The optimal duration of therapy in patients receiving immune-checkpoint inhibitors (ICIs) is a new but crucial question that has arisen owing to the observation of durable remissions in >85% of ...patients with metastatic melanoma who stop receiving an anti-PD-1 antibody after a complete response (CR). Long-term treatment-free remissions have also been seen, albeit much less frequently, in patients receiving ICIs for other forms of cancer who have a CR. Despite these promising observations, the optimal duration of treatment with ICIs remains unknown and requires further investigation in randomized controlled trials. In the absence of prospective data, some general criteria to guide the safe cessation of ICIs can be proposed, at least for patients with melanoma, in whom ICI cessation after a confirmed CR and at least 6 months of treatment is generally deemed safe. In this Perspective, we describe the available data on ICI interruption in patients with melanoma and in those with various other cancers. We also address the patient management implications of stopping ICI therapy.
Prostate cancer is the most common cancer and the second leading cause of death from cancer in males in most Western countries. Prostate cancer has an exquisite sensitivity to androgen deprivation ...therapy and is the most endocrine-sensitive solid neoplasm, although advanced disease eventually progresses to castration-resistant prostate cancer (CRPC). Recent evidence has shown that cancer progression at the CRPC stage is often mediated by androgen receptor signaling, so that subsequent androgen receptor targeting may further contribute to disease control and, eventually, survival improvement. Abiraterone acetate, an androgen biosynthesis inhibitor, was tested in patients with CRPC pretreated with docetaxel in a phase III trial with demonstration of an overall survival benefit, confirming that CRPC remains hormone driven, even in advanced stages of the disease. Several novel agents also targeting androgen receptor signaling are currently being evaluated, including MDV3100 and orteronel (TAK-700). With the availability of newer endocrine treatments and also nonendocrine treatments (e.g., chemotherapy, immunotherapy, and bone-targeting agents), data supporting a more rational use of therapeutic agents are urgently required in patients with CRPC. It is likely that molecular characterization of prostate cancer will lead to the identification of different subsets of prostate cancer disease with a different natural history, sensitivity, and resistance to treatment; efforts to develop, validate, and implement predictive biomarkers in clinical trials and eventually in routine care should now be strongly supported.
Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis ...and death in men with nonmetastatic, castration-resistant prostate cancer.
We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg two 300-mg tablets twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks.
In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P<0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo.
Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).
Abstract The last 2 years (2014 and 2015) have witnessed major advances in the treatment of genitourinary malignancies. Of note and in marked contrast to previous years, all four major cancers ...(prostate cancer, testicular cancer, kidney cancer, and bladder cancer) have benefited from this progress. In prostate cancer, it was clearly demonstrated that a local treatment should be administered for high-risk localised disease. The standard of care was changed for patients with upfront metastatic disease with combined androgen deprivation therapy plus docetaxel becoming the new standard for fit patients with multiple bony metastases. In castrate-resistant disease, AR-V7 variants were shown to be predictive factors for resistance to next-generation AR axis-targeting agents and DNA repair targeting emerged as a promising new strategy. In poor-prognosis advanced non-seminoma, a better outcome was randomly demonstrated for the first time when a switch-intensified treatment was used in patients with a slow tumour marker decline. In metastatic kidney cancer, both cabozantinib and checkpoint inhibitors (nivolumab) are now associated with improved outcomes in pretreated patients and should soon change the standard of care for these patients. Last but not least, in urothelial bladder cancer, molecular classification is evolving and suggesting that immunotherapy with checkpoint inhibitors is active, as demonstrated in early trials.
We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic ...castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.
In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in
,
, or
, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously.
The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval CI, 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients 67% in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.
Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in
,
, or
and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).
Carcinoma of unknown primary (CUP) Pavlidis, Nicholas; Fizazi, Karim
Critical reviews in oncology/hematology,
03/2009, Letnik:
69, Številka:
3
Journal Article
Recenzirano
Abstract Carcinoma of unknown primary (CUP) is one of the 10 most frequent cancers worldwide. It constitutes 3–5% of all human malignancies. Patients with CUP present with metastases without an ...established primary site. CUP manifests as an heterogenous group of mainly epithelial cancers recognised by distinct clinicopathological entities. The diagnostic work-up includes extensive histopathology investigations and modern imaging technology. Nevertheless, the primary tumour remains undetected most of the time. Molecular diagnosis with DNA microarrays demonstrates high sensitivity, but its prognostic contribution is still uncertain. Certain clinicopathological CUP entities are considered as favourable sub-sets responding to systemic platinum-based chemotherapy or managed by locoregional treatment. These sub-sets are: the poorly differentiated carcinomas involving the mediastinal–retroperitoneal nodes, peritoneal papillary serous adenocarcinomatosis in females, poorly differentiated neuroendocrine carcinomas, isolated axillary node adenocarcinomas in females or cervical nodal involvement by a squamous cell carcinoma. Patients who belong to the non-favourable sub-sets have a worse prognosis.
Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of ...abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer.
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival.
After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval CI, 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group.
The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, ...prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group.
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).
Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer (mPC). However, nearly all patients with mPC progress to castration-resistant PC (CRPC). Arrays ...of treatments, including secondary hormonal therapies, are available for the treatment of mPC and CRPC, which show efficacy when administered with ADT. Continuation of ADT is recommended for CRPC treatment as therapies are added. New secondary hormonal therapies include abiraterone, targeting the CYP17 enzyme family, and enzalutamide, an androgen receptor inhibitor with heightened binding specificity. The optimal decision-making process for CRPC treatment option remains unclear, pending further research and experience.
PDF
