External Validation of a Digital Pathology-based Multimodal Artificial Intelligence Architecture in the NRG/RTOG 9902 Phase 3 Trial.

BACKGROUND: Accurate risk stratification is critical to guide management decisions in localized prostate cancer (PCa). Previously, we had developed and validated a multimodal artificial intelligence (MMAI) model generated from digital histopathology and clinical features. Here, we externally validate this model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial. OBJECTIVE: To externally validate the MMAI model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial. DESIGN, SETTING, AND PARTICIPANTS: Our validation cohort included 318 localized high-risk PCa patients from NRG/RTOG 9902 with available histopathology (337 [85%] of the 397 patients enrolled into the trial had available slides, of which 19 [5.6%] failed due to poor image quality). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Two previously locked prognostic MMAI models were validated for their intended endpoint: distant metastasis (DM) and PCa-specific mortality (PCSM). Individual clinical factors and the number of National Comprehensive Cancer Network (NCCN) high-risk features served as comparators. Subdistribution hazard ratio (sHR) was reported per standard deviation increase of the score with corresponding 95% confidence interval (CI) using Fine-Gray or Cox proportional hazards models. RESULTS AND LIMITATIONS: The DM and PCSM MMAI algorithms were significantly and independently associated with the risk of DM (sHR [95% CI] = 2.33 [1.60-3.38], p < 0.001) and PCSM, respectively (sHR [95% CI] = 3.54 [2.38-5.28], p < 0.001) when compared against other prognostic clinical factors and NCCN high-risk features. The lower 75% of patients by DM MMAI had estimated 5- and 10-yr DM rates of 4% and 7%, and the highest quartile had average 5- and 10-yr DM rates of 19% and 32%, respectively (p < 0.001). Similar results were observed for the PCSM MMAI algorithm. CONCLUSIONS: We externally validated the prognostic ability of MMAI models previously developed among men with localized high-risk disease. MMAI prognostic models further risk stratify beyond the clinical and pathological variables for DM and PCSM in a population of men already at a high risk for disease progression. This study provides evidence for consistent validation of our deep learning MMAI models to improve prognostication and enable more informed decision-making for patient care. PATIENT SUMMARY: This paper presents a novel approach using images from pathology slides along with clinical variables to validate artificial intelligence (computer-generated) prognostic models. When implemented, clinicians can offer a more personalized and tailored prognostic discussion for men with localized prostate cancer.

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591.

PURPOSE: Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225. METHODS: Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of 225Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D. RESULTS: Radiochemistry and animal studies were favorable. Thirty-two patients received 225Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%). CONCLUSION: To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of 225Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.

Longitudinal Monitoring of Circulating Tumor DNA to Assess the Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Genitourinary Malignancies.

PURPOSE: Circulating tumor DNA (ctDNA) detection in blood has emerged as a prognostic and predictive biomarker demonstrating improved assessment of treatment response in patients receiving immune checkpoint inhibitors (ICIs). Here, we performed a pilot study to support the role of ctDNA for longitudinal treatment response monitoring in patients with advanced genitourinary (GU) malignancies receiving ICIs. MATERIALS AND METHODS: Patients with histologically confirmed advanced GU malignancies were prospectively enrolled. All eligible patients received ICI treatment for at least 12 weeks, followed by serial collection of blood samples every 6-8 weeks and conventional scans approximately every 12 weeks until disease progression. ctDNA analysis was performed using Signatera, a tumor-informed multiplex-polymerase chain reaction next-generation sequencing assay. Overall, the objective response rate (ORR) was reported and its association with ctDNA status was evaluated. Concordance rate between ctDNA dynamics and conventional imaging was also assessed. RESULTS: ctDNA analysis was performed on 98 banked plasma samples from 20 patients (15 renal, four urothelial, and one prostate). The median follow-up from the time of initiation of ICI to progressive disease (PD) or data cutoff was 67.7 weeks (range, 19.6-169.6). The ORR was 70% (14/20). Eight patients ultimately developed PD. The overall concordance between ctDNA dynamics and radiographic response was observed in 83% (15/18) of patients. Among the three patients with discordant results, two developed CNS metastases and one progressed with extracranial systemic disease while ctDNA remained undetectable. CONCLUSION: In this pilot study, longitudinal ctDNA analysis for monitoring response to ICI in patients with advanced GU tumors was feasible. Larger prospective studies are warranted to validate the utility of ctDNA as an ICI response monitoring tool in patients with advanced GU malignancies.

