649P Abiraterone acetate in men with metastatic castration-resistant prostate cancer and no prior chemotherapy: A double-arm, multiple-centre, phase III clinical study
Z. Hu1, Z. Ye1, H. Zeng2, Y. Huang3, D. Ye4, B. Shi5, H. Luo6, C. Du7, W. An8, L. Zhou9, L. Hua10, T. Pan11, C. He12, F. Zhou13, J. Li14, Y. Deng15, Y. Bai16, H. Li17
1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;2Department of Urology, West China Hospital, Sichuan University, Chengdu, China;3Department of Urology, Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, China; 4
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China; 5
Department of Urology, Qilu Hospital of Shandong University, Jinan, China; 6
Department of Urology, Chongqing Cancer Hospital, Chongqing, China;7Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;8Department of Urology, The First Affiliated Hospital of Jilin Uni-versity, Changchun, China;9Department of Urology, Peking University First Hospital, Beijing, China; 10Department of Urology, The First Af
filiated Hospital of Nanjing Medical University, Nanjing, China;11Department of Urology, Wuhan General Hospital of Guangzhou Military Region, Wuhan, China;12Department of Urology, Henan Cancer Hospital, Zhengzhou, China;13Department of Urology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; 14Department of Urology, Gansu Cancer Hospital, Lanzhou, China;15Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China; 16Department of Medicine, Affiliated Tumor Hospital of Harbin Medical University, Harbin, China;17Department of Urology, Peking Union Medical College Hospital, Chi-nese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Background:Prostate cancer is described as a hormonal dependent cancer so that androgen-deprivation therapy (ADT) is the major strategy for patients with prostate cancer. Abiraterone acetate is a CYP17 inhibitor which can suppress androgen biosynthesis. This phase III study aims to further evaluate the safety and efficacy of abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) who had not received chemotherapy.
Methods:In this double-blind study, men aged18 years who have previously received ADT, with histologically or cytologically confirmed mCRPC were eligible; documented metastases and had PSA progression. 258 patients were randomized 2:1 abiraterone acetate was administered orally (1000 mg, qd) plus prednisone (5 mg, bid) or placebo plus prednisone till disease progression, death or intolerant toxicity. The primary endpoint was time to PSA progression (TTPP) and the secondary end-points included PSA response rate, quality of life, objective response rate (ORR), time to pain progression and overall survival (OS).
Results:Patients were enrolled from October 2015 to May 2019, 178 patients received abiraterone acetate and 84 patients received placebo. The median follow-up of abiraterone and placebo was 22.8 and 21.5 months, respectively. The median time to PSA progression was 11.5 months (95%CI, 10.12-14.0) with abiraterone acetate compared with 5.65 months (95%CI, 4.60-8.34) with placebo (hazard ratio, 0.57; 95% CI, 0.40 to 0.80; P¼0.0011). The PSA response rate was 63.79% in abiraterone acetate and 32.14% in placebo (P<0.0001). And the median OS was 23.95 months (95%CI, 17.18-NR) in abiraterone acetate. Grade 3 or 4 AEs were reported in 18.97% of patients in the abiraterone group versus 19.05% of pa-tients in the placebo group; Most of the occurring AEs included upper respiratory tract infection (13.22%), hypertension (12.64%), nasopharyngitis (12.07%), cough (9.77%), hy-pokalemia (8.62%), and diarrhea (8.62%). Neither unexpected safety signals.
Conclusions:Abiraterone acetate produces PSA response rate and TTPP benefits, showed a promising efficacy with a favorable toxicity profile for patients with mCRPC. Legal entity responsible for the study:The authors.
Funding:Has not received any funding.
