Clinical testing of transcriptome-wide expression profiles in high-risk localized and metastatic prostate cancer starting androgen deprivation therapy: an ancillary study of the STAMPEDE abiraterone Phase 3 trial.

Metastatic and high-risk localized prostate cancer respond to hormone therapy but outcomes vary. Following a pre-specified statistical plan, we used Cox models adjusted for clinical variables to test associations with survival of multi-gene expression-based classifiers from 781 patients randomized to androgen deprivation with or without abiraterone in the STAMPEDE trial. Decipher score was strongly prognostic (p<2×10-5) and identified clinically-relevant differences in absolute benefit, especially for localized cancers. In metastatic disease, classifiers of proliferation, PTEN or TP53 loss and treatment-persistent cells were prognostic. In localized disease, androgen receptor activity was protective whilst interferon signaling (that strongly associated with tumor lymphocyte infiltration) was detrimental. Post-Operative Radiation-Therapy Outcomes Score was prognostic in localized but not metastatic disease (interaction p=0.0001) suggesting the impact of tumor biology on clinical outcome is context-dependent on metastatic state. Transcriptome-wide testing has clinical utility for advanced prostate cancer and identified worse outcomes for localized cancers with tumor-promoting inflammation.

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10-9 ) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.

Quality of life among symptomatic compared to PSA-detected prostate cancer survivors - results from a UK wide patient-reported outcomes study.

BACKGROUND: Quality of life among prostate cancer survivors varies by socio-demographic factors and treatment type received; however, less in known about differences in functional outcomes by method of presentation. We investigate differences in reported urinary, bowel, sexual and hormone-related problems between symptomatic and PSA-detected prostate cancer survivors. METHODS: A UK wide cross-sectional postal survey of prostate cancer survivors conducted 18-42 months post-diagnosis. Questions were included on presentation method and treatment. Functional outcome was determined using the EPIC-26 questionnaire. Reported outcomes were compared for symptomatic and PSA-detected survivors using ANOVA and multivariable log-linear regression. RESULTS: Thirty-five thousand eight hundred twenty-three men responded (response rate: 60.8%). Of these, 31.3% reported presenting via PSA test and 59.7% symptomatically. In multivariable analysis, symptomatic men reported more difficulty with urinary incontinence (Adjusted mean ratio (AMR): 0.96, 95% CI: 0.96-0.97), urinary irritation (AMR: 0.95, 95% CI: 0.95-0.96), bowel function (AMR: 0.97, 95% CI: 0.97-0.98), sexual function (AMR: 0.90, 95% CI: 0.88-0.92), and vitality/hormonal function (AMR: 0.96, 95% CI: 0.96-0.96) than PSA-detected men. Differences were consistent across respondents of differing age, stage, Gleason score and treatment type. CONCLUSION: Prostate cancer survivors presenting symptomatically report poorer functional outcomes than PSA-detected survivors. Differences were not explained by socio-demographic or clinical factors. Clinicians should be aware that men presenting with symptoms are more likely to report functional difficulties after prostate cancer treatment and may need additional aftercare if these difficulties persist. Method of presentation should be considered as a covariate in patient-reported outcome studies of prostate cancer.

Abiraterone in "High-" and "Low-risk" Metastatic Hormone-sensitive Prostate Cancer.

BACKGROUND: Abiraterone acetate received licencing for use in only "high-risk" metastatic hormone-naïve prostate cancer (mHNPC) following the LATITUDE trial findings. However, a "risk"-related effect was not seen in the STAMPEDE trial. There remains uncertainty as to whether men with LATITUDE "low-risk" M1 disease benefit from androgen deprivation therapy (ADT) combined with abiraterone acetate and prednisolone (AAP). OBJECTIVE: Evaluation of heterogeneity of effect between LATITUDE high- and low-risk M1 prostate cancer patients receiving ADT + AAP in the STAMPEDE trial. DESIGN, SETTING, AND PARTICIPANTS: A post hoc subgroup analysis of the 2017 STAMPEDE "abiraterone comparison". Staging scans for M1 patients contemporaneously randomised to ADT or ADT + AAP within the STAMPEDE trial were evaluated centrally and blind to treatment assignment. Stratification was by risk according to the criteria set out in the LATITUDE trial. Exploratory subgroup stratification incorporated the CHAARTED criteria. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome measure was overall survival (OS) and the secondary outcome measure was failure-free survival (FFS). Further exploratory analysis evaluated clinical skeletal-related events, progression-free survival (PFS), and prostate cancer-specific death. Standard Cox-regression and Kaplan-Meier survival estimates were employed for analysis. RESULTS AND LIMITATIONS: A total of 901 M1 STAMPEDE patients were evaluated after exclusions. Of the patients, 428 (48%) were identified as having a low risk and 473 (52%) a high risk. Patients receiving ADT + AAP had significantly improved OS (low-risk hazard ratio [HR]: 0.66, 95% confidence interval or CI [0.44-0.98]) and FFS (low-risk HR: 0.24, 95% CI [0.17-0.33]) compared with ADT alone. Heterogeneity of effect was not seen between low- and high-risk groups for OS or FFS. For OS benefit in low risk, the number needed to treat was four times greater than that for high risk. However, this was not observed for the other measured endpoints. CONCLUSIONS: Men with mHNPC gain treatment benefit from ADT + AAP irrespective of risk stratification for "risk" or "volume". PATIENT SUMMARY: Coadministration of abiraterone acetate and prednisolone with androgen deprivation therapy (ADT) is associated with prolonged overall survival and disease control, compared with ADT alone, in all men with metastatic disease starting hormone therapy for the first time.

