Summary Background Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is ...an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. Methods We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×108 plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×109 plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov , number NCT00113984. Findings We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%. Interpretation The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC. Funding US National Institutes of Health.
Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant ...prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high-throughput and mechanistic analysis.
Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested >20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin.
All PDX models proliferated as organoids in culture. Greater than 50% could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously reported conditions. In addition, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in
organoids, similar to responses observed in patients.
The LuCaP PDX/organoid models provide an expansive, genetically characterized platform to investigate the mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC.
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Therapeutic prostate-specific antigen (PSA) -targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of ...progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study.
In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections.
Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061.
PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study.
Androgen Deprivation Therapy for Prostate Cancer Sharifi, Nima; Gulley, James L; Dahut, William L
JAMA : the journal of the American Medical Association,
07/2005, Letnik:
294, Številka:
2
Journal Article
Recenzirano
Odprti dostop
CONTEXT Prostate cancer is the most common nonskin cancer and second most common
cause of cancer mortality in US men. Androgen deprivation therapy (ADT), specifically
surgical or medical castration, ...is the first line of treatment against advanced
prostate cancer and is also used as an adjuvant to local treatment of high-risk
disease. OBJECTIVE To review systematically the evidence on the risks and benefits of ADT
for prostate cancer as well as clinical management of its adverse effects. EVIDENCE ACQUISITION We performed MEDLINE searches of English-language literature (1966 to
March 2005) using the terms androgen deprivation therapy, hormone treatment, and prostate cancer. We reviewed bibliographies of literature to extract
other relevant articles. Studies were selected based on clinical pertinence,
with an emphasis on controlled study design. EVIDENCE SYNTHESIS Androgen deprivation therapy is effective for palliation in many patients
with advanced prostate cancer and improves outcomes for high-risk patients
treated with radiation therapy for localized disease. Although patients with
increasing prostate-specific antigen levels after local treatment without
metastatic disease frequently undergo ADT, the benefits of this strategy are
not clear. Adverse effects of ADT include decreased libido, impotence, hot
flashes, osteopenia with increased fracture risk, metabolic alterations, and
changes in cognition and mood. CONCLUSIONS Androgen deprivation therapy has clear roles in the management of advanced
prostate cancer and high-risk localized disease. The benefits of ADT in other
settings need to be weighed carefully against substantial risks and adverse
effects on quality of life.
The novel coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global health threat (1). Patients with cancer are one of the most ...vulnerable populations. During this pandemic, clinical trial accrual to NCI studies has fallen dramatically. Investigators quickly turned to regulatory bodies to simplify treatment schedules, facilitate telemedicine, and decrease required data collection. Going forward, the oncology research community must use the lessons learned to focus on redesigning studies to ensure that critical scientific questions are answered safely while expanding access and increasing partnerships with community physicians. These changes will accelerate clinical progress while protecting our patients.
The COVID-19 (coronavirus disease 2019) pandemic has worldwide implications on health care, especially in our most vulnerable population: cancer patients. Flexibility and adaptation are needed to ...continue clinical research and for clinical trial development. At the Intramural Research Program, National Cancer Institute, swift changes have been implemented to protect our patients while maintaining the scientific integrity of our cancer clinical trials. Many lessons have been learned including incorporation of telehealth into clinical trials, partnerships with the oncology community at both academic institutions and community practices, focusing on diversity and inclusion to improve scientific innovation, and strengthened relationships with regulatory agencies and institutional review boards. These changes will enhance the clinical trials we conduct well beyond the pandemic.
Androgen deprivation therapy (ADT) with gonadal testosterone depletion is the frontline treatment for advanced prostate cancer. Other hormonal interventions have a role in the treatment of prostate ...cancer. We sought to examine systematically the evidence for hormonal interventions in prostate cancer, risks of ADT, and interventions that mitigate these risks. Search results for therapeutic studies were focused primarily on randomized controlled clinical trials, and the Jadad scale criteria were used to evaluate the quality of these studies. Four trials of the efficacy of intermittent ADT versus continuous ADT were included. One randomized study analysis and six postrandomization analyses were included on the effects of ADT on cardiovascular mortality. Seven randomized controlled trials of pharmacologic interventions were included for the treatment of metabolic effects due to ADT. One randomized trial of GnRH antagonist versus GnRH agonist was included. Six phase I/II clinical trials of secondary hormonal therapies with novel mechanisms of action were included. Randomized studies completed to date indicate that intermittent ADT might be equivalent to continuous ADT. Although adverse effects of ADT include risk factors for cardiovascular disease, effects on cardiovascular mortality are uncertain. Bone loss and increased risk of fracture may be effectively treated with pharmacologic interventions. Benefits of ADT must be balanced with a consideration of the risks.
Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. ...Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations.
Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations.
Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7-72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8-18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response.
Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.
ClinicalTrials.gov identifier: NCT02484404 .
Background Angiogenesis inhibitors have emerged as an effective targeted therapy in the treatment of patients with many cancers. One of the most widely used angiogenesis inhibitors is bevacizumab, a ...neutralizing antibody against vascular endothelial growth factor. The overall risk of proteinuria and hypertension in patients with cancer on bevacizumab therapy is unclear. We performed a systematic review and meta-analysis of published clinical trials of bevacizumab to quantify the risk of proteinuria and hypertension. Methods The databases MEDLINE (OVID, 1966 to June 2006) and Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2006 were searched to identify relevant studies. Eligible studies were randomized controlled trials of patients with cancer treated with bevacizumab that described the incidence of proteinuria and hypertension. Relative risk (RR) was calculated by using the fixed-effects model. Results A total of 1,850 patients were included in the 7 trials identified from the literature. Bevacizumab was associated with a significant increased risk of proteinuria (RR, 1.4 with low-dose bevacizumab; 95% confidence interval CI, 1.1 to 1.7; RR, 2.2 with high dose; 95% CI, 1.6 to 2.9). Hypertension also was increased significantly among patients receiving bevacizumab (RR, 3.0 for low dose; 95% CI, 2.2 to 4.2; RR, 7.5 for high dose; 95% CI, 4.2 to 13.4). Conclusion There was a significant dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received bevacizumab.
Incidence has increased and racial disparities persist for genitourinary cancers in the USA. Promotion of primary prevention, expansion of access to care, and increases in research funding are needed ...to mitigate racial disparities and halt the rising burden of these cancers.
Previous studies have reported on incidence and mortality patterns for individual genitourinary cancers in the USA. However, these studies addressed individual cancer types rather than genitourinary cancers overall.
To comprehensively examine disparities and trends in the incidence and mortality for the four major genitourinary cancers (bladder, kidney, prostate, and testis) in the USA.
We obtained incidence data from the National Cancer Institute 22-registry Surveillance, Epidemiology and End Results (SEER) database and the US Cancer Statistics database (Centers for Disease Control and Prevention) and mortality data from the National Center for Health Statistics to examine cross-sectional and temporal trends in incidence and death rates stratified by sex, race/ethnicity, and county.
Age-adjusted incidence and death rates were calculated using SEER*Stat software. Temporal trends were analyzed using Joinpoint regression for a two-sided significance level of p < 0.05.
Incidence and mortality rates for bladder and kidney cancers were two to four times higher for men than for women. Among non-Hispanic White individuals, the highest incidence rates were found in the Northeast for bladder cancer and in Appalachia for kidney cancer, whereas the highest death rates for prostate cancer were found in the West. Incidence rates increased for cancers of the kidney and testis and for advanced-stage prostate cancer in almost all racial/ethnic populations and for bladder cancer in the American Indian/Alaska Native population. Death rates increased for testicular cancer in the Hispanic population and stabilized for prostate cancer among White and Asian American/Pacific Islander men after a steady decline since the early 1990s. Study limitations include misclassification of race/ethnicity on medical records and death certificates.
We found persistent sociodemographic disparities and unfavorable trends in incidence or mortality for all four major genitourinary cancers. Future studies should elucidate the reasons for these patterns.
In the USA, rates of cancer cases are increasing for kidney, testis, and advanced-stage prostate cancers in the overall population, and for bladder cancer in the American Indian/Alaska Native population. Differences in the rates by sex and race/ethnicity remain.
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