Addressing controversial areas in the management of advanced prostate cancer in Canada Areas of consensus and controversy from the third Canadian consensus forum.

INTRODUCTION: The management of prostate cancer (PCa) is rapidly evolving. Treatment and diagnostic options grow annually, however, high-level evidence for the use of new therapeutics and diagnostics is lacking. In November 2022, the Genitourinary Research Consortium held its 3rd Canadian Consensus Forum (CCF3) to provide guidance on key controversial areas for management of PCa. METHODS: A steering committee of eight multidisciplinary physicians identified topics for discussion and adapted questions from the Advanced Prostate Cancer Consensus Conference 2022 for CCF3. Questions focused on management of metastatic castration-sensitive prostate cancer (mCSPC); use of novel imaging, germline testing, and genomic profiling; and areas of non-consensus from CCF2. Fifty-eight questions were voted on during a live forum, with threshold for "consensus agreement" set at 75%. RESULTS: The voting panel consisted of 26 physicians: 13 urologists/uro-oncologists, nine medical oncologists, and four radiation oncologists. Consensus was reached for 32 of 58 questions (one ad-hoc). Consensus was seen in the use of local treatment, to not use metastasis-directed therapy for low-volume mCSPC, and to use triplet therapy for synchronous high-volume mCSPC (low prostate-specific antigen). Consensus was also reached on sufficiency of conventional imaging to manage disease, use of germline testing and genomic profiling for metastatic disease, and poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA-positive prostate cancer. CONCLUSIONS: CCF3 identified consensus agreement and provides guidance on >30 practice scenarios related to management of PCa and nine areas of controversy, which represent opportunities for research and education to improve patient care. Consensus initiatives provide valuable guidance on areas of controversy as clinicians await high-level evidence.

Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer.

No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org ). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.

BeTTer Outcomes Workgroup Health Quality Initiative to optimize bone health for prostate cancer patients in the British Columbia Cancer System.

INTRODUCTION: Bone-targeted therapies (BTTs) are integral to the management of bone metastases in metastatic castration-resistant prostate cancer (mCRPC). BTTs vary considerably in referral and drug access pathways and optimal BTT use requires multi-specialty consultation and supervision. Health quality improvement (HQI) has become the predominant framework to improve patient care in multidisciplinary settings. METHODS: HQI initiatives on use of BTT in mCRPC were developed and evaluated in five centers of a provincial cancer center network using Plan-Do-Study-Act (PDSA) methodology. Multidisciplinary teams (MDTs) completed a common quality assessment form and an HQI template and then implemented an HQI initiative. Feedback and findings were shared and discussed at regional events. It was subsequently determined whether to adopt, adapt, or abandon initiatives. RESULTS: Patterns of unmet needs varied across type of BTT. Gaps in use of radium-223 were mostly referral and education issues that could be directly addressed at the local level by participating clinician teams. Conversely, most supportive BTT gaps were related to coverage and resourcing support. HQI initiatives selected by each site consisted of implementation or expansion of local MDT meetings, referral documents, databases, and improvement charters. The main HQI initiative was completed in four sites and was adapted or adopted in three. Improvements in BTT use were observed in two of three centers with data on HQI process measures. CONCLUSIONS: Despite the overall heterogenous structure of the groups and metrics used, this study demonstrated that the PDSA framework provides the needed structure for improvements in BTT use in mCRPC across multiple sites.

Real-world utilization and outcomes of docetaxel among older men with metastatic prostate cancer: a retrospective population-based cohort study in Canada.

