Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer.

Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2-12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.

Apalutamide efficacy, safety and wellbeing in older patients with advanced prostate cancer from Phase 3 randomised clinical studies TITAN and SPARTAN.

BACKGROUND: Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant PC (nmCRPC) in the Phase 3 randomised TITAN and SPARTAN studies, respectively, and maintained health-related quality of life (HRQoL). Apalutamide treatment effect by patient age requires assessment. METHODS: Post-hoc analysis assessed patients receiving 240 mg/day apalutamide (525 TITAN and 806 SPARTAN) or placebo (527 TITAN and 401 SPARTAN) with ongoing ADT, stratified by age groups. Prostate-specific antigen declines, radiographic progression-free survival, metastasis-free survival, overall survival (OS), HRQoL and safety were assessed using descriptive statistics, Kaplan-Meier method, Cox proportional-hazards model and mixed-effects model for repeated measures. RESULTS: Hazard ratios (95% confidence intervals) generally favoured apalutamide plus ADT versus ADT alone across all endpoints regardless of age; e.g., OS values were 0.57 (0.40-0.80), 0.70 (0.54-0.91) and 0.74 (0.40-1.39) (TITAN) and 0.39 (0.19-0.78), 0.89 (0.69-1.16) and 0.81 (0.58-1.15) (SPARTAN) in patients aged <65, 65-79 and ≥80 years. Regardless of age, apalutamide also maintained HRQoL and was tolerated well with a potential trend in rates of adverse events increasing with age. Limitations include post-hoc nature and variability in sample size of age groups. CONCLUSIONS: Apalutamide plus ADT was an effective and well-tolerated option maintaining HRQoL in patients with mCSPC and nmCRPC regardless of age. CLINICAL TRIAL REGISTRATION: TITAN (NCT02489318); SPARTAN (NCT01946204).

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

Prostate-specific antigen and health-related quality of life in individuals with advanced prostate cancer treated with apalutamide: a plain language summary of the SPARTAN and TITAN studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper that describes the results of the SPARTAN and TITAN studies, which looked at whether a treatment called apalutamide can help treat individuals with advanced prostate cancer.The SPARTAN study included 1207 participants with nonmetastatic castration-resistant prostate cancer (or nmCRPC). The TITAN study included 1052 participants with metastatic castration-sensitive prostate cancer (or mCSPC). Treatment with apalutamide was compared with treatment with placebo. In both studies, all participants were also given androgen deprivation therapy (or ADT), which has been used for many years for the treatment of prostate cancer.The results showed that treatment with apalutamide plus ADT increased participants' survival time while their health-related quality of life stayed the same, compared with placebo plus ADT. Also, apalutamide plus ADT increased the length of time that the cancer did not spread to other parts of the body (metastasize) or did not continue to grow. In both studies, treatment with apalutamide plus ADT was associated with a deep decline in blood prostate-specific antigen (or PSA) levels (called a deep PSA decline). This additional analysis of the SPARTAN and TITAN studies was performed to understand whether the deep PSA decline in participants who received apalutamide plus ADT was linked to their overall health-related quality of life. WHAT WERE THE RESULTS OF THE ADDITIONAL ANALYSIS?: In participants who received apalutamide plus ADT, those who achieved a deep PSA decline after the start of treatment had a greater chance that their health-related quality of life would remain stable. When participants achieved a deep PSA decline at 3 months after the start of treatment, the benefit to their health-related quality of life, including physical wellbeing, was even greater. WHAT DO THESE RESULTS MEAN FOR INDIVIDUALS WITH ADVANCED PROSTATE CANCER?: For individuals with advanced prostate cancer, it is important to monitor both PSA decline and any impacts on health-related quality of life. These results will help doctors and other healthcare professionals have a better understanding of patients' cancer experience and the impact of their treatment.Clinical Trial Registration: NCT01946204 (SPARTAN) and, NCT02489318 (TITAN) (ClinicalTrials.gov).

Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance.

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.

COVID-19 Outcomes Among Patients With Cancer: Observations From the University of California Cancer Consortium COVID-19 Project Outcomes Registry.

