Molecular reflex testing in patients with early metastatic castration-resistant prostate cancer within the PROMPT-study.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

40 Background: Castration-resistant prostate cancer (CRPC) comprises distinct molecular actionable subtypes. Radboudumc, a tertiary referral center for PCa, hosts a Molecular Tumor Board (MTB), and frequently sees CRPC patients (pts) for referral for genetic testing. In the period 2017-2020, almost 50% of heavily pre-treated CRPC pts received a recommendation for a genetically matched therapy (GMT). In 2020 we initiated the PROMPT trial (NCT04746300) to prospectively study the impact of routine early molecular characterization in CRPC. Increased GMT utilization of targeted- and immunotherapy may improve outcome and quality of life of pts with metastatic CRPC, and lead to lower medical resource utilization (MRU). Here we report on first results from our observational trial. Methods: Within the PROMPT trial, prior to receiving first- or second line standard of care CRPC therapy, up to 300 pts were offered molecular tumor characterization with the TruSightOncology 500 panel (TSO500). Formalin-fixed paraffin-embedded prostate or metastatic tissue biopsies were used, preferably newly obtained. To assess both mutations and copy number alterations, the TSO500 required a minimal tumor cell percentage (TC%) of 30%. Results were discussed within the Radboudumc MTB for GMT recommendation. Actionable targets were defined per Precision Medicine Working group criteria and, when druggable, within the Drug Rediscovery Protocol trial (NCT02925234). All pts with tumor mutations carrying with a risk for cancer predisposition were referred for genetic counselling. Follow-up with patient-reported outcomes (EORTC QLQ-C30, EQ5D, BPI & EPIC-26 questionnaires) and MRU was conducted every 3 months until withdrawal or death. Results: From February 2020 until October 2021 we included 284 consecutive CRPC pts with a median age of 70 years (range 46-86) with a median follow-up of 6.8 months. Newly obtained biopsies and archival material was used in 131 and 126 pts, respectively. Median TC% was 60% (range: 20-90%). TSO500 results could be reported in 254 (89%) cases, with at least one putative clinically relevant aberration in 188 evaluable pts (74%). In 100 pts (39,4%) ≥ 1 druggable target was found. Most common actionable alterations were in PTEN (19%), BRCA2 (9%) or in mismatch-repair genes or resulting in high tumor mutational burden (5%). Out of the 100 druggable pts, 31 pts (31%) initiated a form of GMT, 4 pts (4%; 2 BRCA2, 2 PTEN) died prior to receiving GMT, in 65 pts (65%) GMT is pending as they receive standard of care. Conclusions: Routine molecular profiling early in the CRPC setting is feasible in a tertiary referral center with a MTB and high volume of CRPC pts. Almost 40% CRPC pts harbored an actionable target with 31% of these pts already allocated to a GMT. Failure rates of NGS were low at 11%.

Practical Guidance on Establishing a Molecular Testing Pathway for Alterations in Homologous Recombination Repair Genes in Clinical Practice for Patients with Metastatic Prostate Cancer

Bone Scan Index as an Imaging Biomarker in Metastatic Castration-resistant Prostate Cancer: A Multicentre Study Based on Patients Treated with Abiraterone Acetate (Zytiga) in Clinical Practice

