, 1680 mg, every 28 days) for one year if tolerated. Response assessment, by cross sectional imaging will occur every 12 weeks. AURORA uses a Simon's 2-stage optimal design with best overall objective response rate (ORR, by RECIST v1.1) at a minimum of 12 weeks from commencing treatment as the primary endpoint. Secondary endpoints will include overall survival, progression-free survival, duration of response, magnitude of response using waterfall plots of target lesion measurements, quality of life using the EORTC QLQ-C30 tool, safety and tolerability (CTCAE v5) and evaluation of potential biomarkers of treatment response including PD-L1 expression. Archival tumour samples and blood samples will be collected for translational analyses. DISCUSSION: If this trial shows atezolizumab to be safe and effective it may lead to a future late phase randomised controlled trial in UTSCC. Ultimately, we hope to provide a new option for treatment for such patients. TRIAL REGISTRATIONS: EudraCT Number: 2021-001995-32 (issued 8th September 2021); ISRCTN83474167 (registered 11 May 2022); NCT05038657 (issued 9th September 2021).
Subject(s)
Carcinoma, Squamous Cell , Urinary Tract , Humans , B7-H1 Antigen , Quality of Life , Carcinoma, Squamous Cell/drug therapy , Tumor Microenvironment , Randomized Controlled Trials as Topic , Clinical Trials, Phase II as Topic , Multicenter Studies as TopicABSTRACT
BACKGROUND: Androgen deprivation therapy (ADT) is prescribed to almost half of all men diagnosed with prostate cancer. Although ADT is effective treatment, with virtually all men with advanced disease showing initial clinical response, it is associated with troublesome side effects including hot flushes and night sweats (HFNS). HFNS can be both frequent and severe and can have a significant impact on quality of life (QoL). They can occasionally be so debilitating that patients stop ADT altogether, despite the increased risk of disease relapse or death. Previous research has found that guided self-help cognitive behavioural therapy (CBT) can be effective in reducing HFNS due to ADT when delivered by a clinical psychologist. MANCAN2 aims test whether we can train the existing NHS Prostate Cancer Nurse Specialist (CNS) team to deliver guided self-help CBT and whether it is effective in reducing the impact of HFNS in men undergoing ADT. METHODS: MANCAN2 is a phase III multicentre randomised controlled trial and process evaluation. Between 144 and 196 men with prostate cancer who are currently receiving ADT and are experiencing problematic HFNS will be individually randomised in a 1:1 ratio in groups of 6-8 participants to either treatment as usual (TAU) or participation in the guided self-help CBT intervention plus TAU. A process evaluation using the normalisation process theory (NPT) framework will be conducted, to understand the CNS team's experiences of delivering the intervention and to establish the key influencers to its implementation as a routine practice service. Fidelity of implementation of the intervention will be conducted by expert assessment. The cost-effectiveness of the intervention and participant adherence to the trial intervention will also be assessed. DISCUSSION: MANCAN2 will advance the program of work already conducted in development of management strategies for HFNS. This research will determine whether the severity of ADT-induced HFNS in men with prostate cancer can be reduced by a guided self-help CBT intervention, delivered by the existing NHS prostate cancer CNS team, within a multicentre study. The emphasis on this existing team, if successful, should facilitate translation through to implementation in routine practice. TRIAL REGISTRATION: ISRCTN reference 58720120 . Registered 13 December 2022.
