13 results on '"Corn, Paul G."'
Search Results
2. Data from Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series
- Author
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Anselmino, Nicolas, primary, Labanca, Estefania, primary, Shepherd, Peter D.A., primary, Dong, Jiabin, primary, Yang, Jun, primary, Song, Xiaofei, primary, Nandakumar, Subhiksha, primary, Kundra, Ritika, primary, Lee, Cindy, primary, Schultz, Nikolaus, primary, Zhang, Jianhua, primary, Araujo, John C., primary, Aparicio, Ana M., primary, Subudhi, Sumit K., primary, Corn, Paul G., primary, Pisters, Louis L., primary, Ward, John F., primary, Davis, John W., primary, Vazquez, Elba S., primary, Gueron, Geraldine, primary, Logothetis, Christopher J., primary, Futreal, Andrew, primary, Troncoso, Patricia, primary, Chen, Yu, primary, and Navone, Nora M., primary
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- 2024
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3. Supplementary Figure S4 from Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series
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Anselmino, Nicolas, primary, Labanca, Estefania, primary, Shepherd, Peter D.A., primary, Dong, Jiabin, primary, Yang, Jun, primary, Song, Xiaofei, primary, Nandakumar, Subhiksha, primary, Kundra, Ritika, primary, Lee, Cindy, primary, Schultz, Nikolaus, primary, Zhang, Jianhua, primary, Araujo, John C., primary, Aparicio, Ana M., primary, Subudhi, Sumit K., primary, Corn, Paul G., primary, Pisters, Louis L., primary, Ward, John F., primary, Davis, John W., primary, Vazquez, Elba S., primary, Gueron, Geraldine, primary, Logothetis, Christopher J., primary, Futreal, Andrew, primary, Troncoso, Patricia, primary, Chen, Yu, primary, and Navone, Nora M., primary
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- 2024
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4. Prostate cancer-induced endothelial-cell-to-osteoblast transition drives immunosuppression in the bone-tumor microenvironment through Wnt pathway-induced M2 macrophage polarization.
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Guoyu Yu, Corn, Paul G., Sze Ling Mak, Celia, Xin Liang, Miao Zhang, Troncoso, Patricia, Song, Jian H., Song-Chang Lin, Xingzhi Song, Jingjing Liu, Jianhua Zhang, Logothetis, Christopher J., Melancon, Marites P., Panaretakis, Theocharis, Guocan Wang, and Sue-Hwa Lin
- Subjects
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CASTRATION-resistant prostate cancer , *LYSYL oxidase , *BONE metastasis , *IMMUNE checkpoint proteins , *LYMPHATIC metastasis , *PROSTATE cancer patients - Abstract
Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor-associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl-TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC-to-osteoblast (EC-to-OSB) transition, the precursors of tumor-induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2-like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC-to-OSB transition reduced the levels of M2-like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC-to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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5. Radium-223 Treatment Produces Prolonged Suppression of Resident Osteoblasts and Decreased Bone Mineral Density in Trabecular Bone in Osteoblast Reporter Mice.