Nursing and Residential CareVol. 17, No. 3 EditorialCancer treatment: at what cost?Beverley AndersonBeverley AndersonSearch for more papers by this authorBeverley AndersonPublished Online:18 Feb 2015https://doi.org/10.12968/nrec.2015.17.3.173AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Aapro MS (2012) Management of advanced prostate cancer in senior adults: the new landscape. Oncologist 17(Suppl 1): 16–22 Crossref, Google ScholarAttard G, Reid AHM, Yap TA et al. (2008) Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. 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Background: We previously developed a liquid biopsy assay called Enhancer and neighboring loci of Androgen Receptor Sequencing (EnhanceAR-Seq) (Dang & Chauhan et al, JCO PO, 2020). We applied it to a heterogeneous cohort of metastatic prostate cancer patients after the start of AR-directed therapy, and showed that alterations in the AR locus were associated with worse survival. Here we asked if AR/enhancer genomic alterations detected in plasma cell-free DNA prior to the administration of first-line AR-selective inhibitors (ARSIs) can predict survival in metastatic castration resistant prostate cancer (mCRPC) patients. Methods: We applied EnhanceAR-Seq to plasma cell-free DNA isolated from 20 mCRPC patients from Tulane University collected between April 2015 and June 2017. Assay results were correlated with patient overall survival (OS) and progression-free survival (PFS) from the time of blood collection. Results: Median follow up time was 32 months. Seventeen patients had blood plasma analyzed before first-line ARSI treatment, while three patients had received prior ARSI treatment before blood collection. EnhanceAR-Seq revealed that the most frequent genomic events detected were AR/enhancer alterations (copy number gain, tandem duplication or missense mutations) in 9 patients (45%), of which 5 patients had both AR gene body and enhancer copy number gain. The other 4 patients each had a single genomic event detected by EnhanceAR-Seq: AR amplification, AR enhancer amplification, AR and AR enhancer tandem duplication, and AR W742C single nucleotide variation. Cell-free DNA-detected alterations in the full AR locus including the AR enhancer were highly significant for inferior OS (P = 0.0009; HR = 17.0) but not for PFS (P = 0.2; HR = 2.2) by Kaplan-Meier analysis across all 20 patients. Subset analysis of the 17 patients with plasma analyzed prior to first-line ARSI treatment revealed that AR/enhancer alterations again predicted significantly worse OS with a median survival of 16.1 months vs. not-reached (P = 0.0009; HR = 14.1). Conclusions: AR locus alterations detected by EnhanceAR-seq in plasma cell-free DNA collected prior to ARSI administration correlated with significantly worse overall survival in patients with mCRPC. If corroborated, our results suggest that AR/enhancer genomic alterations represent a potent pre-treatment prognostic biomarker in mCRPC patients. Citation Format: Pradeep Singh Chauhan, Steven H. Hartman, Ha X. Dang, Jace Webster, Haley Ellis, Wenjia Feng, Peter K. Harris, Elisa M. Ledet, Ellen B. Jaeger, Patrick J. Miller, Sydney A. Caputo, Russell K. Pachynski, Oliver Sartor, Christopher A. Maher, Aadel A. Chaudhuri. Cell-free DNA alterations in the AR/enhancer locus measured before AR signaling inhibition portend poor overall survival in metastatic castration resistant prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 550.

Systematic Literature Review of the Epidemiology of Advanced Prostate Cancer and Associated Homologous Recombination Repair Gene Alterations.

Second-line treatment options in metastatic castration-resistant prostate cancer: A comparison of key trials with recently approved agents

Comparative Analysis of Genomic Alterations across Castration Sensitive and Castration Resistant Prostate Cancer via Circulating Tumor DNA Sequencing.