BACKGROUND: The risks associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated illness, coronavirus disease 2019 (COVID-19), among patients with a cancer diagnosis have not been fully characterized. This study leverages data from a multi-institutional cohort study, the University of California Cancer COVID Consortium, to evaluate outcomes associated with SARS-CoV-2 infection among patients with cancer. METHODS: Clinical data were collected from March to November 2020 and included patient demographics, cancer history and treatment, SARS-CoV-2 exposure and testing, and COVID-19 clinical management and outcomes. Multivariate ordinal logistic regression permitting unequal slopes was used to evaluate the impact of demographic, disease, and treatment factors on SARS-CoV-2 related hospitalization, intensive care unit (ICU) admission, and mortality. FINDINGS: Among all evaluated patients (n = 303), 147 (48%) were male, 118 (29%) were older adults (≥65 years old), and 104 (34%) were non-Hispanic white. A subset (n = 63, 21%) had hematologic malignancies and the remaining had solid tumors. Patients were hospitalized for acute care (n = 79, 26%), ICU-level care (n = 28, 9%), or died (n = 21, 7%) due to COVID-19. Patients with ≥2 comorbidities were more likely to require acute care (odds ratio [OR] 2.09 [95% confidence interval (CI), 1.23-3.55]). Cough was identified as a significant predictor of ICU hospitalization (OR 2.16 [95% CI, 1.03-4.57]). Importantly, mortality was associated with an active cancer diagnosis (OR 3.64 [95% CI, 1.40-9.5]) or advanced age (OR 3.86 [95% CI, 1.2-12.44]). INTERPRETATION: This study observed that patients with active cancer or advanced age are at an increased risk of death from COVID-19. These study observations can inform risk counseling related to COVID-19 for patients with a cancer diagnosis.

Prostate-specific antigen nadir and testosterone level at prostate-specific antigen failure following radiation and androgen suppression therapy for unfavorable-risk prostate cancer and the risk of all-cause and prostate cancer-specific mortality.

BACKGROUND: Although both PSA nadir (PSAn) and testosterone levels at PSA failure are known prognostic factors in men undergoing radiation therapy (RT) and androgen deprivation therapy (ADT) for unfavorable-risk prostate cancer (PC), it is unclear whether their prognostic significance is independent or overlapping. METHODS: Seventy-five men treated with RT with or without 6 months of ADT for unfavorable-risk nonmetastatic PC enrolled in 2 prospective clinical trials between 1986 and 2001 formed the study cohort. Competing risks and Cox multivariable regression were used to assess whether low versus normal serum testosterone at the time of PSA failure and higher PSAn after initial therapy were independently associated with the risk of PC-specific (PCSM) and all-cause mortality (ACM) adjusting for PC prognostic factors. RESULTS: After a median follow-up of 15.34 years (interquartile range, 6.66-16.88 years), there were 53 deaths (73.3%): 30 (56.6%) were from PC. Low testosterone at PSA failure was significantly associated with an increased risk of PCSM (adjusted HR [AHR], 7.77; 95% CI, 1.14-52.99; P = .04) and ACM (AHR, 3.01; 95% CI, 1.01-8.96; P = .05), as was higher PSAn (PCSM AHR, 1.03; 95% CI, 1.01-1.05; P < .01; ACM AHR, 1.04; 95% CI, 1.02-1.07; P < .01), although the prognostic significance of PSAn was only noted in men with a normal testosterone at PSA failure. CONCLUSIONS: Low testosterone level at PSA failure in high-risk patients with PC treated with RT is associated with increased PCSM and ACM risk. In men with normal testosterone levels at the time of PSA failure, an elevated PSAn was associated with worse PCSM and ACM risk. LAY SUMMARY: This study investigates whether the prostate-specific antigen (PSA) nadir and normal versus low testosterone at the time of PSA failure provide mutually exclusive or overlapping prognostic information following treatment with radiation and androgen deprivation therapy for unfavorable-risk patients with prostate cancer using data from 2 prospective clinical trials. It was found that both provided prognostic information; however, higher PSA nadir was only found to be of prognostic significance in men with normal testosterone levels at PSA failure.