Comprehensive Genomic Profiling of Cell-Free DNA in Men With Advanced Prostate Cancer: Differences in Genomic Landscape Based on Race.

Advanced prostate cancer (aPC) in Black men was reported to present with aggressive features and to be associated with poor prognosis. Herein, we compared the cell-free DNA (cfDNA) genomic landscape of aPC in Black vs White men. Patients (pts) with aPC from 6 academic institutions and available cfDNA comprehensive genomic profiling (CGP) were included. Association between mutated genes and race was evaluated using Barnard's test and a Probabilistic Graphical Model (PGM) machine learning approach. Analysis included 743 aPC pts (217 Black, 526 White) with available cfDNA CGP. The frequency of alterations in the androgen receptor gene was significantly higher in Black vs White men (55.3% vs 35% respectively, P < .001). Additionally, alterations in EGFR, MYC, FGFR1, and CTNNB1 were present at higher frequencies in Black men. PGM analysis and Barnard's test were concordant. Findings from the largest cohort of Black men with aPC undergoing cfDNA CGP may guide further drug development in these men.

The Influence of the Pretreatment Immune State on Response to Radiation Therapy in High-Risk Prostate Cancer: A Validation Study From NRG/RTOG 0521.

PURPOSE: The immunoinflammatory state has been shown to be associated with poor outcomes after radiation therapy (RT). We conducted an a priori designed validation study using serum specimens from Radiation Therapy Oncology Group (RTOG) 0521. It was hypothesized the pretreatment inflammatory state would correlate with clinical outcomes. METHODS AND MATERIALS: Patients on RTOG 0521 had serum banked for biomarker validation. This study was designed to validate previous findings showing an association between elevations in C-reactive protein (CRP) and shorter biochemical disease free survival (bDFS). CRP levels were measured in pretreatment samples. An exploratory panel of related cytokines was also measured including: monocyte chemotactic protein-1, granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-23, and tumor necrosis factor. The primary endpoint examined was bDFS. Additional exploratory endpoints included overall survival, distant metastases, and toxicity events attributed to RT. RESULTS: Two hundred and two patients in RTOG/NRG 0521 had serum samples available. Median age was 66 years (48-83), and 90% of patients were White. There was not an association between CRP and bDFS (adjusted hazard ratio [HR], 1.07 per 1 log increase in CRP; 95% confidence interval, 0.83-1.38; P = .60). In the exploratory, unplanned analysis, pretreatment IL-10 was significantly associated with worse bDFS (adjusted HR, 1.61 per log increase; P = .0027) and distant metastases (HR, 1.55 per log increase; P = .028). The association of IL-10 with bDFS was maintained on a multiplicity adjustment. The exploratory analyses of pretreatment levels of interferon-γ, IL-1b, IL-2, IL-13, IL-23 were negatively associated with grade 2 or higher pollakiuria (adjusted odds ratio, 0.64, 0.65, 0.71, 0.72, and 0.74, respectively, all P < .05), and IL-6 was negatively associated with grade 2 or higher erectile dysfunction (odds ratio, 0.62; P = .027). CONCLUSIONS: Pretreatment CRP was not associated with a poorer bDFS after RT. In a hypothesis- generating analysis, higher baseline levels of IL-10 were associated with lower rates of bDFS. These findings require additional prospective evaluation.

Interim analysis of companion, prospective, phase II, clinical trials assessing the efficacy and safety of multi-modal total eradication therapy in men with synchronous oligometastatic prostate cancer.

Multimodal therapies were combined to eradicate the primary site, metastatic, and micrometastatic disease in men with newly diagnosed, synchronous, oligometastatic prostate cancer. The investigation included companion, phase II studies: total eradication therapy-1 (TET-1) for those treatment-naïve and total eradication therapy-2 (TET-2) for those post-prostatectomy. The treatment-naive protocol included androgen deprivation and docetaxel (with concurrent abiraterone added in a protocol amendment), followed by a prostatectomy, adjuvant radiation (if positive margins, T3/4, or detectable PSA), and metastasis-directed therapy. The post-prostatectomy protocol assigned the same therapies (omitting the prostatectomy). The primary endpoint was an undetectable PSA with recovered testosterone. The safety boundaries were ≤ 50% for grade 3/4 neutropenic and ≤ 20% for grade 3/4 surgical- and radiation-related toxicities. Enrollment was planned for 60 patients per protocol, to detect a PSA progression-free survival ≥ 32%, as compared to 15% in a historic control. Enrollment closed early. An interim analysis was conducted once > 50% of patients were evaluable for the primary endpoint. The primary endpoint duration was assessed by median progression-free survival. 52 patients were enrolled (n = 26 per protocol). Medium follow-up was 30.3 months. 80% (24/30) of evaluable patients achieved the primary endpoint; the duration was not reached. Of those not evaluable, 77% (17/22) had not reached the endpoint and 23% (5/22) had exited. There were 8% (4/52) grade 3/4 neutropenic and 2% (1/48) grade 3/4 surgical or radiation-induced toxicities. Interim findings suggest the trials' endpoints were met, advancing the concept of total eradication therapy in men with oligometastatic prostate cancer.

Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer.

Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS: We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. RESULTS: A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION: PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.

A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.

BACKGROUND: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. METHODS: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. RESULTS: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. CONCLUSIONS: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer.

INTRODUCTION: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA). METHODS: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2-4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety. RESULTS: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6-5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone (n = 2) or enzalutamide (n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT (n = 9), yet no association between clinical outcomes and ctDNA findings was observed. CONCLUSIONS: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed.

Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials.

Importance: Both α-emitting and ß-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and ß-emitting RIs. Objective: To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with ß-emitting RIs. Data Sources: PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018. Study Selection: Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data. Data Extraction and Synthesis: Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model. Main Outcomes and Measures: Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events. Results: Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (χ25 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the ß-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ23 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ23 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001). Conclusions and Relevance: In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not ß-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.

Germline BLM mutations and metastatic prostate cancer.

BACKGROUND: Biallelic loss-of-function BLM mutations result in Bloom syndrome: a genetic disorder characterized by growth deficiencies, photosensitivity, and multiple cancer susceptibilities. There are conflicting reports about whether or not heterozygous BLM carriers are at a higher risk of various cancers. Without BLM protein functionality, there is evidence of increased sister chromatid exchange and chromosomal instability. METHODS: Metastatic prostate cancer patients (N = 796) underwent germline genetic testing as part of routine care at three academic centers. Patients with heterozygous BLM mutations were identified. Tumor tissue was analyzed for somatic alterations in those patients who had a germline pathogenic mutation. Control data using a population sample were extracted from the Genome Aggregation Database. RESULTS: Heterozygous BLM germline mutations in 5 of 796 patients (prevalence, 0.63%). All mutations were loss-of-function truncating alterations. None of the mutations were BLMAsh . The control population (gnomAD) frequency of pathogenic or likely pathogenic BLM mutations was 0.18% (212 of 116 653). The relative risk (RR) of BLM mutations in metastatic prostate cancer patients was 3.4 (95% CI, 1.42-8.33; P < .0062) compared to gnomAD controls. Tumor DNA sequencing in the BLM carriers showed no evidence of somatic BLM mutations. Interestingly, 3 of 5 BLM germline carriers had bi-allelic BRCA2 inactivation evident on tumor sequencing. One patient had both germline and somatic mutations in BRCA2. Excluding the patient with the germline BRCA2 mutation (BLM prevalence, 4 of 796: 0.50%) still yielded a statistically significant finding vs the gnomAD controls (RR, 2.8; 95% CI, 1.02-7.39; P < .04). CONCLUSION: Truncating BLM germline mutations occur at a higher frequency in patients with advanced prostate cancer as compared to control populations. Though no biallelic loss of BLM was no noted in cancers, a surprising number of the BLM germline heterozygotes had pathogenic BRCA2 mutations in their tumor.

PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal. RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

Relationship between serum markers and volume of liver metastases in castration-resistant prostate cancer.

BACKGROUND: Prostate cancer patients with liver metastases have a poor prognosis. To date, no study exists investigating the relationship between liver tumor burden and clinical laboratory markers. MATERIALS AND METHODS: Metastatic castrate-resistant prostate cancer (mCRPC) patients with radiographic evidence of liver metastases were selected for this study. Volumetric measurements of liver metastases were ascertained for all available patients. Prostate specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), total bilirubin and hemoglobin (HGB) levels were then assessed to coincide with the scan dates. Univariate and multivariate mixed-model regression analysis were performed to evaluate the relationship between laboratory markers and liver lesion volume. Data sets with non-normal distribution were logarithmically transformed. Akaike information criteria (AIC) was used to identify the most reliable multivariate model. RESULTS: In our heavily pretreated liver-metastatic patient population, univariate analysis demonstrated a statistically significant positive correlation between PSA (p = 0.0002), ALP (p = 0.0305), AST (p < 0.0001), ALT (p = 0.0049), and LDH (p = 0.0019) and liver lesion volume. Additionally, ALB (p = 0.0006) and HGB (p = 0.0103) had statistically significant negative correlation. Multivariate analysis identified AST and hemoglobin assessments as the best predictors of increasing liver lesion burden. Preliminary data on circulating tumor DNA (ctDNA) mutational and amplification findings are also reported. CONCLUSIONS: Analysis identified AST and hemoglobin as optimal predictors of liver lesion volume. These patients have a heavy burden of ctDNA abnormalities. Further studies with a larger patient population are needed to verify these results. Micro Abstract: This study investigates the association between liver lesion burden and clinical laboratory markers in castrate-resistant prostate cancer patients with hepatic metastases. Our univariate analysis identified multiple laboratory markers as significant indicators of worsening hepatic disease. Multivariate analysis demonstrated that AST and hemoglobin were the most effective predictors of change in liver lesion volume.