Background: Trophoblast cell surface antigen 2 (TROP2) promotes breast cancer (BC) development, invasion and metastasis, with promising role as a biomarker and therapeutic target in triple negative BC. Due to the dynamic tumor evolution during disease progression, a significant discordance in tumor cell profiles is frequently observed among primary tissues and distant metastases. In this regard, analyses of circulating tumor cells (CTCs) in the peripheral blood (PB) can inform on the expression of biomarkers in real-time. In the current study we assessed in parallel the expression of TROP2 on CTCs and matched primary tumors and metastatic sites from patients with triple negative BC. Methodology: PB was collected from 54 patients and CTCs were enriched by ficoll-density gradient centrifugation. Cytospins were immunofluorescently stained using antibodies for cytokeratins (Clones: AE1/AE3 & C11), CD45 and TROP-2 (Enzo Life Sciences); TROP2 expression on CTCs was defined as high, low or negative, by using the high TROP2-expressing MDA.MB.231 triple negative BC cell line as internal control. Matched primary (n=51) and metastatic (n=7) tumor tissue samples were evaluated for TROP-2 expression by immunocytochemistry (IHC); H-score was calculated as follows: (3 × % cells with strong intensity staining) + (2 × % cells with moderate intensity staining) + (1 × % cells with mild intensity staining), ranging from 0 to 300, and the following expression categories were defined: H-score 0 to <100: TROP2 low; H-score 100-200: TROP2 medium; H-score >200-300: TROP2 high. Results: CTCs (CK+/CD45- cells) were identified in 12 out of 54 patients evaluated (total CTC counts: n=80; mean CTC counts per patient: n=6.7). TROP2-expressing CTCs were detected in 75% of CTC-positive patients and represented the 95% of total CTCs. Specifically, high and low TROP2-expressing CTCs were identified in 66.7% and 41.7% of patients, representing the 81.3% and 13.7% of total CTCs, respectively. Differential TROP2 expression levels (high, medium and low) were also observed in both primary and metastatic tumors, showing a great intra-tumoral heterogeneity. High TROP2 expression was identified in 58.8% and 57.1% of primary and metastatic tissues, respectively. When matched primary and metastatic tissues were analyzed, a decrease in TROP2 expression was observed [median H-Score: 172.5 (range: 11-300) versus 87.5 (range: 5-150) in primary and metastatic tissue, respectively, p=0.068)]. CTC detection in the PB was not associated with TROP2 expression levels in primary or metastatic tissue (CTCs were identified in 13.3% and 50% of patients with high TROP2-expressing primary and metastatic tumors, respectively). Finally, there was no concordance in TROP2 expression pattern among CTCs and the respective tumor (high, low and negative TROP2-expressing CTCs were identified in 50%, 25% and 25% of patients with high TROP2-expressing primary tumors, respectively; high and low TROP2 -expressing CTCs were evident in all patients with high TROP2-expressing metastatic tumors). Conclusions: Herein we demonstrate for the first time a significant discrepancy in TROP2 expression among CTCs, primary and metastatic tumor tissue samples in triple negative BC. A lower TROP2 expression was observed in metastatic as compared to primary tissue, while no concordance was demonstrated among CTCs and the respective tumors. The results suggest the dynamic change in TROP2 expression status among different disease sites, thus highlighting the value of using liquid biopsy as a tool for real-time biomarker assessment in triple negative BC. Citation Format: Dimitrios Mavroudis, Eleni Lagoudaki, Sofia Gounaki, Sofia Hatziavraam, Charalampos Fotsitzoudis, Kleita Michaelidou, Sofia Agelaki, Maria A Papadaki. Comparative analysis of TROP2 expression in tumor tissues and circulating tumor cells (CTCs) in the peripheral blood of patients with triple negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-05-27.