Subject(s)
Cognitive Behavioral Therapy , Prostatic Neoplasms , Male , Humans , Androgen Antagonists/adverse effects , Androgens , Quality of Life , Prostatic Neoplasms/drug therapy , Sweat , Neoplasm Recurrence, Local , Hot Flashes/therapyABSTRACT
Muscle-invasive bladder cancer has poor prognosis. If organ confined, it is potentially curable; however, across all prognostic groups, approximately half of patients will relapse. For patients with advanced disease, the median overall survival remains under two years. Systemic treatment options are centered on the use of platinum-based combination chemotherapy, with the choice of cisplatin- or carboplatin-based regimens determined on the basis of criteria including performance status and renal function. PD-1/PD-L1 checkpoint-directed immunotherapy has been established for use in advanced disease with modest overall improvements in survival outcomes. Based on current data, optimal utilization appears to be a switch maintenance strategy on completion of chemotherapy. In the curative setting, cisplatin-based chemotherapy provides modest improvements in cure rates in those fit to receive it. Data on the use of adjuvant immunotherapy are currently contradictory, with disease-free survival demonstrated for adjuvant nivolumab, but not atezolizumab, and no overall survival benefit has yet been confirmed. The Nectin-4 directed antibody drug conjugate enfortumab vedotin is an established treatment option for patients previously treated with both chemotherapy and immunotherapy. The emerging therapeutic targets under evaluation include Trop-2 with sacituzumab govitecan, fibroblast growth factor receptors, HER2, and DNA repair deficiency in biomarker-selected patients. The development of properly validated predictive biomarkers has proven challenging for this disease and should be a central priority in the future development of treatment options. This review summarizes the available systemic treatment options in both palliative and curative disease settings, and highlights the available evidence and current limitations for making treatment recommendations.
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BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Male , Female , Humans , Carcinoma, Transitional Cell/pathology , Cisplatin/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy ProtocolsABSTRACT
Background: Prostate cancer is the most commonly diagnosed malignancy in the UK. Castrate resistant prostate cancer (CRPC) can be difficult to manage with response to next generation hormonal treatment variable. AR-V7 is a protein biomarker that can be used to predict response to treatment and potentially better inform management in these patients. Our aim was to establish the feasibility of conducting a definitive randomised controlled trial comparing the clinical utility of AR-V7 biomarker assay in personalising treatments for patients with metastatic CRPC within the United Kingdom (UK) National Health Service (NHS). Due to a number of issues the trial was not completed successfully, we aim to discuss and share lessons learned herein. Methods: We conducted a randomised, open, feasibility trial, which aimed to recruit 70 adult men with metastatic CRPC within three secondary care NHS trusts in the UK to be run over an 18-month period. Participants were randomised to personalised treatment based on AR-V7 status (intervention) or standard care (control). The primary outcome was feasibility, which included: recruitment rate, retention and compliance. Additionally, a baseline prevalence of AR-V7 expression was to be estimated. Results: Fourteen participants were screened and 12 randomised with six into each arm over a nine-month period. Reliability issues with the AR-V7 assay meant prevalence was not estimated. Due to limited recruitment the study did not complete to target. Conclusions: Whilst the trial did not complete to target, we have ascertained that men with advanced cancer are willing to take part in trials utilising biomarker guided treatment. A number of issues were identified that serve as important learning points in future clinical trials.
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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.
Subject(s)
Carcinoma, Transitional Cell , Ovarian Neoplasms , Urinary Bladder Neoplasms , Female , Humans , Ovarian Neoplasms/drug therapy , Poly(ADP-ribose) Polymerases/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Urinary Bladder Neoplasms/drug therapy , Platinum/therapeutic use , Biomarkers , Adenosine Diphosphate Ribose/therapeutic use , Double-Blind Method , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Maintenance ChemotherapyABSTRACT
BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors have activity in various cancers. Metastatic urothelial carcinoma (MUC) is platinum sensitive and a subset harbour DNA repair gene alterations. OBJECTIVE: To assess evidence for efficacy and safety of PARP inhibition for MUC. METHODS: This systematic review included randomised clinical trials (RCTs) evaluating PARP inhibitors as monotherapy, or in therapeutic combinations, compared to relevant comparators or best supportive care. The primary endpoint was progression free survival (PFS). We searched MEDLINE (Ovid), EMBASE, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials from March 2013 to March 2023. Each study was appraised using the Cochrane Risk of Bias 2 Tool. Study results were synthesised descriptively. Registration: PROSPERO CRD42023403145. RESULTS: From 247 identified reports, we included three phase 2 RCTs including 252 patients. Two RCTs assessed PARP inhibition in unselected patient groups (one first line platinum ineligible, one post chemotherapy maintenance) and found no evidence of efficacy. All three RCTs assessed subgroups defined by biomarker selection for somatic DNA repair defects. Two of these identified PFS benefit with PARP inhibition compared to a relevant comparator (one first line in combination with immunotherapy, one maintenance monotherapy). Safety outcomes were consistent with prior experience of PARP inhibitors. The risk of bias across the outcomes was generally low. CONCLUSIONS: PARP inhibitors lack efficacy for unselected MUC patients. Phase 2 RCTs support further investigation of PARP inhibition within biomarker-selected patient subsets. The optimal biomarker is not yet determined. Limitations in the current evidence relate to small sample sizes and low statistical power.