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Lin, Song-Chang, Yu, Guoyu, Corn, Paul G., Damasco, Jossana, Lee, Yu-Chen, Song, Jian H., Navone, Nora M., Logothetis, Christopher J., Melancon, Marites P., Panaretakis, Theocharis, and Lin, Sue-Hwa
- Subjects
OSTEOBLASTS ,BONE density ,RADIOTHERAPY ,RESEARCH funding ,T-test (Statistics) ,TRABECULECTOMY ,COMPUTED tomography ,PROSTATE tumors ,DESCRIPTIVE statistics ,MICE ,ANIMAL experimentation ,DATA analysis software - Abstract
Simple Summary: Radium 223 (Ra-223) is a radiopharmaceutical that targets tumor-induced osteoblasts (bone-forming cells). Ra-223 reduces bone pain and prolongs overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. The aim of this study was to examine the effects of Ra-223 on resident osteoblasts and normal bone structure in mouse models. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the reduction lasted for at least 18 weeks. Ra-223 reduced the osteoblasts mainly localized in trabecular bone areas. Ra-223 also reduced bone mineral density and altered bone microstructure in the trabecular area of femurs. Furthermore, Ra-223 treatment also significantly reduced tumor-induced osteoblasts. These studies show that Ra-223 affects the structure of bones that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223. Radium 223 (Ra-223) is an α-emitting bone-homing radiopharmaceutical that targets tumor-induced osteoblasts and is used to reduce bone pain and prolong overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. Both luciferase- or green fluorescence protein (GFP)-labeled osteoblast reporter mice were used to monitor the effect of Ra-223 on resident osteoblasts and normal bone structure. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the osteoblast reduction lasted for at least 18 weeks without detectable recovery, as measured by in vivo bioluminescent imaging. In GFP-labeled osteoblast reporter mice, Ra-223 mainly reduced osteoblasts localized in the trabecular bone areas; the osteoblasts in the growth plates were less affected. Micro-computed tomography analyses showed that Ra-223 significantly reduced bone mineral density and bone microstructure in the trabecular area of femurs but not in the cortical bone. Tumor-induced bone was generated by inoculating osteogenic TRAMP-BMP4 prostate cancer cells into the mouse femurs; Ra-223 treatment significantly reduced tumor-induced osteoblasts. Our study shows that Ra-223 affects bone structures that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series
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Anselmino, Nicolas, primary, Labanca, Estefania, additional, Shepherd, Peter D.A., additional, Dong, Jiabin, additional, Yang, Jun, additional, Song, Xiaofei, additional, Nandakumar, Subhiksha, additional, Kundra, Ritika, additional, Lee, Cindy, additional, Schultz, Nikolaus, additional, Zhang, Jianhua, additional, Araujo, John C., additional, Aparicio, Ana M., additional, Subudhi, Sumit K., additional, Corn, Paul G., additional, Pisters, Louis L., additional, Ward, John F., additional, Davis, John W., additional, Vazquez, Elba S., additional, Gueron, Geraldine, additional, Logothetis, Christopher J., additional, Futreal, Andrew, additional, Troncoso, Patricia, additional, Chen, Yu, additional, and Navone, Nora M., additional
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- 2024
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7. MORPHOLOGICAL PROGRESSION IN RELAPSING PATIENTS WITH SMALL CELL BLADDER CANCER
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Moussa, Mohammad Jad, primary, Radtke, Arlene O. Siefker, additional, Shah, Amishi Y., additional, Gao, Jianjun, additional, Goswami, Sangeeta, additional, Logothetis, Christopher J., additional, Corn, Paul G., additional, Aparicio, Ana, additional, Tannir, Nizar M., additional, Kamat, Ashish M., additional, Navai, Neema, additional, Lee, Byron, additional, Dinney, Colin P.N., additional, Czerniak, Bogdan A., additional, Guo, Charles C., additional, Hansel, Donna E., additional, Campbell, Matthew T., additional, Alhalabi, Omar, additional, and Wilson, Nathaniel R., additional
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- 2024
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8. Whole-body magnetic resonance imaging for staging patients with high-risk prostate cancer
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Fang, Andrew M., Chapin, Brian F., Shi, Charles W., Sun, Jia, Qayyum, Aliya, Kundra, Vikas, Corn, Paul G., Kuban, Deborah A., Ravizzini, Gregory C., Surasi, Devaki Shilpa S., Ma, Jingfei, and Bathala, Tharakeswara K.
- Abstract
Background: Staging patients with high-risk prostate cancer (HRPCa) with conventional imaging of computed tomography (CT) and bone scintigraphy (BS) is suboptimal. Therefore, we aimed to compare the accuracy of whole-body magnetic resonance imaging (WBMRI) with conventional imaging to stage patients with HRPCa. Methods: We prospectively enrolled patients with newly diagnosed HRPCa (prostate‐specific antigen ≥20 ng/ml and/or Grade Group ≥4). Patients underwent BS, CT of the abdomen and pelvis, and WBMRI within 30 days of evaluation. The primary endpoint was the diagnostic performances of detecting metastatic disease to the lymph nodes and bone for WBMRI and conventional imaging. The reference standard was defined by histopathology or by all available clinical information at 6 months of follow-up. To compare diagnostic tests, Exact McNemar’s test and area under the curve (AUC) of the receiver operating characteristics curves were utilized. Results: Among 92 patients enrolled, 15 (16.3%) and 8 (8.7%) patients were found to have lymphatic and bone metastases, respectively. The sensitivity, specificity, and accuracy of WBMRI in detecting lymphatic metastases were 0.60 (95% confidence interval 0.32–0.84), 0.84 (0.74–0.92), and 0.80 (0.71–0.88), respectively, while CT were 0.20 (0.04–0.48), 0.92 (0.84–0.97), and 0.80 (0.71–0.88). The sensitivity, specificity, and accuracy of WBMRI to detect bone metastases were 0.25 (0.03–0.65), 0.94 (0.87–0.98), and 0.88 (0.80–0.94), respectively, while CT and BS were 0.12 (0–0.53), 0.94 (0.87–0.98), and 0.87 (0.78–0.93). For evaluating lymphatic metastases, WBMRI demonstrated a higher sensitivity (p= 0.031) and discrimination compared to CT (0.72 versus 0.56, p= 0.019). Conclusions: For staging patients with HRPCa, WBMRI outperforms CT in the detection of lymphatic metastases and performs as well as CT and BS in the detection of bone metastases. Further studies are needed to assess the cost effectiveness of WBMRI and the utility of combined PSMA PET and WBMRI.