70 Background: 177-Lutetium Prostate-specific membrane antigen (Lu-PSMA) therapy is under current scientific investigation and aims to become an established part in treatment of metastatic castration resistant prostate cancer (mCRPC). However, real-world evidence in treatment comparison is scant. Methods: We relied on the FRAMCAP database and compared cabazitaxel vs. Lu-PSMA therapy in mCRPC patients regarding progression-free (PFS) and overall (OS). Sensitivity analyses addressed 2 nd to 4 th line mCRPC patients to approximate current Phase-III patient selection criteria. Results: Of 373 mCRPC patients, 14% received cabazitaxel vs. 65% Lu-PSMA vs. 21% both. Patients undergoing Lu-PSMA therapy were significantly older (median 72 vs. 66 years, p<0.01) and displayed a higher proportion of ECOG ≥2 (12 vs. 5.0%, p=0.1), relative to cabazitaxel patients. Rates of PSA50 were 32% vs. 0% for Lu-PSMA vs. cabazitaxel. In outcome analyses, significant superior median PFS was observed for Lu-PSMA vs. cabazitaxel (13.4 vs. 7.1 months, p<0.001), even after multivariable adjustment (HR: 0.38, p<0.001). Regarding OS, rates also significantly differed with median OS of 14.7 vs. 16.5 vs. 29.6 months for cabazitaxel vs. Lu-PSMA vs. both treatments (p<0.01). In sensitivity analyses of 2 nd to 4 th line mCRPC, PFS rates and median OS rates for cabazitaxel vs. Lu-PSMA vs. both therapies qualitatively remained the same compared to the entire cohort. Conclusions: In real-world setting, Lu-PSMA provides significantly better PFS and qualitatively better OS rates compared to cabazitaxel chemotherapy and should therefore be considered as a valuable treatment option for advanced mCRPC patients according to the EMA-approval. Characteristics of 296 metastatic castration resistant prostate cancer (mCRPC) patients stratified according to treatment of cabazitaxel vs. 177 - Lutetium- prostate-specific membrane antigen radioligand therapy (Lu-PSMA). Characteristic N Overall,N = 296 1 CabazitaxelN = 52 (18%) 1 Lu-PSMA,N = 244 (82%) 1 p-value 2 Age at mCRPC, years 192 71 (64, 76) 66 (58, 71) 72 (66, 78) <0.001 PSA at m CRPC, ng/ml 141 18 (6, 72) 63 (12, 144) 15 (6, 64) 0.044 Number of CRPC lines 296 3 (2, 4) 4 (3, 5) 3 (2, 4) <0.001 Cycles systemic treatment 229 3 (2, 6) 5 (3, 6) 3 (2, 6) 0.031 PSA response, % 39 20 (0, 66) 15 (0, 23) 25 (0, 68) 0.3 PSA50 39 11 (28%) 0 (0%) 11 (32%) 0.3 PSA90 39 5 (13%) 0 (0%) 5 (15%) 0.9 ECOG status at mCRPC 109 0.10 0 52 (48%) 14 (70%) 38 (43%) 1 45 (41%) 5 (25%) 40 (45%) >=2 12 (11%) 1 (5%) 11 (12%) Cardiovascular disease 183 66 (36%) 13 (35%) 53 (36%) 0.9 Gleason Score 8-10 259 181 (70%) 39 (80%) 142 (68%) 0.10 De Novo mHSPC 290 161 (56%) 33 (63%) 128 (54%) 0.2 High volume mHSPC 146 99 (68%) 24 (73%) 75 (66%) 0.5 Metastatic sites at mCRPC 130 0.8 M1a 14 (11%) 3 (13%) 11 (10%) M1b 104 (80%) 20 (83%) 84 (79%) M1c 12 (9%) 1 (4%) 11 (10%) Treatment mHSPC 126 0.034 ADT mono 25 (20%) 4 (20%) 21 (20%) ARSI 58 (46%) 4 (20%) 54 (51%) Docetaxel 34 (27%) 10 (50%) 24 (23%) Triplet 3 (2%) 1 (5%) 2 (2%) Other 6 (5%) 1 (5%) 5 (5%) Treatment 1st line mCRPC 296 <0.001 ADT mono 29 (10%) 6 (12%) 23 (9%) Chemotherapy 53 (18%) 19 (37%) 34 (14%) Lu-PSMA 28 (10%) 0 (0%) 28 (11%) ARSI 163 (55%) 26 (50%) 137 (56%) PARPi +/- ARSI 1 (0.3%) 0 (0%) 1 (0.4%) Radium 20 (7%) 0 (0%) 20 (8%) None/Other/NA 2 (1%) 1 (2%) 1 (0.4%) Treatment 2nd line mCRPC 296 <0.001 Chemotherapy 69 (23%) 27 (52%) 42 (17%) Lu-PSMA 73 (25%) 0 (0%) 73 (30%) ARSI 114 (39%) 25 (48%) 89 (36%) PARPi+/- ARSI 5 (2%) 0 (0%) 5 (2%) Radium 13 (4%) 0 (0%) 13 (5%) None/Other/NA 22 (7%) 0 (0%) 22 (9%) 1 Median (IQR); n (%). 2 Wilcoxon rank sum test; Fisher’s exact test; Pearson’s Chi-square test. PSA: Prostate-specific antigen, ECOG: Eastern Cooperative Oncology group, mHSPC: metastatic hormone-sensitive prostate cancer, ADT: Androgen deprivation therapy, ARSI: Androgen receptor signaling inhibitor, PARPi: poly-(ADP-ribose)-polymerase inhibitors, NA: Unknown.