Disclosure:All authors have declared no conflicts of interest.
https://doi.org/10.1016/j.annonc.2020.08.908
650P Comparing the predictive value of exosome, circulating tumor cells, and tumor tissue in detecting AR-V7 among metastatic castration-resistant prostate cancer treated with abiraterone
S. Zhu, G. Sun, X. Zhao, J. Zhao, J. Chen, P. Shen, N. Chen, H. Zeng Urology, West China Hospital of Sichuan University, Chengdu, China
Background:Androgen Receptor Splice Variant-7 (AR-V7) can predict primary and sec-ondary resistance to abiraterone in metastatic castration-resistant prostate cancer (mCRPC). However, the predictive value of different AR-V7 detecting methods (plasma-derived exo-some, circulating tumor cells (CTCs), and tumor tissue) has never been compared. Methods:Matched whole blood and tumor tissue from 23 mCRPC patients was collected prior to the initiation of abiraterone. Exosomes were extracted from plasma and analyzed for AR-V7 mRNA expression by digital droplet polymerase chain reaction (ddPCR). CTCs were extracted and analyzed for AR-V7 mRNA expression by RNA in situ hybridization (RISH). AR-V7 protein expression in prostate cancer tissue was deter-mined by immunohistochemistry (IHC). Circulating tumor DNA (ctDNA) was also extracted and analyzed by 90-gene next-generation sequencing (NGS). The primary outcome is biochemical progression-free survival (b-PFS).
Results:AR-V7 was positive in 39.1% (n¼9/23), 36.4% (n¼4/11) and 21.7% (n¼5/23) patients evaluated with plasma-derived exosome, CTC and tumor tissue, respectively. The concordance of AR-V7 status between exosome and tumor tissue was 65.2%, while the concordance between CTC and tumor tissue was 72.7%. Positive AR-V7 detected in exosome was associated with shorter bPFS compared with AR-V7 nega-tive patients (HR 4.08, 95%CI 1.13-14.69, P¼0.03). However, AR-V7 positivity in tumor tissue and CTC failed to predict clinical prognosis in mCRPC treated with abiraterone (AR-V7 detected in CTC: HR 1.00, 95%CI 0.24-4.18, P¼0.74; AR-V7 detected in tumor tissue: HR 1.16, 95%CI 0.32-4.16, P¼0.97). Genomic alterations in the AR pathway (AR, FOXA1, NCOR1, NCOR2, ZBTB16) were detected in 71.4% patients, who had inferior bPFS (HR 3.56, 95%CI 1.13-11.18, log-rank P¼0.03) compared with those with AR pathway of wildtype.
Conclusions:The concordance of AR-V7 status between plasma-derived exosomes, CTCs, and tumor tissue is moderate. The positivity of AR-V7 in plasma-derived exo-somes outperforms CTC and tumor tissue as a predictor of primary resistance in mCRPC patients treated with abiraterone.
Legal entity responsible for the study:Hao Zeng. Funding:Has not received any funding.
Disclosure:All authors have declared no conflicts of interest.
https://doi.org/10.1016/j.annonc.2020.08.909
651P Impact of abiraterone acetate plus prednisone (AAP) in patients with castration-sensitive prostate cancer (mCSPC) and visceral metastases: Subgroup analyses of the LATITUDE study
G. Baciarello1, M. Ozguroglu2, S.D. Mundle3, G. Leitz3, U. Richarz3, P. Hu3, K.N. Chi4, K. Fizazi1
1Medical Oncology Department, Institut Gustave Roussy, Villejuif, France;2Medical Oncology, Cerrahpas¸a Medical Faculty, Istanbul University Cerrahpas¸a, Istanbul, Turkey;3Global Medical Affairs, Janssen Research & Development, Raritan, NJ, USA; 4BC Cancer Agency, Vancouver, BC, Canada
Background:Visceral metastases (VM), largely in lungs and liver, are uncommon in men with advanced prostate cancer. This subgroup analysis of the phase 3 LATITUDE study (NCT01715285) assessed the impact of AAP on overall survival (OS) and radiographic progression-free survival (rPFS) in men with mCSPC and VM. Methods:Men with newly diagnosed mCSPC enrolled in the LATITUDE study were randomized (1:1) to AAP + androgen deprivation therapy (ADT) or placebo + ADT (PBO). Patients with VM in liver or lungs with or without other soft tissue and bone metastases (based on CT/MRI) at baseline were included in this subgroup analysis. Coprimary ef-ficacy endpoints, OS and rPFS were assessed using the Kaplan-Meier method. Non-stratified Cox regression model was used to estimate hazard ratios (HR) and 95% CI. Results:Among 1199 patients who received either AAP + ADT or PBO + ADT, 228 (19%) had VM at baseline (114 in each group), of which 53 (AAP: 29, PBO: 24) had liver me-tastases and 117 (AAP: 60, PBO: 57) had lung meme-tastases. AAP showed comparable improvement vs PBO in OS in patients with VM (median 55.4 vs 33.0 months; HR: 0.582; 95% CI: 0.406-0.835; p¼0.0029). Improvement in rPFS was also observed following AAP treatment vs PBO in patients with VM (median 30.7 vs 18.3 months; HR: 0.527; 95% CI: 0.366-0.759; p¼0.0005). The incidence of treatment-emergent adverse events was similar between patients with VM (112 [98.2%]) and without VM (103 [90.4%]).