Differential treatment outcomes in BRCA1/2-, CDK12-, and ATM-mutated metastatic castration-resistant prostate cancer.

BACKGROUND: DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described. METHODS: A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors. RESULTS: The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS. CONCLUSIONS: Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.

Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.

BACKGROUND: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS: We conducted a 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 apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).

Baseline Testosterone Levels in Men with Clinically Localized High-Risk Prostate Cancer Treated with Radical Prostatectomy with or without Neoadjuvant Chemohormonal Therapy (Alliance).

PURPOSE: Men with low serum testosterone at the time of prostate cancer diagnosis are frequently considered to have more aggressive disease. We examined treatment outcomes in men with clinically localized high-risk cancer to determine if baseline testosterone level identified men at higher risk for cancer progression after treatment. MATERIALS AND METHODS: Alliance/CALGB 90203 randomized men with clinically localized high-risk prostate cancer to radical prostatectomy alone or neoadjuvant chemohormonal therapy and radical prostatectomy. Men with available baseline testosterone levels who had not received androgen deprivation prior to study enrollment were studied (656). Testosterone level was examined as a continuous variable, as quartiles, and separately in men with an absolute testosterone level above/below 150 ng/dl. Outcomes evaluated were overall survival and event-free survival with events defined by biochemical recurrence, secondary treatment, prostate cancer metastasis, and death. RESULTS: We were unable to demonstrate a difference between baseline serum testosterone level measured as a continuous variable, as quartiles, or as a dichotomous variable (above/below 150 ng/dl) with the outcomes measured. This finding was observed in both arms of the study. CONCLUSIONS: Baseline serum testosterone level did not predict outcomes in men with clinically localized high-risk prostate cancer treated with radical prostatectomy alone or neoadjuvant chemohormonal therapy and radical prostatectomy.

Effect of a Behavioral Intervention to Increase Vegetable Consumption on Cancer Progression Among Men With Early-Stage Prostate Cancer: The MEAL Randomized Clinical Trial.

Importance: Guidelines endorsing vegetable-enriched diets to improve outcomes for prostate cancer survivors are based on expert opinion, preclinical studies, and observational data. Objective: To determine the effect of a behavioral intervention that increased vegetable intake on cancer progression in men with early-stage prostate cancer. Design, Setting, and Participants: The Men's Eating and Living (MEAL) Study (CALGB 70807 [Alliance]) was a randomized clinical trial conducted at 91 US urology and medical oncology clinics that enrolled 478 men aged 50 to 80 years with biopsy-proven prostate adenocarcinoma (International Society of Urological Pathology grade group = 1 in those <70 years and ≤2 in those ≥70 years), stage cT2a or less, and serum prostate-specific antigen (PSA) level less than 10 ng/mL. Enrollment occurred from January 2011 to August 2015; 24-month follow-up occurred from January 2013 to August 2017. Interventions: Patients were randomized to a counseling behavioral intervention by telephone promoting consumption of 7 or more daily vegetable servings (MEAL intervention; n = 237) or a control group, which received written information about diet and prostate cancer (n = 241). Main Outcomes and Measures: The primary outcome was time to progression; progression was defined as PSA level of 10 ng/mL or greater, PSA doubling time of less than 3 years, or upgrading (defined as increase in tumor volume or grade) on follow-up prostate biopsy. Results: Among 478 patients randomized (mean [SD] age, 64 [7] years; mean [SD] PSA level, 4.9 [2.1] ng/mL), 443 eligible patients (93%) were included in the primary analysis. There were 245 progression events (intervention: 124; control: 121). There were no significant differences in time to progression (unadjusted hazards ratio, 0.96 [95% CI, 0.75 to 1.24]; adjusted hazard ratio, 0.97 [95% CI, 0.76 to 1.25]). The 24-month Kaplan-Meier progression-free percentages were 43.5% [95% CI, 36.5% to 50.6%] and 41.4% [95% CI, 34.3% to 48.7%] for the intervention and control groups, respectively (difference, 2.1% [95% CI, -8.1% to 12.2%]). Conclusions and Relevance: Among men with early-stage prostate cancer managed with active surveillance, a behavioral intervention that increased vegetable consumption did not significantly reduce the risk of prostate cancer progression. The findings do not support use of this intervention to decrease prostate cancer progression in this population, although the study may have been underpowered to identify a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT01238172.