Regional Variations in Quality of Survival Among Men with Prostate Cancer Across the United Kingdom.

BACKGROUND: Prostate cancer incidence, treatment, and survival rates vary throughout the UK, but little is known about regional differences in quality of survival. OBJECTIVE: To investigate variations in patient-reported outcomes between UK countries and English Cancer Alliances. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional postal survey of prostate cancer survivors diagnosed 18-42mo previously. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Urinary, bowel, and sexual problems and vitality were patient reported using the Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire. General health was also self-assessed. Regional variations were identified using multivariable log-linear regression. RESULTS AND LIMITATIONS: A total of 35823 men responded, 60.8% of those invited. Self-assessed health was significantly lower than the UK average in Wales and Scotland. Respondents reported more urinary incontinence in Scotland, more urinary irritation/obstruction in Scotland and Northern Ireland (NI), poorer bowel function in Scotland and NI, worse sexual function in Scotland, and reduced vitality/hormonal function in Scotland, Wales, and NI. Self-assessed health was poorer than the English average in South Yorkshire and North-East and Cumbria, with more urinary incontinence in North-East and Cumbria and Peninsula, greater sexual problems in West Midlands, and poorer vitality in North-East and Cumbria and West Midlands. Limitations include difficulty identifying clinically significant differences and limited information on pretreatment conditions. CONCLUSIONS: Despite adjustment for treatment, and clinical and sociodemographic factors, quality of survival among prostate cancer survivors varied by area of residence. Adoption of best practice from areas performing well could support enhanced survival quality in poorer performing areas, particularly with regard to bowel problems and vitality, where clinically relevant differences were reported. PATIENT SUMMARY: We conducted a UK-wide survey of patient's quality of life after treatment for prostate cancer. Outcomes were found to vary depending upon where patients live. Different service providers need to ensure that all prostate cancer patients receive the same follow-up care.

Urinary, bowel and sexual health in older men from Northern Ireland.

OBJECTIVES: To provide data on the prevalence of urinary, bowel and sexual dysfunction in Northern Ireland (NI), to act as a baseline for studies of prostate cancer outcomes and to aid service provision within the general population. SUBJECTS AND METHODS: A cross-sectional postal survey of 10 000 men aged ≥40 years in NI was conducted and age-matched to the distribution of men living with prostate cancer. The EuroQoL five Dimensions five Levels (EQ-5D-5L) and 26-item Expanded Prostate Cancer Composite (EPIC-26) instruments were used to enable comparisons with prostate cancer outcome studies. Whilst representative of the prostate cancer survivor population, the age-distribution of the sample differs from the general population, thus data were generalised to the NI population by excluding those aged 40-59 years and applying survey weights. Results are presented as proportions reporting problems along with mean composite scores, with differences by respondent characteristics assessed using chi-squared tests, analysis of variance, and multivariable log-linear regression. RESULTS: Amongst men aged ≥60 years, 32.8% reported sexual dysfunction, 9.3% urinary dysfunction, and 6.5% bowel dysfunction. In all, 38.1% reported at least one problem and 2.1% all three. Worse outcome was associated with increasing number of long-term conditions, low physical activity, and higher body mass index (BMI). Urinary incontinence, urinary irritation/obstruction, and sexual dysfunction increased with age; whilst urinary incontinence, bowel, and sexual dysfunction were more common among the unemployed. CONCLUSION: These data provide an insight into sensitive issues seldom reported by elderly men, which result in poor general health, but could be addressed given adequate service provision. The relationship between these problems, raised BMI and low physical activity offers the prospect of additional health gain by addressing public health issues such as obesity. The results provide essential contemporary population data against which outcomes for those living with prostate cancer can be compared. They will facilitate greater understanding of the true impact of specific treatments such as surgical interventions, pelvic radiation or androgen-deprivation therapy.

Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness.

BACKGROUND: Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources. OBJECTIVE: To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting. DESIGN, SETTING, AND PARTICIPANTS: We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. INTERVENTION: SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75mg/m2) was administered alongside SOC for six three-weekly cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS AND LIMITATIONS: The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled. CONCLUSIONS: Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. PATIENT SUMMARY: Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body.

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

Diethylstilboestrol (1 mg) in the management of castration-resistant prostate cancer.

