Anti-angiogenic agents, such as vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and anti-VEGF antibodies, and immune checkpoint inhibitors (CPIs) are standard treatments ...for advanced renal cell carcinoma (aRCC). In the past, these agents were administered as sequential monotherapies. Recently, combinations of anti-angiogenic agents and CPIs have been approved for the treatment of aRCC, based on evidence that they provide superior efficacy when compared with sunitinib monotherapy. Here we explore the possible mechanisms of action of these combinations, including a review of relevant preclinical data and clinical evidence in patients with aRCC. We also ask whether the benefit is additive or synergistic, and, thus, whether concomitant administration is preferred over sequential monotherapy. Further research is needed to understand how combinations of anti-angiogenic agents with CPIs compare with CPI monotherapy or combination therapy (e.g., nivolumab and ipilimumab), and whether the long-term benefit observed in a subset of patients treated with CPI combinations will also be realised in patients treated with an anti-angiogenic therapy and a CPI. Additional research is also needed to establish whether other elements of the tumour microenvironment also need to be targeted to optimise treatment efficacy, and to identify biomarkers of response to inform personalised treatment using combination therapies.
To test the hypothesis that sequential (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), ...patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant.
Forty-four untreated mRCC patients were enrolled into this prospective phase II study. (18)F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUV(max)) at 4 and 16 weeks with overall survival (OS).
Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUV(max) = 6.8, range: <2.5-18.4). In multivariate analysis, a high SUV(max) and an increased number of PET-positive lesions correlated with shorter OS HR: 3.30 (95% CI: 1.36-8.45) and 3.67 (95% CI: 1.43-9.39), respectively. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40-1.99) or OS (HR for responders = 0.80; 95% CI: 0.34-1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS HR = 5.96 (95% CI: 2.43-19.02) and HR = 12.13 (95% CI: 3.72-46.45), respectively.
Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant.
Purpose
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that imposes a major burden on patients and healthcare systems. Three structured literature reviews (treatment ...guidelines, treatment landscape, and human/clinical/patient burden) and one systematic literature review (economic burden) were conducted to better understand the disease burden and unmet needs for patients with late-stage mCRPC, for whom optimal treatment options are unclear.
Methods
Embase
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, MEDLINE
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, MEDLINE
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In-Process, the CENTRAL database (structured and systematic reviews), and the Centre for Reviews and Dissemination database (systematic review only) were searched for English-language records from 2009 to 2021 to identify mCRPC treatment guidelines and studies related to the treatment landscape and the humanistic/economic burden of mCRPC in adult men (aged ≥18 years) of any ethnicity.
Results
In total, six records were included for the treatment patterns review, 14 records for humanistic burden, nine records for economic burden, three records (two studies) for efficacy, and eight records for safety. Real-world treatment patterns were broadly aligned with treatment guidelines and provided no optimal treatment sequencing beyond second line other than palliative care. Current post-docetaxel treatments in mCRPC are associated with adverse events that cause relatively high rates of treatment discontinuation or disruption. The humanistic and economic burdens associated with mCRPC are high.
Conclusion
The findings highlight a lack of treatment options with novel mechanisms of action and more tolerable safety profiles that satisfy a risk-to-benefit ratio aligned with patient needs and preferences for patients with late-stage mCRPC. Treatment approaches that improve survival and health-related quality of life are needed, ideally while simultaneously reducing costs and healthcare resource utilization.
Prostate cancer remains a major cause of male mortality. Genetic alteration of the PI3K/AKT/mTOR pathway is one of the key events in tumor development and progression in prostate cancer, with ...inactivation of the PTEN tumor suppressor being very common in this cancer type. Extensive evaluation has been performed on the therapeutic potential of PI3K/AKT/mTOR inhibitors and the resistance mechanisms arising in patients with PTEN-mutant background. However, in patients with a PTEN wild-type phenotype, PI3K/AKT/mTOR inhibitors have not demonstrated efficacy, and this remains an area of clinical unmet need. In this study, we have investigated the response of PTEN wild-type prostate cancer cell lines to the dual PI3K/mTOR inhibitor DS-7423 alone or in combination with HER2 inhibitors or mGluR1 inhibitors. Upon treatment with the dual PI3K/mTOR inhibitor DS-7423, PTEN wild-type prostate cancer CWR22/22RV1 cells upregulate expression of the proteins PSMA, mGluR1, and the tyrosine kinase receptor HER2, while PTEN-mutant LNCaP cells upregulate androgen receptor and HER3. PSMA, mGluR1, and HER2 exert control over one another in a positive feedback loop that allows cells to overcome treatment with DS-7423. Concomitant targeting of PI3K/mTOR with either HER2 or mGluR1 inhibitors results in decreased cell survival and tumor growth in xenograft studies. Our results suggest a novel therapeutic possibility for patients with PTEN wild-type PI3K/AKT-mutant prostate cancer based in the combination of PI3K/mTOR blockade with HER2 or mGluR1 inhibitors.
Background
Metastatic prostate cancer has a 30% 5-year survival rate despite recent therapeutic advances. There is a need to improve the clinical understanding and treatment of this disease, ...particularly in the real-world setting and among patients who are under-represented in clinical trials.
Objective
We aimed to evaluate the characteristics and clinical outcomes of patients who received their first treatment for metastatic castration-resistant prostate cancer (mCRPC) in routine clinical practice, independent of treatment used, including subgroups with baseline cardiac disease, diabetes mellitus, or visceral metastases.