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- 2024
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9. Body composition as a determinant of the therapeutic index with androgen signaling inhibition
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Hahn, Andrew W., Tidwell, Rebecca S., Pilie, Patrick G., Yu, Yao, Liu, Jingjing, Surasi, Devaki Shilpa, Titus, Mark, Zhang, Jianhua, Venkatesh, Neha, Panaretakis, Theocharis, Gregg, Justin R., Zurita, Amado J., Siddiqui, Bilal A., Corn, Paul G., Subudhi, Sumit K., Msaouel, Pavlos, Koutroumpakis, Efstratios, Huff, Chad D., Aparicio, Ana, McQuade, Jennifer L., Frigo, Daniel E., and Logothetis, Christopher J.
- Abstract
Background: Androgen signaling is central to prostate cancer and men’s health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC). Methods: A post-hoc analysis was done of NCT02703623 where men with mCRPC (n= 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma. Results: Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3rs12529, CYP17A1rs6162, SRD5A2rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p= 0.02), visceral adipose tissue index (VATi, p= 0.03), and BMI (p= 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r= 0.47) and SATi (r= 0.48). Conclusion: Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.
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- 2024
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10. Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer
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Fecteau, Ryan E., Koontz, Bridget F., Hoffman, Karen E., Halabi, Susan, Howard, Lauren E., Anand, Monika, George, Daniel J., Zhang, Tian, Berry, William R., Lee, W. Robert, Harrison, Michael R., Corn, Paul G., and Armstrong, Andrew J.
- Abstract
Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.
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- 2024
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11. Body composition in recurrent prostate cancer and the role of steroidogenic genotype.
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Venkatesh N, Tidwell RS, Yu Y, Aparicio A, Zurita AJ, Subudhi SK, Siddiqui BA, Mukhida SS, Gregg JR, Corn PG, Koutroumpakis E, McQuade JL, Frigo DE, Pilie PG, Huff C, Logothetis CJ, and Hahn AW
- Abstract
Hormone therapy (HT) to treat prostate cancer is reported to cause adverse changes in body composition. Clinically, interpatient body composition changes are heterogeneous, but the biologic and clinical determinants of body composition toxicity are unknown. Herein, we test the hypothesis that inherited polymorphisms in steroidogenic genes are associated with differential change in body composition after HT. Men with biochemically recurrent prostate cancer (BCR) who received 8 months of LHRH analog (LHRHa) +/- abiraterone acetate (AAP) were eligible if they had: 1) CT imaging of L3 prior to and after treatment, and 2) nucleated cells collected. Cardiometabolic co-morbidities were retrospectively extracted. Body composition was measured using an AI-based segmentation tool. Germline DNA whole exome or genome sequencing was performed. In 162 men treated with 8 months of HT, median skeletal muscle mass (SMMi) loss was 6.6% and subcutaneous adipose gain was 12.3%. Men with type 2 diabetes had higher loss of SMMi after treatment (-11.1% vs. -6.3%, p = 0.003). For the 150 men with germline NGS, SRD5A2 rs523349 genotype was associated with differential loss in skeletal muscle density after HT, (-1.3% vs. -7.1%, p=0.04). In addition, HSD3B1 rs104703 genotype was associated with decreased baseline visceral adipose tissue (63.0 cm2/m2 vs. 77.9, p=0.05). In men with BCR, HT induced notable loss of skeletal muscle and increased subcutaneous adipose tissue. An inherited polymorphism in SRD5A2 and T2DM were associated with differential skeletal muscle toxicity. These findings suggest that inherited polymorphisms may contribute to the body composition toxicity observed with HT.