OBJECTIVE: To investigate the efficacy of diethylstilboestrol (DES) in patients with advanced prostate cancer refractory to androgen suppression. METHODS: This retrospective study comprises 194 patients with prostate cancer treated with DES (1 mg daily) between 1976 and 2010. Study outcome parameters included demographic data, tumour characteristics, treatment history, prostate-specific antigen (PSA) responses, radiologic studies, adverse events and overall survival. RESULTS: At initiation of oestrogen therapy the mean patient age was 69 years (range: 48-89) and the median PSA was 96 ng/ml (range: 1.9-9,500). The median duration of prior prostate cancer treatment was 29 months (range: 1-365). DES was the second-line treatment in 58 patients and the third/fourth-line therapy in 136 men. A formal (≥50%) PSA response was observed in 95 patients (48.9%) and the median time to progression (TTP) was 250 days (95% CI, 180-360) for this group. An additional 62 patients (31.9%) had a partial PSA response with a median TTP of 150 days (95% CI, 92-180). Thirty-seven patients (19.1%) did not have a PSA response and the median TTP was 90 days (95% CI, 90-97). The median overall survival from the start of oestrogen therapy for the entire cohort was 576 days (95% CI, 482-690). The median overall survival of patients who had a formal (≥50%), partial (<50%) and no PSA response was 756 (95% CI, 670-1,429), 428 (95% CI, 340-630) and 329 (95% CI, 287-510) days, respectively. Thirty-nine patients (20.1%) were still alive at the end of the study. No treatment-related deaths occurred. CONCLUSIONS: In the age of chemotherapy this study highlights the efficacy of oestrogen therapy in castration-refractory prostate cancer. The optimal point in the therapeutic pathway at which DES should be prescribed remains to be established.

Do prostate cancer nomograms give accurate information when applied to European patients?

OBJECTIVE: The aim of this study was to validate and compare the performance of preoperative risk assessment tools in a population of men treated with radical prostatectomy at a single European institution. MATERIAL AND METHODS: Patients were identified from databases of radical prostatectomy between 1996 and 2011 from a single UK centre. Information was obtained on demographics, prostate-specific antigen, staging, biopsy and specimen histopathology, and follow-up. Data were inputted into the Memorial Sloan-Kettering Cancer Center (MSKCC), Partin 1997 and Makarov/Partin 2007 nomograms, and the University of California San Francisco-Cancer of the Prostate Risk Assessment tool (UCSF-CAPRA). The risks of extracapsular extension (ECE), seminal vesicle invasion (SVI) and lymph-node involvement (LNI) were calculated and compared with known outcomes. Nomogram performance was measured using Hosmer-Lemeshow (HL) goodness-of-fit tests, calculating concordance indices (c-indices) and calibration curves. RESULTS: Data were obtained for 541 patients. Prediction of ECE was relatively poor using all nomograms, with the Makarov/Partin 2007 the most accurate at prediction over the range of risk stratification (HL 9.9, c-index 0.62). Predictions of SVI and LNI were better than for ECE, with the MSKCC nomogram performing best for SVI (HL 10.9, c-index 0.73) and all nomograms performing well for LNI prediction (c-indices 0.8 to 0.815). CAPRA predicted best for SVI (OR 1.49, 95% confidence interval 1.27-1.74). CONCLUSIONS: To the authors' knowledge, this is the first head-to-head comparison of the accuracy of these commonly used risk calculators in a North European population. Caution should be used when counselling patients using nomograms. Although nomograms may be used as a guide, patients should be warned that they often have not been validated on different European populations and may give misleading information regarding a patient's specific risks.

FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases.

PURPOSE: FGFR3 is considered a good therapeutic target for bladder cancer. However, to our knowledge it is unknown whether the FGFR3 status of primary tumors is a surrogate for related metastases, which must be targeted by FGFR targeted systemic therapies. We assessed FGFR3 protein expression in primary bladder tumors and matched nodal metastases. MATERIALS AND METHODS: We examined matched primary tumor and nodal metastases from 150 patients with bladder cancer clinically staged as N0M0. Four samples per patient were incorporated into a tissue microarray and FGFR3 expression was assessed by immunohistochemistry. FGFR3 expression was tested for an association with categorical clinical data using the Fisher exact test, and with overall and recurrence-free survival by Kaplan-Meier analysis. RESULTS: Duplicate spots from primary tumors and lymph node metastases were highly concordant (OR 8.6 and 16.7, respectively, each p <0.001). Overall FGFR protein expression levels did not differ between primary and metastatic lesions (p = 0.78). Up-regulated expression was recorded in 53 of 106 evaluable primary tumor spots and 56 matched metastases. Concordance of FGFR3 expression levels in 79 matched primary tumor and metastasis specimens was high (OR 8.45, p <0.001). In 15 and 12 patients expression was up-regulated in only metastasis and in only the primary tumor, respectively. Overall and recurrence-free survival was not related to FGFR3 expression. CONCLUSIONS: FGFR3 expression in matched primary and metastasized bladder cancer specimens showed good but not absolute concordance. Thus, in most patients primary tumor FGFR3 status can guide the selection of FGFR targeted therapy.