Patients and methods
Prospective, noninterventional analysis of patient record data in the multicenter Prostate Cancer Registry (PCR) of men with mCRPC. The data were collected in 16 countries with the aim of recruiting more than 3000 patients between 2013 and 2016. The study end date was 9 July 2018. Data evaluated included baseline characteristics, treatment exposure, and efficacy outcomes overall survival (OS) and time to progression (TTP) of patients treated with abiraterone acetate plus prednisone or prednisolone (collectively, “abiraterone”), enzalutamide, or docetaxel. Descriptive outcomes are reported from the overall patient population and subgroups of patients with baseline cardiovascular disease, diabetes mellitus, or visceral metastases. The treatment effects for time to progression were compared for the overall patient population.
Results
The study enrollment period lasted 2.5 years, and each patient was followed for a maximum of 3 years. A total of 1874 patients in the PCR had not received previous mCRPC treatment at baseline, although they had received androgen-deprivation therapy. Prevalent co-morbidities included cardiovascular disease in 65.4% and diabetes mellitus in 17.4% of patients. Baseline characteristics suggested that patients with more advanced disease received docetaxel treatment. In the overall patient population, the median time to progression with abiraterone, enzalutamide, and docetaxel as first-line mCRPC therapy was 9.6, 10.3, and 7.6 months, respectively, and median OS was 27.1, 27.1, and 27.9 months, respectively. Outcomes in the subgroups of patients with cardiovascular disease or diabetes mellitus were similar to those of the whole population in the analysis. As expected, patients with visceral metastases had shorter TTP and OS than patients in the overall population.
Conclusions
This analysis shows, for the first time, the effectiveness in parallel of first-line abiraterone, enzalutamide, and docetaxel in mCRPC, including in patients with co-morbidities such as cardiovascular disease or diabetes mellitus or in patients with visceral metastases. These real-world findings from the PCR provide meaningful information to help manage mCRPC, particularly in patients under-represented in clinical studies.
Trial Registration
ClinicalTrials.gov identifier NCT02236637; registered September 2014.
Introduction
The present study aimed to indirectly compare apalutamide and enzalutamide with respect to tolerability and health-related quality of life (HRQoL) among men with non-metastatic ...castration-resistant prostate cancer (nmCRPC).
Methods
Patient-level data from the SPARTAN study apalutamide + androgen deprivation therapy (ADT) versus placebo + ADT and aggregate published data from the PROSPER study (enzalutamide + ADT versus placebo + ADT) were used. Anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting patients’ baseline characteristics from SPARTAN to match aggregated baseline characteristics in PROSPER. Odds ratios (ORs) of reported adverse events (AEs) and baseline-to-follow-up least squares mean differences in HRQoL measured with Functional Assessment of Cancer Therapy-Prostate (FACT-P) score with 95% credible intervals were re-estimated for SPARTAN arms using weighted population and indirectly compared with those in PROSPER through a Bayesian framework. Events of special interest included fatigue, hot flush, nausea, diarrhea, hypertension, falls, dizziness, decreased appetite, arthralgia, asthenia and headache. In addition, any AEs and serious AEs were explored.
Results
Of 1207 SPARTAN patients, 1171 were matched to 1401 PROSPER patients. Relative to enzalutamide, apalutamide demonstrated better tolerability as evidenced by the highest probability of reduced occurrence of fatigue
p
(OR < 1) = 99.5%, hypertension
p
(OR < 1) = 99.2%, decreased appetite
p
(OR < 1) = 98.3%, fall
p
(OR < 1) = 90.3%, headaches
p
(OR < 1) = 86.7%, and nausea
p
(OR < 1) = 80.0%. The probabilities of reduced occurrence of any AEs and SAEs with apalutamide versus enzalutamide were 66.9% and 90.9%, respectively. Relative to enzalutamide, apalutamide treatment was associated with a higher probability of a better HRQoL based on the FACT-P total score
p
(diff > 0) = 73.1%. The probability of a better HRQoL with apalutamide versus enzalutamide was highest for the physical
p
(diff > 0) = 97.3% and functional
p
(diff > 0) = 86.7% wellbeing subscales, and the pain-related subscale
p
(diff > 0) = 90.1%.
Conclusion
Anchored MAIC suggests that treatment of men with nmCRPC with apalutamide is associated with a higher probability of better tolerability due to fewer AEs and better HRQoL than enzalutamide.
Metastatic urothelial cancer (UC) is the eighth most common cause of cancer death in the UK. Standard first-line treatment, for most patients, is cytotoxic chemotherapy. Although UC is initially ...sensitive to chemotherapy, relapse is almost inevitable and outcomes are poor; median overall survival is 8 months. Therefore, there is an urgent need for novel therapies to improve outcomes for this patient group.
ATLANTIS is a randomised phase II umbrella-design screening trial of maintenance therapy in biomarker-defined subgroups of patients with advanced UC. The primary end point is progression-free survival, and the study involves over 30 UK cancer centres.
ATLANTIS is the first study in the UK to employ a precision-medicine approach to patients with UC for maintenance treatment. Agents with a positive efficacy signal will proceed to randomised phase III trials to confirm the activity of novel, biologically stratified therapies in UC.
ATLANTIS trial EudraCT number 2015-003249-25. ISRCTN25859465.
The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.
To establish the safety and efficacy of upfront pazopanib therapy prior to ...cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.
Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months.
Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression.
The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis.
Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median interquartile range age, 64 56-71 years). Overall, 84 of 100 (84% 95% CI, 75%-91%) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 95% CI, 2.6-10.8 and 3.9 95% CI, 0.5-9.1 months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response.
Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.
The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with ...apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg (n = 111) or placebo (n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio HR: 0.68; 95% confidence interval CI: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.
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