BACKGROUND: The adoption of docetaxel for systemic treatment of metastatic prostate cancer (PCa), in both castration-sensitive (mCSPC) and castration-resistant (mCRPC) settings, is poorly understood. This study examined the real-world utilization of docetaxel in these patients and their outcomes. METHODS: A retrospective population-based study used administrative data from Ontario, Canada, to identify men aged ≥66 years who were diagnosed with de novo mCSPC or mCRPC between 2014 and 2019 and received docetaxel. The study assessed treatment tolerability and toxicity, and survival in both cohorts. Descriptive and comparative statistical analysis were conducted. RESULTS: The study identified 11.2% (399/3556) and 13.2% (203/1534) patients diagnosed with de novo mCSPC and with mCRPC who received docetaxel respectively. The median age in both cohorts was 72 years (IQR: 68-76). Overall, 43.9% (n = 175) patients with de novo mCSPC and 52.1% (n = 85) with mCRPC completed ≥6 cycles of docetaxel. Over two-fifth also needed dose adjustments in both cohorts. Hospitalization or emergency department visit for febrile neutropenia were noted in 15.8% (n = 63) of de novo mCSPC patients and similarly in 19% (n = 31) of mCRPC cohort. The median survival of PCa patients who completed ≥6 cycles of docetaxel was significantly longer relative to those who completed <4 cycles: 32.7 vs. 23.5 months (p < 0.001) for mCSPC and 20.5 vs. 10.7 (p = 0.012) for mCRPC respectively. CONCLUSIONS: In this population-based study of elderly patients with metastatic PCa, treatment with docetaxel was associated with poor tolerability and higher toxicity compared with clinical trials. Receipt of limited cycles and reduced overall dose of docetaxel were associated with inferior overall survival.

Assessment of the epidemiological trends for prostate cancer using administrative data in Ontario.

INTRODUCTION: Studies have shown fluctuations in prostate cancer (PCa) incidence and prevalence over time and by region. Less is known about the most recent epidemiological trends by PCa disease stage. METHODS: This study was a population-based, sequential, cross-sectional analysis that used administrative health data from Ontario, Canada. After inclusion, patients were classified into non-metastatic (nm) PCa and metastatic (m) PCa. The primary study outcome was a description of temporal trends in the incidence and prevalence of PCa over the study period (2010-2019), stratified by disease state. Crude incidence and prevalence rates were estimated for each year in the study period. RESULTS: Overall, there were 131 718 men living with PCa in 2019. The incident cohort contained 86 123 patients with nmPCa (n=65 691, 76.3%), mPCa (n=8431, 9.8%), or unknown stage (n=12 001, 13.9%). The prevalence increased from 216 to 253 per 10 000 men between 2010 and 2019, respectively. Between 2011 and 2014, overall PCa incidence decreased from 20.9 to 15.4 per 10 000 men, followed by an increase to 18.8 per 10 000 in 2018. The nmPCa incidence rate was considerably higher compared with mPCa and followed a trend similar to the overall incidence. In contrast, the incidence rate for mPCa demonstrated a continuous increase from 1.5 per 10 000 in 2010 to 2.4 per 10 000 in 2018. CONCLUSIONS: The overall prevalence of PCa has risen steadily over the last decade, despite fluctuations in nmPCa incidence. The concurrent rise in mPCa and nmPCa requires further study regarding the burden of localized and systemic treatment.

Patterns of care for non-metastatic castration-resistant prostate cancer: A population-based study.

Objectives: To describe patterns of practice of PSA testing and imaging for Ontario men receiving continuous ADT for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). Patients and Methods: This was a retrospective, longitudinal, population-based study of administrative health data from 2008 to 2019. Men 65 years and older receiving continuous androgen deprivation therapy (ADT) with documented CRPC were included. An administrative proxy definition was applied to capture patients with nmCRPC and excluded those with metastatic disease. Patients were indexed upon progression to CRPC and were followed until death or end of study period to assess frequency of monitoring with PSA tests and conventional imaging. A 2-year look-back window was used to assess patterns of care leading up to CRPC as well as baseline covariates. Results: At a median follow-up of 40.1 months, 944 patients with nmCRPC were identified. Their median time from initiation of continuous ADT to CRPC was 26.0 months. 60.7% of patients had their PSA measured twice or fewer in the year prior to index, and 70.7% patients did not receive any imaging in the year following progression to CRPC. Throughout the study period, 921/944 (97.6%) patients with CRPC progressed to high-risk (HR-CRPC) with PSA doubling time ≤ 10 months, of which more than half received fewer than three PSA tests in the year prior to developing HR-CRPC, and 30.9% received no imaging in the subsequent year. Conclusion: PSA testing and imaging studies are underutilized in a real-world setting for the management of nmCRPC, including those at high risk of developing metastatic disease. Infrequent monitoring impedes proper risk stratification, disease staging and detection of treatment failure and/or metastases, thereby delaying the necessary treatment intensification with life-prolonging therapies. Adherence to guideline recommendations and the importance of timely staging should be reinforced to optimize patient outcomes.

