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1. Co-occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer

Author

Orme, Jacob J., Taza, Fadi, De Sarkar, Navonil, Tewari, Alok K., Arsalan Naqvi, Syed, Riaz, Irbaz B., Childs, Daniel S., Omar, Noha, Adra, Nabil, Ashkar, Ryan, Cheng, Heather H., Schweizer, Michael T., Sokolova, Alexandra O., Agarwal, Neeraj, Barata, Pedro, Sartor, Oliver, Bastos, Diogo, Smaletz, Oren, Berchuck, Jacob E., McClure, Heather, Taplin, Mary-Ellen, Aggarwal, Rahul, Sternberg, Cora N., Vlachostergios, Panagiotis J., Alva, Ajjai S., Mehra, Niven, Nelson, Peter S., Hwang, Justin, Dehm, Scott M., Shi, Qian, Fleischmann, Zoe, Sokol, Ethan S., Elliott, Andrew, Huang, Haojie, Bryce, Alan, Marshall, Catherine H., and Antonarakis, Emmanuel S.

Published
2024
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3. High‐dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

Author

Richardson, Noah H., Taza, Fadi, Abonour, Rafat, Althouse, Sandra K., Ashkar, Ryan, Abu Zaid, Mohammad, Hanna, Nassar H., Kesler, Kenneth A., Adra, Nabil, and Einhorn, Lawrence H.

Subjects
SALVAGE therapy, OVERALL survival, SURVIVAL rate, BLOOD cells, COMBINATION drug therapy, STEM cell transplantation, GERM cell tumors
Abstract

Background: Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high‐dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. Methods: The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first‐line cisplatin‐based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression‐free survival and overall survival were analyzed using the Kaplan–Meier method. Medians with 95% confidence intervals were also calculated along with 2‐year probabilities. Results: The median age at HDCT was 30 years (range, 18–61 years). With a median follow‐up of 4.7 years (range, 1–14 years), the 2‐year progression‐free survival rate was 31% (95% confidence interval, 16%–47%), and the 2‐year overall survival rate was 35% (95% confidence interval, 19%–52%). At last follow‐up, nine patients (28%) remained without evidence of disease, including two platinum‐refractory patients and two patients who were receiving HDCT as third‐line therapy. There were three treatment‐related deaths. Conclusions: Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum‐refractory and third‐line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population. Patients who have relapsed primary mediastinal nonseminomatous germ cell tumors have poor outcomes with salvage chemotherapy. The authors report the results of high‐dose chemotherapy and peripheral blood stem cell transplantation, which permit more rapid succession to the subsequent cycle and potentially improved efficacy compared with historical regimens. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Co-occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer

Author

Orme, Jacob J., primary, Taza, Fadi, additional, De Sarkar, Navonil, additional, Tewari, Alok K., additional, Arsalan Naqvi, Syed, additional, Riaz, Irbaz B., additional, Childs, Daniel S., additional, Omar, Noha, additional, Adra, Nabil, additional, Ashkar, Ryan, additional, Cheng, Heather H., additional, Schweizer, Michael T., additional, Sokolova, Alexandra O., additional, Agarwal, Neeraj, additional, Barata, Pedro, additional, Sartor, Oliver, additional, Bastos, Diogo, additional, Smaletz, Oren, additional, Berchuck, Jacob E., additional, McClure, Heather, additional, Taplin, Mary-Ellen, additional, Aggarwal, Rahul, additional, Sternberg, Cora N., additional, Vlachostergios, Panagiotis J., additional, Alva, Ajjai S., additional, Mehra, Niven, additional, Nelson, Peter S., additional, Hwang, Justin, additional, Dehm, Scott M., additional, Shi, Qian, additional, Fleischmann, Zoe, additional, Sokol, Ethan S., additional, Elliott, Andrew, additional, Huang, Haojie, additional, Bryce, Alan, additional, Marshall, Catherine H., additional, and Antonarakis, Emmanuel S., additional

Published
2023
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7. Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer

Author

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., and Antonarakis, Emmanuel S.

Published
2021
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9. Differential responses to taxanes and PARP inhibitors in ATM‐ versus BRCA2 ‐mutated metastatic castrate‐resistant prostate cancer

Author

Su, Christopher T., primary, Nizialek, Emily, additional, Berchuck, Jacob E., additional, Vlachostergios, Panagiotis J., additional, Ashkar, Ryan, additional, Sokolova, Alexandra, additional, Barata, Pedro C., additional, Aggarwal, Rahul R., additional, McKay, Rana R., additional, Agarwal, Neeraj, additional, McClure, Heather M., additional, Nafissi, Nellie, additional, Bryce, Alan H., additional, Sartor, Oliver, additional, Sayegh, Nicolas, additional, Cheng, Heather H., additional, Adra, Nabil, additional, Sternberg, Cora N., additional, Taplin, Mary‐Ellen, additional, Cieslik, Marcin, additional, Alva, Ajjai S., additional, and Antonarakis, Emmanuel S., additional