Table: 651P
Lung (but not liver) metastases (n[117) Liver metastases (n[53) AAP (n[60) PBO (n[57) AAP (n[29) PBO (n[24) OS (months) 57.2 37.9 36.8 25.6 HR (95% CI) 0.60 (0.35, 1.04) 0.82 (0.41, 1.66) rPFS (months) 33.0 21.9 10.9 14.6 HR (95% CI) 0.50 (0.29, 0.89) 1.05 (0.53, 2.09)
Conclusions:AAP improved both rPFS and OS in men with mCSPC and visceral dis-ease, especially those with lung metastases. Presence of liver metastases was asso-ciated with a poorer prognosis than lung metastases. Whether patients with de novo liver metastases benefit or not from next generation androgen receptor targeting requires additional data.
Clinical trial identification:NCT01715285.
Editorial acknowledgement:Editorial assistance was provided by Ramji Narayanan of SIRO Clinpharm Pvt Ltd and funded by Janssen Global Services, LLC.
Legal entity responsible for the study:Janssen Research & Development, LLC. Funding:Janssen Research & Development, LLC.
Disclosure: G. Baciarello: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Ex-penses: Janssen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/ExTravel/Accommodation/Ex-penses: Roche; Advisory/Consultancy: Amgen; Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas Oncology; Travel/Accommodation/Expenses: Ipsen. S.D. Mundle: Full/Part-time employment:
Annals of Oncology
abstracts
Janssen. G. Leitz: Full/Part-time employment: Janssen. U. Richarz: Full/Part-time employment: Janssen. P. Hu: Full/Part-time employment: Janssen. K.N. Chi: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Astellas Pharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bayer; Honoraria (self), Advisory/Consultancy, Research grant/ Funding (institution): Janssen; Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Advisory/Consultancy: AstraZeneca; Advisory/Consul-tancy: ESSA; Research grant/Funding (institution): Lilly/ImClone; Research grant/Funding (institu-tion): Merck ; Advisory/Consultancy, Research grant/Funding (institu(institu-tion): Roche; Research grant/ Funding (institution): Tokai Pharmaceuticals ; Research grant/Funding (institution): Bristol-Myers Squibb. K. Fizazi: Honoraria (self), Advisory/Consultancy: Astellas Pharma; Honoraria (self), Advisory/ Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy: Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Curevac; Advisory/Consultancy: ESSA; Advisory/Consultancy: Orion Pharma GmbH; Advisory/Consultancy: Roche; Advisory/Consul-tancy: Genentech. All other authors have declared no conflicts of interest.
https://doi.org/10.1016/j.annonc.2020.08.910
652P Comparison of current systemic combination therapies for metastatic hormone-sensitive prostate cancer and selection of candidates for optimal treatment: A systematic review and Bayesian network meta-analysis
J. Chen, Y. Ni, G. Sun, X. Zhang, J. Zhao, S. Zhu, Z. Wang, H. Zhang, X. Zhu, P. Shen, H. Zeng
Urology, West China Hospital, Sichuan University, Chengdu, China
Background:We conducted this systematic review and network meta-analysis aiming to compare the efficacy and safety of current systemic combination therapies for patients with metastatic hormone-sensitive prostate cancer (mHSPC) and help select candidates for optimal treatment.