Metastatic castration-sensitive prostate cancer: Abiraterone, docetaxel, or .

For decades, the management of patients with advanced prostate cancer has been hormonal therapy, known as androgen deprivation therapy, which is intended to lower testosterone levels. Further incremental progress in the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC) has come from the addition of docetaxel or abiraterone acetate to androgen deprivation therapy for more aggressive upfront treatment regimens. Other combinatorial regimens testing the addition of novel therapies currently are in the late stages of development and are expected to further improve the clinical outcomes of these patients. The emergence of new positron emission tomography tracers specifically for prostate cancer, particularly prostate-specific membrane antigen and fluciclovine, has increased the ability to detect metastatic disease earlier in the course of the disease and has helped to describe a new group of patients with mHSPC and oligometastatic disease. For this group of patients with mHSPC, the authors discuss the existing data with metastasis-directed therapy and primary tumor-directed therapy.

The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer.

BACKGROUND: Breast cancer 2 (BRCA2)-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment. METHODS: A retrospective analysis of a single-institution cohort of men with castration-resistant, metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001 through 2015, 8081 adult men with prostate cancer who had a consultation and/or underwent treatment at Dana-Farber Cancer Institute provided blood samples and consented to analyses of biologic material and clinical records. A subgroup of 141 men received at least 2 doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These patients were categorized according to the absence or presence of pathogenic germline mutations in BRCA2 based on DNA sequencing from whole blood. The primary outcome was the response rate to carboplatin/docetaxel chemotherapy, defined according to a decline in prostate-specific antigen that exceeded 50% within 12 weeks of initiating this regimen. Associations between BRCA2 mutation status and response to carboplatin-based chemotherapy were tested using the Fisher exact test, with a 2-sided P value < .05 as the threshold for significance. RESULTS: Pathogenic germline BRCA2 variants were observed in 8 of 141 men (5.7%; 95% confidence interval, 2.5%-10.9%). Six of 8 BRCA2 carriers (75%) experienced prostate-specific antigen declines >50% within 12 weeks, compared with 23 of 133 noncarriers (17%; absolute difference, 58%; 95% confidence interval, 27%-88%; P < .001). Prostate cancer cell lines functionally corroborated these clinical findings. CONCLUSIONS: BRCA2-associated, castration-resistant prostate cancer is associated with a higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2-associated prostate cancer. Cancer 2017;123:3532-9. © 2017 American Cancer Society.

The Development of Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP).

New systemic therapies have prolonged the lives of men with metastatic castration-resistant prostate cancer (mCRPC). Use of these therapies in the adjuvant setting when the disease may be micrometastatic and potentially more sensitive to therapies may decrease mortality from prostate cancer. However, the conduct of adjuvant prostate cancer clinical trials is hampered by taking longer than a decade to reach the meaningful endpoint of overall survival (OS) and the fact that many men never die from prostate cancer, even if they relapse. A validated intermediate clinical endpoint (ICE) in prostate cancer that is a robust surrogate for OS has yet to be defined. This paper details the plans, process, and progress of the international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group to pool individual patient data from all available clinical trials of radiation or prostatectomy for localized disease and conduct the requisite analyses to determine whether an ICE can be identified. This paper further details the challenges and the a priori statistical analytical plans and strategies to define an ICE for adjuvant prostate cancer clinical trials. In addition, a brief review of the health economic analyses to model the benefits to patients, society and manufacturers is detailed. If successful, the results from this work will provide a robust surrogate for OS that will expedite the design and conduct of future adjuvant therapy trials using new agents that have proven activity in mCRPC. Moreover, it will also define the health economic benefits to patients and societies.