Real-world use of systemic therapies in men with metastatic castration resistant prostate cancer (mCRPC) in Canada.

BACKGROUND: Management of advanced prostate cancer has evolved rapidly with the availability of multiple systemic treatments such as androgen-receptor axis-targeted therapies (ARATs), taxane-based chemotherapy, radium-223, and other approaches. However, limited data exists on real-world treatment selection and clinical outcomes. This study examines the utilization and survival impact of these therapies in men with metastatic castration-resistant prostate cancer (mCRPC) in the real-world setting of Ontario, Canada. METHODS: This study was a retrospective, longitudinal, population-based study of administrative claims data between January 2016 and April 2020. Men ≥ 66 years with mCRPC receiving advanced treatment were included. Patients were indexed on the day they initiated mCRPC treatment and followed up until death or end of study period to assess treatment and survival. Multinomial regression was used to model the association between baseline covariates, treatment and survival. RESULTS: Median age was 75 years among the 944 mCRPC patients who received life-prolonging therapies during this time period. Over 90% of patients used an ARAT as a first-line therapy, and 71.5% received only first-line therapy before death or censoring. Of patients that received two or more lines, over 80% received subsequent therapy with a different mechanism of action. Median overall survival was 18.9 months. CONCLUSIONS: ARATs have become the predominant first-line systemic treatment option for mCRPC patients in recent years. Notably, the majority of patients received only a single line of life-prolonging therapy after developing mCRPC. In keeping with the recognized efficacy-effectiveness gap, real-world outcomes in this cohort appear poorer than in clinical trials.

Real-World Use of Androgen-Deprivation Therapy: Intensification Among Older Canadian Men With de Novo Metastatic Prostate Cancer.

Background: Despite the wealth of evidence demonstrating the efficacy of treatment intensification beyond androgen-deprivation therapy (ADT) among patients with de novo metastatic castration-sensitive prostate cancer (mCSPC), little is known of its real-world use. This study examined the real-world uptake of ADT treatment intensification among older men in a large Canadian province. Methods: We performed a retrospective population-based cohort study using province-wide linked administrative data in Ontario, Canada. Patients 66 years of age and older with de novo mCSPC were included and their treatment with conventional ADT-based regimens, ADT plus next-generation androgen receptor axis-targeted therapy, and ADT plus docetaxel were identified and stratified by time. Results: From 2014 to 2019, 3556 patients were identified with de novo mCSPC. Most patients (n = 2794 [78.6%]) were treated with a conventional ADT regimen, whereas 399 (11.2%) patients received ADT intensification with docetaxel and 52 (1.5%) patients received abiraterone acetate plus prednisone. In a time-stratified analysis of ADT intensification before and after the pivotal AA+P trial (LATITUDE), AA+P uptake increased from 0.5% to 3.0%, whereas docetaxel use dropped from 12.0% to 10.0%. The median survival of the study population was 18 months (interquartile range = 10-31). Conclusions: The majority of patients with de novo mCSPC are treated with ADT alone in the Canadian real-world setting, despite randomized clinical trial evidence of benefit with the use of ADT-intensified regimens. As ADT treatment intensification is substantially underused, better understanding of the barriers to treatment and targeted education to address them are needed.

Prognostic Association between Common Laboratory Tests and Overall Survival in Elderly Men with De Novo Metastatic Castration Sensitive Prostate Cancer: A Population-Based Study in Canada.