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- 2024
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12. Prostate cancer-induced endothelial-cell-to-osteoblast transition drives immunosuppression in the bone-tumor microenvironment through Wnt pathway-induced M2 macrophage polarization.
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Yu G, Corn PG, Mak CSL, Liang X, Zhang M, Troncoso P, Song JH, Lin SC, Song X, Liu J, Zhang J, Logothetis CJ, Melancon MP, Panaretakis T, Wang G, and Lin SH
- Subjects
- Male, Humans, Animals, Mice, Prostatic Neoplasms, Castration-Resistant immunology, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant metabolism, Cell Line, Tumor, Prostatic Neoplasms pathology, Prostatic Neoplasms immunology, Prostatic Neoplasms metabolism, Tumor-Associated Macrophages metabolism, Tumor-Associated Macrophages immunology, Tumor Microenvironment immunology, Bone Neoplasms immunology, Bone Neoplasms secondary, Bone Neoplasms pathology, Bone Neoplasms metabolism, Wnt Signaling Pathway, Macrophages metabolism, Macrophages immunology, Endothelial Cells metabolism, Endothelial Cells immunology, Osteoblasts metabolism, Osteoblasts immunology
- Abstract
Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206
+ ) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor-associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl-TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC-to-osteoblast (EC-to-OSB) transition, the precursors of tumor-induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2-like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC-to-OSB transition reduced the levels of M2-like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC-to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC., Competing Interests: Competing interests statement:The authors declare no competing interest.- Published
- 2024
- Full Text
- View/download PDF
13. A Modular Trial of Androgen Signaling Inhibitor Combinations Testing a Risk-Adapted Strategy in Patients with Metastatic Castration-Resistant Prostate Cancer.
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Aparicio AM, Tidwell RSS, Yadav SS, Chen JS, Zhang M, Liu J, Guo S, Pilié PG, Yu Y, Song X, Vundavilli H, Jindal S, Zhu K, Viscuse PV, Lebenthal JM, Hahn AW, Soundararajan R, Corn PG, Zurita-Saavedra A, Subudhi SK, Zhang J, Wang W, Huff C, Troncoso P, Allison JP, Sharma P, and Logothetis CJ
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- Humans, Male, Aged, Middle Aged, Thiohydantoins administration & dosage, Thiohydantoins therapeutic use, Thiohydantoins adverse effects, Aged, 80 and over, Androgen Antagonists therapeutic use, Carboplatin administration & dosage, Carboplatin therapeutic use, Ipilimumab administration & dosage, Ipilimumab therapeutic use, Taxoids, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant mortality, Prostatic Neoplasms, Castration-Resistant genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Prednisone administration & dosage, Prednisone therapeutic use, Abiraterone Acetate therapeutic use, Abiraterone Acetate administration & dosage
- Abstract
Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers., Patients and Methods: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; module 1) and then allocated to modules 2 or 3 based on satisfactory (≥50% PSA decline from baseline and <5 circulating tumor cell/7.5 mL) versus unsatisfactory status. Men in the former were randomly assigned to continue AAPA alone (module 2A) or with ipilimumab (module 2B). Men in the latter group had carboplatin + cabazitaxel added to AAPA (module 3). Optional baseline biopsies were subjected to correlative studies., Results: Median overall survival (from allocation) was 46.4 [95% confidence interval (CI), 39.2-68.2], 41.4 (95% CI, 33.3-49.9), and 18.7 (95% CI, 14.3-26.3) months in modules 2A (n = 64), 2B (n = 64), and 3 (n = 59), respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pretreatment metastatic biopsies. The aggressive-variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with unsatisfactory status. Exploratory analyses suggested that secreted phosphoprotein 1-positive and insulin-like growth factor-binding protein 2-positive macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the unsatisfactory group., Conclusions: Adding ipilimumab to AAPA did not improve outcomes in men with androgen-responsive metastatic castration-resistant prostate cancer. Despite the addition of carboplatin + cabazitaxel, men in the unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer., (©2024 American Association for Cancer Research.)
- Published
- 2024
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