Introduction: In experimental and epidemiological studies, alterations in several core circadian genes at the germline and tumor level have been associated with prostate cancer. The aim of this study was to investigate mRNA expression of circadian related genes in men with metastatic castration-resistant prostate cancer (mCRPC), and the association with survival. Methods: We assessed whole exome and RNA sequencing data from 317 mCRPC patients from the Stand Up to Cancer-Prostate Cancer Foundation (SU2C-PCF) database. Data were obtained from six sites: metastasis to bone (n=107; n=65 deaths), lymph node (n=129; n=88 deaths), liver (n=42; n=35 deaths), lung (n=6; n=3 deaths), and other soft tissue (n=26; n=20 deaths), as well as primary prostate (n=7; n=5 deaths) over a median follow-up of 71.8 months. We evaluated expression of twelve core circadian genes (ARNTL, CLOCK, CRY1, CRY2, CSNK1E, NR1D1, NPAS2, PER1, PER2, PER3, RORA, TIMELESS) as transcripts per million (TPM). We used the correlation of correlations method to estimate inter-gene correlations between tissue. Unpaired Wilcoxon rank sum tests compared circadian expression differences with tumor mutations in AR and p53, two of the most common genomic alterations in mCRPC. We conducted multivariable Cox regression, overall and stratified by tissue type, to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for expression (modeled continuously) and overall survival, adjusted for age and PSA at diagnosis, Gleason, treatment, and histology. Results: Many genes showed low or negative correlation across tissues, with the greatest discordance in CSNK1E (μICC=0.10), and greatest concordance in TIMELESS (μICC=0.55). Lower expression of ARNTL was found in patients with alterations to both p53 and AR. Similarly, higher expression of PER2 and RORA was found in AR-/p53+, compared to those AR+ and AR-/p53-. Higher expression of TIMELESS was associated with risk of death overall and across all tissue sites (HRoverall: 1.02, 95% CI: 1.01-1.03). In liver, higher expression of CLOCK (HR: 0.22, 95% CI: 0.07 - 0.71) and CSNK1E (HR: 0.87, 95% CI: 0.76 - 1.00), and lower expression of CRY1 (HR: 1.62, 95% CI: 1.16 - 2.26) was associated with a lower risk of death. Higher expression of CRY2 (HR: 1.25, 95% CI: 1.02 - 1.53) in liver, but lower expression in bone (HR: 0.95, 95% CI: 0.90 - 1.00) was associated with an increased risk of death. We found no association between ARNTL, NR1D1, NPAS2, PER3, or RORA and survival in any metastatic site. Conclusion: Our results show that circadian gene expression is altered in tissue from mCRPC patients, with substantial heterogeneity in circadian related expression patterns between metastatic tissue sites. These results support prior research on the role of circadian gene expression, particularly CRY1 and CLOCK, and outcomes in localized prostate cancer. Citation Format: Benjamin D. Booker, Konrad H. Stopsack, Travis A. Gerke, Kathryn Penny, Philip W. Kantoff, Lorelei A. Mucci, Sarah C. Markt, PCF/SU2C International Prostate Cancer Dream Team. Circadian gene expression in metastatic sites and association with survival in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 863.