Cabozantinib Versus Sunitinib for Untreated Patients with Advanced Renal Cell Carcinoma of Intermediate or Poor Risk: Subgroup Analysis of the Alliance A031203 CABOSUN trial.

Cabozantinib treatment prolonged progression-free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. Clinical trial identification number NCT01835158.

Germline and Somatic Mutations in Prostate Cancer for the Clinician.

It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

Treatment of advanced renal cell carcinoma patients with cabozantinib, an oral multityrosine kinase inhibitor of MET, AXL and VEGF receptors.

Von Hippel-Lindau (VHL), a tumor suppressor gene, is frequently inactivated in renal cell carcinoma (RCC). It drives tumorigenesis by activating downstream hypoxia responsive genes and proangiogenic factors like VEGFR, and is responsible for the activity of tyrosine kinase inhibitors in RCC. Resistance to VEGFR therapy eventually occurs, in part due to activation of alternative signaling pathways like AXL and MET. Cabozantinib is a potent inhibitor of VEGF, AXL and MET receptors providing rationale for its use in RCC. Cabozantinib has been approved for use in the first- and second-line setting in patients with advanced RCC. This manuscript reviews the preclinical data, pharmacology, clinical efficacy and safety of the use of cabozantinib in RCC.

Apalutamide and its use in the treatment of prostate cancer.

High-risk nonmetastatic castration-resistant prostate cancer is a lethal disease that previously lacked clear treatment options. Progression to bone metastases is associated with significant morbidity and high cost. Apalutamide, an androgen receptor inhibitor, has substantial clinical response in nonmetastatic castration-resistant prostate cancer. Apalutamide + androgen deprivation therapy is well tolerated and improves metastasis-free survival, progression-free survival and time to symptomatic progression, and is associated with a favorable trend of improved overall survival. Future research is needed to elucidate mechanisms of resistance to treatment with androgen signaling inhibitors.

Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.

BACKGROUND: In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL). METHODS: SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204. FINDINGS: Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8-26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group. INTERPRETATION: In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL. FUNDING: Janssen Research & Development.

Low testosterone at first prostate-specific antigen failure and assessment of risk of death in men with unfavorable-risk prostate cancer treated on prospective clinical trials.

BACKGROUND: Low testosterone at the time of diagnosis of prostate cancer has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at the time of first prostate-specific antigen (PSA) failure to the authors' knowledge has not been elucidated to date and was studied herein. METHODS: Between 1995 and 2001, a total of 58 men with unfavorable-risk PC who were treated on clinical trials with radiotherapy and androgen deprivation therapy (ADT) had available testosterone levels at the time of PSA failure. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone was associated with the risk of PC-specific mortality, other-cause mortality, and all-cause mortality adjusting for age, salvage ADT, and known PC prognostic factors. RESULTS: After a median follow-up of 6.68 years after PSA failure, 31 men (53.4%) had died; 10 of PC (32.3%), of which 8 of 11 (72.7%) versus 2 of 47 (4.3%) deaths occurred in men with low versus normal testosterone at the time of PSA failure, respectively. A significant increase in the risk of all-cause mortality (adjusted hazard ratio [AHR], 2.54; 95% confidence interval [95% CI], 1.04-6.21 [P = .04]) and PC-specific mortality (AHR, 13.71; 95% CI, 2.4-78.16 [P = .003]), with a reciprocal trend toward a decreased risk of other-cause mortality (AHR, 0.18; 95% CI, 0.02-1.55 [P = .12]) was observed in men with low versus normal testosterone. CONCLUSIONS: Low, but not necessarily castrate, testosterone levels at the time of PSA failure confer a very poor prognosis. These observations provide evidence to support testosterone testing at the time of PSA failure. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic PC and possibly localized high-risk PC provides a rationale supporting their use with ADT in men with low testosterone in the setting of a phase 2 trial. Cancer 2018;124:1383-90. © 2017 American Cancer Society.

