Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics.

BACKGROUND: Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles. METHODS: We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared. RESULTS: Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease. CONCLUSIONS: The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions.

Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine.

BACKGROUND: Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology. OBJECTIVE: To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials. DESIGN SETTING AND PARTICIPANTS: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature. INTERVENTION: Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression. RESULTS AND LIMITATIONS: Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of "skeletal-related events" complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index <0.89 in 24/31 patients) but limited to the last year of life. Biomarker review identified 30 categories of mPC biomarkers in need of winnowing in future trials. All findings require validation in larger cohorts, preferably alongside data from this study. CONCLUSIONS: The study identified novel outcome subgroups for future validation and provides "vision for mPC precision oncology 2020-2050" draft recommendations for future data collection and biomarker studies. PATIENT SUMMARY: To better understand variation in metastatic prostate cancer behavior, we assembled and analyzed longitudinal clinical and autopsy records in 33 men. We identified novel outcomes, phenotypes, and aspects of disease burden to be tested and refined in future trials.

Cost-Effectiveness of Metastasis-Directed Therapy in Oligorecurrent Hormone-Sensitive Prostate Cancer.

PURPOSE: Oligorecurrent prostate cancer has historically been treated with indefinite androgen deprivation therapy (ADT), although many patients and providers opt to defer this treatment at the time of recurrence given quality-of-life and/or comorbidity considerations. Recently, metastasis-directed therapy (MDT) has emerged as a potential intermediary between surveillance and immediate continuous ADT. Simultaneously, advanced systemic therapy in addition to ADT has also been shown to improve survival in metastatic hormone-sensitive disease. This study aimed to compare the cost-effectiveness of treating oligorecurrent patients with upfront MDT before standard-of-care systemic therapy. METHODS AND MATERIALS: A Markov-based cost-effectiveness analysis was constructed comparing 3 strategies: (1) upfront MDT → salvage abiraterone acetate plus prednisone (AAP) + ADT → salvage docetaxel + ADT; (2) upfront AAP + ADT → salvage docetaxel + ADT; and (3) upfront docetaxel + ADT → salvage AAP + ADT. Transition probabilities and utilities were derived from the literature. Using a 10-year time horizon and willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY), net monetary benefit values were subsequently calculated for each treatment strategy. RESULTS: At 10 years, the base case revealed a total cost of $141,148, $166,807, and $136,154 with QALYs of 4.63, 4.89, and 4.00, respectively, reflecting a net monetary benefit of $322,240, $322,018, and $263,407 for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. In the probabilistic sensitivity analysis using a Monte Carlo simulation (1,000,000 simulations), upfront MDT was the cost-effective strategy in 53.6% of simulations. The probabilistic sensitivity analysis revealed 95% confidence intervals for cost ($75,914-$179,862, $124,431-$223,892, and $103,298-$180,617) and utility in QALYs (3.85-6.12, 3.91-5.86, and 3.02-5.22) for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. CONCLUSIONS: At 10 years, upfront MDT followed by salvage AAP + ADT, is comparably cost-effective compared with upfront standard-of-care systemic therapy and may be considered a viable treatment strategy, especially in patients wishing to defer systemic therapy for quality-of-life or comorbidity concerns. Additional studies are needed to determine whether MDT causes a sustained meaningful delay in disease natural history and whether any benefit exists in combining MDT with upfront advanced systemic therapy.

A Trial-Based Cost-Utility Analysis of Metastasis-Directed Therapy for Oligorecurrent Prostate Cancer.

The optimal management of patients with oligorecurrent prostate cancer (PCa) is unknown. There is growing interest in metastasis-directed therapy (MDT) for this population. The objective was to assess cost-utility from a Belgian healthcare payer's perspective of MDT and delayed androgen deprivation therapy (ADT) in comparison with surveillance and delayed ADT, and with immediate ADT. A Markov decision-analytic trial-based model was developed, projecting the results over a 5-year time horizon with one-month cycles. Clinical data were derived from the STOMP trial and literature. Treatment costs were derived from official government documents. Probabilistic sensitivity analyses showed that MDT is cost-effective compared to surveillance (ICER: €8393/quality adjusted life year (QALY)) and immediate ADT (dominant strategy). The ICER is most sensitive to utilities in the different health states and the first month MDT cost. At a willingness-to-pay threshold of €40,000 per QALY, the cost of the first month MDT should not exceed €8136 to be cost-effective compared to surveillance. The Markov-model suggests that MDT for oligorecurrent PCa is potentially cost-effective in comparison with surveillance and delayed ADT, and in comparison with immediate ADT.

Are clinical guidelines designed according to guidelines? Cross-sectional assessment of quality and transparency of clinical guidelines in urology.

PURPOSE: Guidelines and recommendations become increasingly important in clinical urologic practice. This study aims to inform clinicians using guidelines on how to evaluate the quality of the methodology and transparency of these documents. METHODS: The guidelines on management of castration-resistant prostate cancer of the American Urology Association, European Association of Urology, National Comprehensive Cancer Network, National Institute for Health and Care Excellence, European Society of Medical Oncology were reviewed using the AGREE-II tool (Appraisal of Guidelines for Research and Evaluation). We reported and compared the domain scores for the domains 1 scope and purpose, 2 stakeholder involvement, 3 rigor of development, 4 clarity of presentation, 5 applicability, and 6 editorial independence (100% indicates highest-best quality score). RESULTS: The domains evaluated highest and with lowest variability were 'editorial independence' (92% {88-95%}) and 'clarity of presentation' (83% {72-90%}), while the domains with the lowest scores and most variability were 'stakeholder involvement' (56% {36-79%}) and 'applicability' (40% {30-63%}). Length and extent of detail of guidelines vary considerably, each with its own strengths and limitations and adapted to target users. Standard external review using AGREE criteria may be preferable. A formal search strategy was not performed. Findings may be outdated by guidelines' updates. CONCLUSIONS: Clinicians using practice guidelines need to be aware of the different domains of methodology and transparency used to assess the quality of guidelines contents and recommendations. Urologists increasingly use guidelines for support in evidence-based recommendations in clinical practice. It is very important to know how to assess these documents. This study applies standard criteria to compare the design and background of different available guidelines on prostate cancer no longer responding to hormonal treatment.