Objective: To investigate the differences of protein expressions in the primary tumors, adjacent tissues, and metastatic tumors of gastrointestinal neuroendocrine neoplasms. Methods: Nine patients with gastrointestinal neuroendocrine tumors (GI-NENs) with liver metastasis who underwent surgery at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences from July 2015 to April 2019 were selected. The protein expressions of the primary tissues, liver metastatic tissues, and adjacent tissues were detected by the data independent acquisition (DIA) technology. P<0.05 and | log2FC|>0.5 (FC as the difference multiple) were used as the criteria to identify the differentially expressed proteins in the primary tissues vs adjacent tissues, primary tissues vs liver metastatic tissues, primary tissues with different degrees of differentiation, and liver metastatic tissues with different degrees of differentiation. The differentially expressed proteins were investigated by volcano map analysis, cluster analysis, Gene Ontology (GO) function analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: Compared with adjacent tissues, 85 proteins were downregulated and 42 proteins were upregulated in the primary tissues of gastric NENs. The differentially expressed proteins were mainly enriched in the biological processes related to the regulation of guanosidase triphosphate activity and the catabolism of deoxyribonucleoside monophosphate, the glycosaminoglycan biosynthesis chondroitin sulfate/dermatan sulfate, pantothenate, and CoA biosynthesis signaling pathways. 114 proteins were downregulated and 155 proteins were upregulated in the primary tissues of intestinal NENs. The differentially expressed proteins were mainly enriched in the biological processes related to glutathione metabolism and sulfur compound metabolism, collecting duct acid secretion, and taurine and hytaurine metabolism signaling pathways. Compared with the primary tissues of neuroendocrine cancers (NECs), 168 proteins were downregulated and 278 proteins were upregulated in G1-2 differentiation primary tissues. The differentially expressed proteins were significantly enriched in biological processes such as DNA metabolism and DNA replication, as well as replication, mismatch repair, and other pathways. Compared with the metastatic tissues of NECs, 95 proteins were downregulated and 97 proteins were upregulated in G1-2 differentiated metastases. The differentially expressed proteins were significantly enriched in the activity and catalytic activity of transcriptional coactivators, base excision repair, and protein efflux pathways. Compared with G1 differentiated primary tissues, 530 proteins were downregulated and 211 proteins were upregulated in G1 differentiated metastatic tissues. Compared with G2 differentiated primary lesions, 53 proteins were downregulated and 96 proteins were upregulated in G2 differentiated metastatic tissues. Compared with the primary lesions of NECs, 109 proteins were downregulated and 92 proteins were upregulated in the metastatic tissues of NECs. In G1 and G2 differentiated GI-NENs, there are many similar signal pathways enriched in differentially expressed proteins between primary lesions and metastases, while only one signal pathway enriched in differentially expressed proteins between primary and metastatic tissues of NECs is the same as that enriched in differentially expressed proteins between primary and metastatic tissues of GI-NENs, which is the drug metabolism signal pathway. The differentially expressed proteins in G1 differentiated primary and metastatic tissues were mainly expressed in cytoplasm (20.26%), mitochondria (18.67%), and nucleus (15.48%). The differentially expressed proteins in the primary and metastatic tissues of G2 differentiation were mainly expressed in the cytoplasm (20.24%), nucleus (18.25%), and cell membrane (15.08%). The differentially expressed proteins in the primary and metastatic tissues of NECs were mainly expressed in the nucleus (23.78%), cytoplasm (22.7%), and cell membrane (11.35%). Conclusion: The protein expressions of GI-NENs in the primary tissues, adjacent tissues, and metastatic tissues were significantly different in different sites and degrees of differentiation.