DNA Repair Gene Alterations and PARP Inhibitor Response in Patients With Metastatic Castration-Resistant Prostate Cancer.

Background: PARP inhibition is a promising therapeutic strategy for the treatment of men with metastatic castration-resistant prostate cancer whose tumors harbor homologous recombination DNA repair gene alterations. However, questions remain for many practicing clinicians about which patients are ideally suited for PARP inhibitor treatment. This report details our institutional experience using PARP inhibitor therapy in patients whose tumors harbored specific DNA repair gene alterations. Patients and Methods: We performed a retrospective chart review to identify patients at Oregon Health & Science University who were treated with PARP inhibition. We identified 8 patients and determined the impact of the specific DNA repair gene alterations on tumor response and time on treatment with PARP inhibition. Results: A number of DNA repair gene alterations were identified. Three patients had pathogenic BRCA2 mutations and one had a BRCA2 mutation of uncertain significance. Conversely, the 4 other patients' tumors harbored alterations in other DNA repair genes, none of which were clearly pathogenic. A statistically significant difference in benefit was seen between patients whose tumors harbored BRCA2 gene alterations and those whose tumors did not, as measured by >50% decline in prostate-specific antigen levels (100% vs 0%; P=.03) and duration on therapy (31.4 vs 6.4 weeks; P=.03). Conclusions: Our results demonstrate that not all DNA repair alterations are equally predictive of PARP inhibitor response. Importantly, all responding patients had tumors harboring BRCA2 DNA repair alterations, including one without a known pathogenic mutation. Conversely, among the 4 nonresponders, several DNA repair alterations in genes other than BRCA2 were identified that were not clearly pathogenic. This demonstrates the need to carefully examine the functional relevance of the DNA repair alterations identified, especially in genes other than BRCA2, when considering patients for PARP inhibitor treatment.

CT-Guided Bone Biopsies in Metastatic Castration-Resistant Prostate Cancer: Factors Predictive of Maximum Tumor Yield.

PURPOSE: To evaluate the success rate of CT-guided bone biopsies in metastatic castration-resistant prostate cancer (mCRPC) and to investigate associated technical, imaging, and clinical parameters affecting diagnostic yields. MATERIALS AND METHODS: Eighty CT-guided bone biopsy specimens were obtained from 72 men (median age, 68 y; range, 49-89 y) enrolled in a multicenter trial to identify mechanisms of resistance in mCRPC. Successful biopsy was determined by histologic confirmation of tumor cells and successful isolation of RNA for molecular analysis. RESULTS: The overall success rate of CT-guided bone biopsies was 69% (55/80) based on histology and 64% (35/55) based on isolation of molecular material for RNA sequencing. Biopsies performed in lesions with areas of radiolucency had significantly higher diagnostic yields compared with lesions of predominantly dense sclerosis (95% vs 33%; P = .002) and lesions of predominantly subtle sclerosis (95% vs 65%; P = .04). Success rates increased in lesions with density ≤ 475 HU (79% for ≤ 475 HU vs 33% for > 475 HU; P = .001) and in lesions with ill-defined margins (76% for ill-defined margins vs 36% for well-circumscribed margins; P = .005). Alkaline phosphatase was the only clinical parameter to correlate significantly with diagnostic yield (83% for > 110 U/L vs 50% for ≤ 110 U/L; P = .001). CONCLUSIONS: Image-guided bone tumor biopsies can be successfully used to acquire cellular and molecular material for analyses in patients with osteoblastic prostate cancer metastases. Diagnostic yields are significantly increased in lesions with areas of radiolucency, density ≤ 475 HU, ill-defined margins, and interval growth and in patients with alkaline phosphatase > 110 U/L.