De novo cases of metastatic prostate cancer (mCSPC) are associated with poorer prognosis. To assist in clinical decision-making, we aimed to determine the prognostic utility of commonly available laboratory-based markers with overall survival (OS). In a retrospective population-based study, a cohort of 3556 men aged ≥66 years diagnosed with de novo mCSPC between 2014 and 2019 was identified in Ontario (Canada) administrative database. OS was assessed by using the Kaplan-Meier method. Multivariate Cox regression analysis was performed to evaluate the association between laboratory markers and OS adjusting for patient and disease characteristics. Laboratory markers that were assessed include neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin, hemoglobin, serum testosterone and PSA kinetics. Among the 3556 older men with de novo mCSPC, their median age was 77 years (IQR: 71-83). The median survival was 18 months (IQR: 10-31). In multivariate analysis, a statistically significant association with OS was observed with all the markers (NLR, PLR, albumin, hemoglobin, PSA decrease, reaching PSA nadir and a 50% PSA decline), except for testosterone levels. Our findings support the use of markers of systemic inflammation (NLR, PLR and albumin), hemoglobin and PSA metrics as prognostic indicators for OS in de novo mCSPC.

Results from a Canadian consensus forum of key controversial areas in the management of advanced prostate cancer: Recommendations for Canadian healthcare providers.

INTRODUCTION: Rapid progress in diagnostics and therapeutics for the management of prostate cancer (PCa) has created areas where high-level evidence to guide practice is lacking. The Genitourinary Research Consortium (GURC) conducted its second Canadian consensus forum to address areas of controversy in the management of PCa and provide recommendations to guide treatment. METHODS: A panel of PCa specialists discussed topics related to the management of PCa. The core scientific committee finalized the design, questions, and analysis of the consensus results. Attendees then voted to indicate their management choice regarding each statement/topic. Questions for voting were adapted from the 2019 Advanced Prostate Cancer Consensus Conference. The thresholds for agreement were set at ≥75% for "consensus agreement," >50% for "near-consensus," and ≤50% for "no consensus." RESULTS: The panel was comprised of 29 PCa experts, including urologists (n=12), medical oncologists (n=12), and radiation oncologists (n=5). Voting took place for 65 predetermined questions and three ad hoc questions. Consensus was reached for 34 questions, spanning a variety of areas, including biochemical recurrence, treatment of metastatic castration-sensitive PCa, management of non-metastatic and metastatic castration-resistant PCa, bone health, and molecular profiling. CONCLUSIONS: The consensus forum identified areas of consensus or near-consensus in more than half of the questions discussed. Areas of consensus typically aligned with available evidence, and areas of variability may indicate a lack of high-quality evidence and point to future opportunities for further research and education.

Effectiveness of first-line abiraterone versus enzalutamide among patients ≥80 years of age with metastatic castration-resistant prostate cancer: A retrospective propensity score-weighted comparative cohort study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects the elderly. There is limited data assessing the efficacy and tolerability of abiraterone acetate (AA) versus enzalutamide in this population. OBJECTIVE: To compare the clinical efficacy and tolerability of AA versus enzalutamide in patients ≥ 80 years with mCRPC. DESIGN, SETTING AND PARTICIPANTS: A retrospective propensity-weighted comparative cohort study of first-line AA versus enzalutamide among patients with mCRPC aged ≥80 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Inverse probability treatment weights based on propensity scores were generated to assess the treatment effect of AA versus enzalutamide on time to PSA progression (TTPP), time to progression (TTP) (first of PSA/radiographic/clinical progression) and overall survival using a weighted Cox proportional hazards model. PSA response rate (PSA RR) was compared between groups using Χ2. RESULTS AND LIMITATIONS: One hundred fifty-three patients received AA, and 125 received enzalutamide. Enzalutamide was associated with higher PSA RR (61.6% vs 43.8%, P < 0.004), and TTP (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50-0.88, P = 0.01) but not TTPP (HR 0.73, 95% CI 0.53-1.01, P = 0.06). There were significantly more dose reductions with enzalutamide (22.9% vs 44.8%, P > 0.001) but there was no interaction between median proportion of full dose received and TTPP or TTP for either drug. Rates of treatment discontinuation (for reasons other than progression) were also significantly different between AA and enzalutamide (28.8% vs 40.8%, respectively, P = 0.04). The most common reason for dose reductions and discontinuation of enzalutamide was fatigue (30.4% and 5.6%, respectively). CONCLUSIONS: Despite more dose reductions and a higher treatment discontinuation rate, enzalutamide was associated with a higher PSA RR and longer time to progression, than AA. Given that clinical outcomes were not adversely impacted by decreased treatment exposure, dose modification may be a useful treatment strategy to balance toxicity and tolerance.