BackgroundTo determine the performance of a multi-gene copy number variation (MG-CNV) risk score in metastatic tissue and plasma biospecimens from treatment-naïve metastatic castration-resistant prostate cancer (mCRPC) patients for prediction of clinical outcomes.MethodsThe mCRPC tissue and plasma cell-free DNA (cfDNA) biospecimen sequencing results obtained from publicly accessed cohorts in dbGaP, cBioPortal, and an institutional mCRPC cohort were used to develop a MG-CNV risk score derived from gains in AR, MYC, COL22A1, PIK3CA, PIK3CB, NOTCH1 and losses in TMPRSS2, NCOR1, ZBTB16, TP53, NKX3-1 in independent cohorts for determining overall survival (OS), progression-free survival (PFS) to first-line androgen receptor pathway inhibitors (ARPIs). The range of the risk scores for each cohort was dichotomized into “high-risk” and “low-risk” groups and association with OS/PFS determined. Univariate and multivariable Cox proportional hazards regressions were applied for survival analyses (P < .05 for statistical significance).ResultsOf 1137 metastatic tissue-plasma biospecimens across all cohorts, 699/1137 were treatment-naive mCRPC (235/699 metastatic tissue; 464/699 plasma-cfDNA), and 311/1137 were matched tissue-cfDNA pairs. In multivariable analysis, the MG-CNV risk score derived from metastatic tissue or in cfDNA was statistically significantly associated with OS with high score associated with short survival (hazard ratio = 2.65, confidence interval = 1.99 to 3.51; P = 1.35−11) and shorter PFS to ARPIs (median PFS of 7.8 months) compared with 14 months in patients with low-risk score.ConclusionsA molecular risk score in treatment-naïve mCRPC state obtained either in metastatic tissue or cfDNA predicts clinical survival outcomes and offers a tumor biology-based tool to design biomarker-based enrichment clinical trials.

BackgroundAs potent systemic therapies transition earlier in the prostate cancer disease course, molecular biomarkers are needed to guide optimal treatment selection for metastatic hormone-sensitive prostate cancer (mHSPC). The value of whole blood RNA to detect candidate biomarkers in mHSPC remains largely undefined.MethodsIn this cohort study, we used a previously optimised whole blood reverse transcription polymerase chain reaction assay to assess the prognostic utility [measured by seven-month undetectable prostate-specific antigen (PSA) and time to castration-resistance (TTCR)] of eight prostate cancer-associated gene transcripts in 43 mHSPC patients. Transcripts with statistically significant associations (P<0.05) were further investigated in a metastatic castration-resistant prostate cancer (mCRPC) cohort (n=119) receiving contemporary systemic therapy, exploring associations with PSA >50% response (PSA50), progression-free survival (PFS) and overall survival (OS). Clinical outcomes were prospectively collected in a protected digital database. Kaplan-Meier estimates and multivariable Cox proportional-hazards models assessed associations between gene transcripts and clinical outcomes (mHSPC covariates: disease volume, docetaxel use and haemoglobin level; mCRPC covariates: prior exposure to chemotherapy or ARPIs, haemoglobin, performance status and presence of visceral disease). Follow-up was performed monthly during ARPI treatment, three-weekly during taxane chemotherapy, and three-monthly during androgen deprivation therapy (ADT) monotherapy. Serial PSA measurements were performed before each follow-up visit and repeat imaging was at the discretion of the investigator.ResultsDetection of circulating Grainyhead-like 2 (GRHL2) transcript was associated with poor outcomes in mHSPC and mCRPC patients. Detectable GRHL2 expression in mHSPC was associated with a lower rate of seven-month undetectable PSA levels (25% vs. 65%, P=0.059), and independently associated with shorter TTCR (HR 7.3, 95% CI: 1.5–36, P=0.01). In the mCRPC cohort, GRHL2 expression predicted significantly lower PSA50 response rates (46% vs. 69%, P=0.01), and was independently associated with shorter PFS (HR 3.1, 95% CI: 1.8–5.2, P<0.001) and OS (HR 2.9, 95% CI: 1.6–5.1, P<0.001). Associations were most apparent in patients receiving ARPIs.ConclusionsDetectable circulating GRHL2 was a negative prognostic biomarker in our mHSPC and mCRPC cohorts. These data support further investigation of GRHL2 as a candidate prognostic biomarker in metastatic prostate cancer, in addition to expanding efforts to better understand a putative role in therapeutic resistance to AR targeted therapies.