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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.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamides , Disease-Free Survival , Docetaxel/therapeutic use , Humans , Male , Nitriles/therapeutic use , Phenylthiohydantoin , Phosphatidylinositol 3-Kinases , Prospective Studies , Prostatic Neoplasms, Castration-Resistant/pathology , Proto-Oncogene Proteins c-akt , Pyrimidines , Pyrroles , Receptors, Androgen , Treatment OutcomeABSTRACT
BACKGROUND: Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC). OBJECTIVE: To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial. DESIGN, SETTING, AND PARTICIPANTS: ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy. INTERVENTION: Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements. RESULTS AND LIMITATIONS: The median follow-up time was 25 mo (95% confidence interval [CI] 25-26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21-41). Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65-94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24-1.5], p = 0.26, and 0.72 [95% CI 0.31-1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09-0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3-13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work. CONCLUSIONS: Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future. PATIENT SUMMARY: We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy.
Subject(s)
Antibodies, Monoclonal, Humanized , Circulating Tumor DNA , Neoadjuvant Therapy , Urinary Bladder Neoplasms , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Circulating Tumor DNA/analysis , Cisplatin/therapeutic use , Cystectomy/methods , Humans , Muscle Neoplasms/drug therapy , Muscles/pathology , Neoadjuvant Therapy/methods , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgeryABSTRACT
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.
Subject(s)
Cisplatin , Urinary Bladder Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/adverse effects , Deoxycytidine/analogs & derivatives , Double-Blind Method , Female , Humans , Indoles , Male , Muscles , Neoadjuvant Therapy/adverse effects , Urinary Bladder Neoplasms/drug therapy , GemcitabineABSTRACT
This study used linked, routinely-collected datasets to explore incidence, clinical characteristics and outcomes of prostate cancer (PC) patients who experience a rise in prostate-specific antigen (PSA) levels despite androgen deprivation therapy (ADT), without evidence of metastases in their patient record, termed non-metastatic castration-resistant PC (nmCRPC). Routinely collected administrative data in Wales were used to identify patients diagnosed with PC and nmCRPC from 2000-2015. Logrank tests and Cox proportional hazard models were used to compare time-to-events across subgroups defined by PSA doubling time and age. Of 38,021 patients identified with PC, 1,465 met nmCRPC criteria. PC incidence increased over the study period, while nmCRPC categorizations reduced. Median time from PC diagnosis to nmCRPC categorization was 3.07 years (95% confidence interval [CI] 2.91-3.26) and from nmCRPC categorization to metastases/death was 2.86 years (95% CI 2.67-3.09). Shorter PSA doubling time (≤ 10 months, versus > 10 months) was associated with reduced time to metastases or death (2.11 years [95% CI 1.92-2.30] versus 5.22 years [95% CI 4.87-5.51]). Age was not significantly associated with time to metastases/death. Our findings highlight key clinical characteristics and outcomes for patients with nmCRPC prior to the introduction of recently approved treatments.