Real-world management of advanced prostate cancer: A description of management practices of community-based physicians and prostate cancer specialists.

INTRODUCTION: The Canadian Genitourinary Research Consortium (GURC) conducted a consensus development conference leading to 31 recommendations. Using the GURC consensus development questionnaire, we conducted a survey to measure the corresponding community-based practices on the management of metastatic castration-sensitive prostate cancer (mCSPC), metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castration-resistant prostate cancer (nmCRPC). METHODS: An 87-item online questionnaire was sent to 600 community urologists and oncologists involved in the treatment of prostate cancer. RESULTS: Seventy-two community physicians responded to the survey. Of note, 50% community physicians indicated they would treat nmCRPC with agents approved for this indication if advanced imaging showed metastases. Radiation to the prostate for low-volume mCSPC was identified as a treatment practice by 27% of community physicians, and 35% indicated docetaxel as the next line of treatment after use of apalutamide. Use of genetic testing was reported in 36% of community physicians for newly diagnosed metastatic prostate cancer. CONCLUSIONS: There are several areas of community-based management of advanced prostate cancer that could represent potential areas for education, practice tools, and future research.

Controversial issues in the management of patients with advanced prostate cancer: Results from a Canadian consensus forum.

INTRODUCTION: The management of advanced prostate cancer (PCa) continues to evolve with the emergence of new diagnostic and therapeutic strategies. As a result, there are multiple areas in this landscape with a lack of high-level evidence to guide practice. Consensus initiatives are an approach to establishing practice guidance in areas where evidence is unclear. We conducted a Canadian-based consensus forum to address key controversial areas in the management of advanced PCa. METHODS: As part of a modified Delphi process, a core scientific group of PCa physicians (n=8) identified controversial areas for discussion and developed an initial set of questions, which were then reviewed and finalized with a larger group of 29 multidisciplinary PCa specialists. The main areas of focus were non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-sensitive prostate cancer (mCSPC), metastatic castration-resistant prostate cancer (mCRPC), oligometastatic prostate cancer, genetic testing in prostate cancer, and imaging in advanced prostate cancer. The predetermined threshold for consensus was set at 74% (agreement from 20 of 27 participating physicians). RESULTS: Consensus participants included uro-oncologists (n=13), medical oncologists (n=10), and radiation oncologists (n=4). Of the 64 questions, consensus was reached in 30 questions (n=5 unanimously). Consensus was more common for questions related to biochemical recurrence, sequencing of therapies, and mCRPC. CONCLUSIONS: A Canadian consensus forum in PCa identified areas of agreement in nearly 50% of questions discussed. Areas of variability may represent opportunities for further research, education, and sharing of best practices. These findings reinforce the value of multidisciplinary consensus initiatives to optimize patient care.

Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial.

BACKGROUND: Abiraterone acetate plus prednisone and enzalutamide are both used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the best sequence in which to use both drugs, as well as their second-line efficacy. METHODS: In this multicentre, randomised, open-label, phase 2, crossover trial done in six cancer centres in British Columbia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group B). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from baseline) on second-line therapy, analysed by intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357. FINDINGS: Between Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group B (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group B had crossed over. Time to second PSA progression was longer in group A than in group B (median 19·3 months [95% CI 16·0-30·5] vs 15·2 months [95% CI 11·9-19·8] months; hazard ratio 0·66, 95% CI 0·45-0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3-33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for abiraterone (χ2 p<0·0001). The most common grade 3-4 adverse events throughout the trial were hypertension (27 [27%] of 101 patients in group A vs 18 [18%] of 101 patients in group B) and fatigue (six [10%] vs four [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in group A and 20 (20%) of 101 patients in group B. There were no treatment-related deaths. INTERPRETATION: Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit. FUNDING: Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Terry Fox New Frontiers Program, BC Cancer Foundation, Jane and Aatos Erkko Foundation, Janssen, and Astellas.