Methods:Databases of MEDLINE (1966 to 2019.10) and EMBASE (1974 to 2019.10), Cochrane Central Register of Controlled Trials (CENTRAL) (1948-2019.10) and Clinical Trial.gov (1999-2019.10) were searched for eligible studies. Direct and network meta-analysis were conducted to compare various systemic combination therapies and the surface under the cumulative ranking curve (SUCRA) was generated for treatment ranking. Subgroup analyses were performed according to the extent of metastasis. Adverse events (AEs) were compared among the effective treatments.
Results:Ten trials were included in this network meta-analysis. Direct and network meta-analysis consistently suggested that androgen-deprivation therapy (ADT) com-bined with docetaxel, abiraterone, enzalutamide or apalutamide could significantly improve overall survival (OS) and failure-free survival (FFS) compared to ADT alone in men with mHSPC. SUCRA analysis demonstrated the superiority of ADT plus abir-aterone or enzalutamide over other therapies. Subgroup analyses indicated that additional abiraterone to ADT had the highest ranking in patients with high-volume diseases or visceral metastases and enzalutamide plus ADT outperformed other treatments in patients with low-volume diseases or without visceral metastases. Different combination therapies had variable AE profiles and ADT in addition with docetaxel or abiraterone had the highest risk of AEs.
Conclusions:ADT plus docetaxel, abiraterone, enzalutamide or apalutamide were associated with significantly improved survival in patients with mHSPC. ADT plus abiraterone or enzalutamide appeared to be the most effective treatments. Clinicians should balance the efficacy, potential AEs and disease status to select the optimal treatment.
Legal entity responsible for the study:Hao Zeng. Funding:National Natural Science Foundation of China. Disclosure:All authors have declared no conflicts of interest.
https://doi.org/10.1016/j.annonc.2020.08.911
653P Features of molecular profile of prostate cancer after neoadjuvant treatment
M. Berkut1, A. Nosov1, A. Artemyeva2, A. Malek3
1Onco-Urology Department, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation;2Pathology Department, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation; 3Scientific Laboratory of Subcellular Technologies, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation
Background:This abstract presents the molecular profiling of prostate adenocarci-noma after surgical or combination treatment.
Methods:The study included 66 formalin-fixed paraffin-embedded (FFPE) tissue specimens of prostate cancer (PCa) (tumor volume at least 75% of the total material volume, without areas of necrosis and hemorrhages): 31 samples were taken after 6 cycles of neoadjuvant therapy with docetaxel and degarelix followed by radical prostatectomy (NCHT/RPE group) and the control group (RPE) included 35 samples after only surgery. The microdissection size was from 3 to 20
m
m. It was performed by a local pathologist. RNA supernatant was isolated from paraffin sections by dewaxingwith mineral oil. RNA supernatant concentration was assessed on a Qubit 2.0 fluo-rimeter (Invitrogen), protocol #0001987. Profiling of all samples were performed on the miRCURY LNAÔ Universal RT(Exiqon) test system with real-time polymerase chain reaction (PCR) with SYBRÒ green on CFX96 Real Time System (“Bio-Rad”) thermo-cycler, protocol #6.2. In the calculations, a semi-quantitative assessment of the level of miRNA expression was used relative to the average expression level of all samples (
DD
Ct).Results:The average concentration of RNA supernatant in the NCHT/RPE group was lower than the control group (P¼0.002):
D
S¼3.774.51ng/ml (0.05-1.1) againstD
S (RPE group)¼ 19.6615.69 ng/ml (2.88-66.0). Profiling showed differences in PCR cycles (D
Ct>1.5) for miRNA primers: hsa-mir-181a-5p, hsa-mir-126-3p, hsa-mir-200c-3p, hsa-mir-106b-5p, hsa-mir221-hsa-mir-200c-3p, hsa-mir34. TheDD
Ct of these miRNAs were different (P>0.05) into groups except miRNA-200c:DD
Ct¼4.754.00ed. against 3.34 3.83ed. (P¼0.14). The correlation analysis revealed association withDD
Ct-miRNA126 and the frequency of the positive surgical margin (F¼ 10.34, P ¼ 0.015). DecreasingDD
Ct-miRNA126 from 10.826.0ed. to 7.375.46ed. was noted after neoadjuvant treatment (U-test P¼0.012). The equation of the dependence of overall survival (OS) was formulated during regression analysis on theDD
Ct-miRNA-106b indices: OS¼24+ 2.2*MIR106B, which was able to predict OS in 19.2% of patients. Conclusions:The analysis revealed that overexpression of some miRNAs is blocked in prostate cancer patients receiving combined treatment.Legal entity responsible for the study:The authors. Funding:Has not received any funding.
