Browsing by Author "Ashkar, Ryan"

Now showing 1 - 5 of 5
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    Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer
    (American Society of Clinical Oncology, 2021-07-22) Taza, Fadi; Holler, Albert E.; Fu, Wei; Wang, Hao; Adra, Nabil; Albany, Costantine; Ashkar, Ryan; Cheng, Heather H.; Sokolova, Alexandra O.; Agarwal, Neeraj; Kessel, Adam; Bryce, Alan; Nafissi, Nellie; Barata, Pedro; Sartor, A. Oliver; Bastos, Diogo; Smaletz, Oren; Berchuck, Jacob E.; Taplin, Mary-Ellen; Aggarwal, Rahul; Sternberg, Cora N.; Vlachostergios, Panagiotis J.; Alva, Ajjai S.; Su, Christopher; Marshall, Catherine H.; Antonarakis, Emmanuel S.; Medicine, School of Medicine
    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.
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    Outcomes in Patients With Postchemotherapy Residual Nonretroperitoneal Disease in Nonseminomatous Germ Cell Tumors
    (American Medical Association, 2024) King, Jennifer; Ashkar, Ryan; Kesler, Kenneth; Althouse, Sandra K.; Hanna, Nasser H.; Einhorn, Lawrence H.; Adra, Nabil; Medicine, School of Medicine
    This case-control study assesses the association between teratoma in the primary tumor or postchemotherapy resections and survival outcomes.
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    Phase II trial of brentuximab vedotin in relapsed/refractory germ cell tumors
    (Springer, 2021) Ashkar, Ryan; Feldman, Darren R.; Adra, Nabil; Zaid, Mohammad Abu; Funt, Samuel A.; Althouse, Sandra K.; Perkins, Susan M.; Snow, Christin I.; Lazzara, Kayla M.; Sego, Lina M.; Quinn, David I.; Hanna, Nasser H.; Einhorn, Lawrence H.; Albany, Costantine; Biostatistics, School of Public Health
    Background: CD-30 is highly expressed in some patients with non-seminomatous germ-cell tumors. Brentuximab vedotin is an antibody–drug conjugate directed to CD-30. We report a phase 2 trial of brentuximab vedotin in patients with chemo-refractory GCT. Patients and methods: This is a single arm, two cohort phase 2 trial investigating brentuximab vedotin 1.8 mg/kg IV every 3 weeks until disease progression or intolerable toxicities in patients with relapsed GCT who have no curative options. Patients with mGCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (high-dose or standard-dose chemotherapy) were eligible. CD30 expression was assessed and two cohorts defined: CD30 positive and CD30 negative/unknown. Results: 18 patients were enrolled. Median age 34.7 (range, 23–56). All patients had non-seminoma. Median AFP 4.9 (range, 1–219,345) and hCG 282 (range, 0.6–172,064). Five patients had late relapse (> 2 years). Median number of previous chemotherapy regimens was 3 (range, 2–7). Ten patients received prior high-dose chemotherapy. Seven patients had positive CD30 staining. There were two grade 3 treatment-related adverse events. No partial or complete responses were observed. 6 patients achieved radiographic stable disease (range, 9–14.9 weeks), 5 had elevated AFP or hCG at trial entry and all 5 had transient > 50% decline in baseline AFP/hCG: 4 had CD30 −ve and 2 had CD30 + ve staining; 10 patients had progression of disease as their best response; 2 were not evaluable for response. Conclusion: Brentuximab vedotin does not appear to have clinically meaningful single-agent activity in patients with refractory GCT.
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    Prediction Model for Brain Metastasis in Patients With Metastatic Germ‐Cell Tumors
    (Wiley, 2025) Salous, Tareq; Ashkar, Ryan; Althouse, Sandra K.; Cary, Clint; Masterson, Timothy; Hanna, Nasser H.; King, Jennifer; Einhorn, Lawrence H.; Adra, Nabil; Medicine, School of Medicine
    Background: Brain metastasis (BM) is an independent adverse prognostic factor in metastatic germ cell tumors (mGCT). We aimed to establish an effective and practical BM prediction model. Patients and methods: Between January 1990 and September 2017, 2291 patients with mGCT who were treated at Indiana University were identified. Patients were divided into two categories: BM present (N = 154) and BM absent (N = 2137). Kaplan-Meier methods were used to analyze progression free survival (PFS) and overall survival (OS). Logistic regression was used to determine a predictive model for whether BM was present. The data was separated into training and validation datasets with equal numbers of events in each. Results: The 2-year PFS and OS for patients with versus without BM: 17% versus 65% (p < 0.001) and 62% versus 91% (p < 0.001) respectively. Among the 154 patients with BM, 64 (42%) had radiation only (whole-brain radiotherapy or gamma knife), 22 (14%) had BM-surgery only, 14 (9%) had both radiation and BM-surgery. 54 patients (35%) did not receive local therapy for BM. Stepwise selection was used to determine the best model with p < 0.15 as the entry and staying criteria. The model with the largest ROC AUC was used moving forward. The model was tested in the validation dataset. A model was generated including age at diagnosis ≥ 40, choriocarcinoma predominant histology, pre-chemotherapy hCG≥ 5000, presence of pulmonary metastases size < 3, or ≥ 3 cm, and presence of bone metastasis. Patients with score of 0, 1, 2, 3, 4, 5, 6, 7, 8 points had a 0.6%, 1.4%, 3.5%, 8.2%, 18.3%, 36%, 58%, 78%, 90% probability of having BM, respectively. Conclusions: The prediction model developed in this study demonstrated discrimination capability of predicting BM occurrence in mGCT and can be used to identify high-risk patients.
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    Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair‐Deficient Prostate Cancer
    (Oxford University Press, 2021-02) Sena, Laura A.; Fountain, Julia; Velho, Pedro Isaacsson; Lim, Su Jin; Wang, Hao; Nizialek, Emily; Rathi, Nityam; Nussenzveig, Roberto; Maughan, Benjamin L.; Gonzalez Velez, Miguel; Ashkar, Ryan; Larson, Amanda C.; Pritchard, Colin C.; Adra, Nabil; Bryce, Alan H.; Agarwal, Neeraj; Pardoll, Drew M.; Eshleman, James R.; Lotan, Tamara L.; Antonarakis, Emmanuel S.; Medicine, School of Medicine
    Background: Genomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer. Methods: To enrich for response to anti-PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort. Results: Nineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy. The PSA50 response rate was 65%, and the median progression-free survival (PFS) was 24 (95% confidence interval 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment and with density of CD8+ tumor-infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort. Conclusion: Tumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity. Implications for practice: Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti-PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.