Clinical effectiveness of docetaxel for castration-sensitive prostate cancer in a real-world population-based analysis.

BACKGROUND: Adding docetaxel to androgen deprivation therapy (ADT) for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) has known efficacy, with an overall survival benefit in Phase III clinical trials. The effectiveness of docetaxel with ADT in the general patient population remains undefined. PATIENTS AND METHODS: We conducted a population-based retrospective review using the British Columbia Provincial Pharmacy Database. To be included, patients had to have castration-sensitive prostate cancer not previously treated (except in the adjuvant setting) and have received at least one cycle of docetaxel, with complete records available for review. Safety and clinical effectiveness were evaluated. RESULTS: From April 2015 to February 2017, we identified 183 cases; 156 met inclusion criteria. Most patients had high-volume disease (80%). All 6 planned docetaxel cycles were delivered in 126 cases (81%). Dose reductions and delays were required in 39% and 16% of cases. Grade 3-4 adverse events were noted in 40%, with no treatment-related deaths. The rate of febrile neutropenia was 18% and was significantly associated with the presence of high-volume disease (P = 0.038). PSA ≤ 0.2 ng/L was achieved in 27% of patients after 6 months of ADT and maintained in 16% after 12 months. Patients with over 20 bone metastases had worse time to castration resistant prostate cancer (CRPC) and time to treatment for CRPC, and a trend toward worse overall survival. CRPC developed in 41% within 1 year, with a median time to CRPC of 14.4 months. Treatment for CRPC was given in 84 cases, with 90% receiving either abiraterone or enzalutamide in the first-line, with a PSA decline ≥50% occurring in 47%. CONCLUSIONS: The effectiveness of docetaxel with ADT in a general population of patients with mCSPC was associated with poorer outcomes and high rates of toxicity compared to the published studies. Response rates to first-line treatment for mCRPC with abiraterone or enzalutamide appear similar to reported outcomes.

Therapeutic Implication of Genomic Landscape of Adult Metastatic Sarcoma.

PURPOSE: This study investigated therapeutic potential of integrated genome and transcriptome profiling of metastatic sarcoma, a rare but extremely heterogeneous group of aggressive mesenchymal malignancies with few systemic therapeutic options. METHODS: Forty-three adult patients with advanced or metastatic non-GI stromal tumor sarcomas of various histology subtypes who were enrolled in the Personalized OncoGenomics program at BC Cancer were included in this study. Fresh tumor tissues along with blood samples underwent whole-genome and transcriptome sequencing. RESULTS: The most frequent genomic alterations in this cohort are large-scale structural variation and somatic copy number variation. Outlier RNA expression as well as somatic copy number variations, structural variations, and small mutations together suggest the presence of one or more potential therapeutic targets in the majority of patients in our cohort. Point mutations or deletions in known targetable cancer genes are rare; for example, tuberous sclerosis complex 2 provides a rationale for targeting the mammalian target of rapamycin pathway, resulting in a few patients with exceptional clinical benefit from everolimus. In addition, we observed recurrent 17p11-12 amplifications, which seem to be a sarcoma-specific event. This may suggest that this region harbors an oncogene(s) that is significant for sarcoma tumorigenesis. Furthermore, some sarcoma tumors carrying a distinct mutational signature suggestive of homologous recombination deficiency seem to demonstrate sensitivity to double-strand DNA-damaging agents. CONCLUSION: Integrated large-scale genomic analysis may provide insights into potential therapeutic targets as well as novel biologic features of metastatic sarcomas that could fuel future experimental and clinical research and help design biomarker-driven basket clinical trials for novel therapeutic strategies.

The Influence of the Evolution of First-Line Chemotherapy on Steadily Improving Survival in Advanced Non-Small-Cell Lung Cancer Clinical Trials.