Disclosure:All authors have declared no conflicts of interest.
https://doi.org/10.1016/j.annonc.2020.08.912
654P Real-world treatment (Tx) patterns in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair mutations (HRRm+)
N. Shore1, R. Ionescu-Ittu2, F. Laliberté2, L. Yang3, A. Gayle4, S. Payne4, M. Mahendran2, S. Amin5, D. Lejeune2, J.E. Burgents3, M.S. Duh6, L. Yu6, S. Ghate3 1
Carolina Urologic Research Center, Myrtle Beach, SC, USA;2Analysis Group, Inc, Montreal, QC, Canada;3Merck & Co. Inc., Kenilworth, NJ, USA;4AstraZeneca, Cam-bridge, United Kingdom;5AstraZeneca, Gaithersburg, MD, USA;6Analysis Group, Inc, Boston, MA, USA
Background: The 2020 NCCN guidelines recommend olaparib, a PARP inhibitor (PARPi) currently awaiting FDA approval, for the treatment of HRRm+ mCRPC. We describe tx patterns of mCRPC pts who tested positive for1 of six a priori selected HRRm (ATM, BRCA1/2, CDK12, PALB2, FANCA) before PARPi approval.
Methods:mCRPC pts with confirmed adenocarcinoma diagnosis (dx) and docu-mented HRRm were identified in the US Flatiron Health EHR-derived deidentified database (01/2013e03/2019; 82.5% and 17.5% of pts with HRRm mCRPC in com-munity and academic settings, respectively). Pts were followed from mCRPC dx to the end of clinical activity/data availability or death. Tx patterns (incl. tx per lines of therapies [LOTs], LOT sequences and time on tx) were described.
Table: 654PLOTs by Tx Class
% Median months on tx Pts with 1 LOT (N ¼ 151) On 1L 1L class NHA 54 5.5 Chemo 19 2.9 I/O 11 3.5 Other 8 2.1 Combinations of classes 8 5.2 NHA-based 7 5.3
Pts with 2 LOTs (N ¼ 121) From 1L start to 2L end
1L/ 2L (by frequency)
NHA/ NHA 20 15.9
NHA/ Chemo 14 9.8
NHA/ Other 12 8.6
Remaining 15 sequences 54 9.4
Pts with 3 LOTs (N ¼ 94) From 1L start to 3L end
1L/ 2L / 3L (by frequency)
NHA/ NHA / Chemo 12 19.3
I/O/ NHA / NHA 7 20.4
NHA/ NHA / Other 6 27.8
Remaining 32 sequences 75 14.4
I/O, immunotherapy (excl. pembrolizumab);
NHA, new hormonal agents (e.g., abiraterone, enzalutamide);
Other, incl. pembrolizumab, targeted tx, radium-223, androgren-deprivation tx, clinical trial tx.