Over the past three decades, survival in advanced non-small-cell lung cancer (NSCLC) clinical trials has doubled with an increase in 1-year survival from 25% to 50 to 55%. This has been mainly attributed to improvements in systemic therapy. Although modern first-line chemotherapy regimens have more favorable toxicity profiles, a statistically significant improvement in overall survival has not been demonstrated in existing meta-analyses of second-generation versus third-generation combinations. Moreover, pivotal trials demonstrating statistically significant survival superiority of third-generation regimens are consistently not reproducible even for nonsquamous populations using pemetrexed-platinum combinations. As enhancement in the efficacy of first-line systemic therapy in patients without identifiable driver mutations is questionable, other factors are discussed that explain the doubling of 1-year survival reported in clinical trials. These factors include second-line or third-line therapy, maintenance chemotherapy, performance status selection, stage migration, sex migration, improved treatment of brain metastases, and better palliative care.

Referral patterns in advanced non-small cell lung cancer: impact on delivery of treatment and survival in a contemporary population based cohort.

INTRODUCTION: Chemotherapy improves overall survival (OS) in advanced non-small cell lung cancer (NSCLC), yet low rates of chemotherapy utilization have been observed. We sought to characterize the clinical effectiveness of chemotherapy in the general population by evaluating referral patterns, predictors of chemotherapy receipt and outcomes. METHODS: All referred cases of stage IIIB/IV NSCLC in British Columbia from January 1 to December 31, 2009 were retrospectively reviewed. Patient demographics, tumor characteristics and treatments were extracted. OS was estimated using the Kaplan-Meier method. Cox Proportional Hazards modeling was used to control for confounding variables. Multiple logistic regression was used to assess factors that predicted for chemotherapy treatment. RESULTS: 1373 patients were identified. Median age 70 years, 53% male, 37% ECOG ≥ 3. HISTOLOGY: 34% non-squamous, 21% squamous and 46% NOS. 748 (54%) patients were assessed by medical oncology and 417 (30%) received chemotherapy. Predictors of chemotherapy treatment were younger age, ECOG 0-2, living in a rural area and not receiving radiotherapy. There was an improvement in OS in patients who received chemotherapy at 13.1 months versus best supportive care 5.4 months (p<0.0001). This remained statistically significant when controlling for ECOG, sex, age, histology (HR 0.68, CI 0.59-0.78). CONCLUSIONS: In this population-based setting, 37% of patients had an ECOG ≥ 3 at the time of referral, 54% were assessed by a medical oncologist and only 30% received chemotherapy. This is despite the awareness that chemotherapy significantly improves survival. Strategies to optimize appropriate referral such that patients do not miss out on life-prolonging therapy should be evaluated.

Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs.

BACKGROUND: Retrospective studies have demonstrated high response rates among patients with advanced pancreatic neuroendocrine tumors (PNETs) treated with capecitabine and temozolamide (CapTem), while responses are infrequently seen among non-PNETs. The objective of the study was to describe progression free survival (PFS) among neuroendocrine tumor (NET) patients treated with CapTem, and to identify factors associated with better activity. METHODS: Patients who were referred to one of five provincial cancer treatment centers between 2009 and 2013 for advanced NETs and initiated CapTem were included. Patients received Cap 1,500 mg/m(2) on days 1-14 and TMZ 200 mg/m(2) on days 10-14 every 28 days. Their characteristics and outcomes were retrospectively analyzed. RESULTS: In our cohort, 29 patients (16 males) with a median age of 59 (range 26-76) received palliative CapTem, 15 of them as first-line chemotherapy. Primary tumors included pancreas (48.3%), small bowel (20.7%), lung (10.3%), unknown (10.3%), rectum (6.9%) and appendix (3.4%). Median number of cycles was three. Fifteen patients (51.7%) received CapTem as first-line chemotherapy and 14 (48.3%) as subsequent lines. Median PFS for the entire cohort was 4.7 months. PNETs had a median PFS of 4.9 months compared to 2.8 months for non-PNETs (P=0.178). Patients with PNETs who received CapTem in the first-line setting had a median PFS of 15.9 months as compared to only 3.1 months for the remainder [P=0.047, hazard ratios (HR) 0.342]. Patients with Ki67 above 5% and ≤5% had median PFS of 4.0 and 4.7 months, respectively (P=0.260). CONCLUSIONS: CapTem showed good activity among PNETs, but its broader role in the treatment of carcinoid tumors remains unclear.