Published
2022
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16. Survival outcomes and toxicity in patients 40 years old or older with relapsed metastatic germ cell tumors treated with high‐dose chemotherapy and peripheral blood stem cell transplantation

Author

Agrawal, Vaibhav, primary, Abonour, Rafat, additional, Abu Zaid, Mohammad, additional, Althouse, Sandra K., additional, Ashkar, Ryan, additional, Albany, Costantine, additional, Hanna, Nasser H., additional, Einhorn, Lawrence H., additional, and Adra, Nabil, additional

Published
2021
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17. Phase II Trial of Brentuximab Vedotin in Relapsed/Refractory Germ Cell Tumors

Author

Ashkar, Ryan, primary, Feldman, Darren R., additional, Adra, Nabil, additional, Zaid, Mohammad Abu, additional, Funt, Samuel A., additional, Althouse, Sandra K., additional, Perkins, Susan M., additional, Snow, Christin I., additional, Lazzara, Kayla M., additional, Sego, Lina M., additional, Quinn, David I., additional, Hanna, Nasser H., additional, Einhorn, Lawrence H., additional, and Albany, Costantine, additional

Published
2021
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19. Outcomes of patients with germ cell tumors diagnosed with stage I disease who subsequently received high dose chemotherapy (HDCT) with peripheral stem cell transplant (PBSCT) following failure of initial therapy for metastatic disease: The Indiana University experience.

Author

Benzinger, Stephen B, primary, Ashkar, Ryan, additional, Abonour, Rafat, additional, Abu Zaid, Mohammad Issam, additional, Adra, Nabil, additional, Einhorn, Lawrence H., additional, and Hanna, Nasser H., additional

Published
2021
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20. Differential responses to taxanes and PARP inhibitors (PARPi) in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer (mCRPC) patients (pts).

Author

Su, Christopher T, primary, Nizialek, Emily, additional, Berchuck, Jacob E, additional, Vlachostergios, Panagiotis J., additional, Ashkar, Ryan, additional, Sokolova, Alexandra, additional, Barata, Pedro C., additional, Aggarwal, Rahul Raj, additional, McClure, Heather, additional, Nafissi, Nellie, additional, Bryce, Alan Haruo, additional, Sartor, A. Oliver, additional, Cheng, Heather H., additional, Adra, Nabil, additional, Sternberg, Cora N., additional, Taplin, Mary-Ellen, additional, Cieslik, Marcin, additional, Antonarakis, Emmanuel S., additional, and Alva, Ajjai Shivaram, additional

Published
2021
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24. Differential activity of PARP inhibitors in BRCA1- versus BRCA2-altered metastatic castration-resistant prostate cancer (mCRPC).

Author

Taza, Fadi, primary, Holler, Albert E, additional, Adra, Nabil, additional, Ashkar, Ryan, additional, Sokolova, Alexandra, additional, Kessel, Adam, additional, Nafissi, Nellie, additional, Barata, Pedro C., additional, Bastos, Diogo Assed, additional, Smaletz, Oren, additional, Aggarwal, Rahul Raj, additional, Berchuck, Jacob E, additional, Vlachostergios, Panagiotis J., additional, Su, Christopher, additional, Marshall, Catherine Handy, additional, and Antonarakis, Emmanuel S., additional

Published
2021
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25. Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair-Deficient Prostate Cancer

Author

Sena, Laura A., primary, Fountain, Julia, additional, Isaacsson Velho, Pedro, additional, Lim, Su Jin, additional, Wang, Hao, additional, Nizialek, Emily, additional, Rathi, Nityam, additional, Nussenzveig, Roberto, additional, Maughan, Benjamin L., additional, Velez, Miguel Gonzalez, additional, Ashkar, Ryan, additional, Larson, Amanda C., additional, Pritchard, Colin C., additional, Adra, Nabil, additional, Bryce, Alan H., additional, Agarwal, Neeraj, additional, Pardoll, Drew M., additional, Eshleman, James R., additional, Lotan, Tamara L., additional, and Antonarakis, Emmanuel S., additional

Published
2020
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27. Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair‐Deficient Prostate Cancer.

Author

Sena, Laura A., Fountain, Julia, Isaacsson Velho, Pedro, Lim, Su Jin, Wang, Hao, Nizialek, Emily, Rathi, Nityam, Nussenzveig, Roberto, Maughan, Benjamin L., Velez, Miguel Gonzalez, Ashkar, Ryan, Larson, Amanda C., Pritchard, Colin C., Adra, Nabil, Bryce, Alan H., Agarwal, Neeraj, Pardoll, Drew M., Eshleman, James R., Lotan, Tamara L., and Antonarakis, Emmanuel S.

Subjects
PROSTATE tumors treatment, CANCER patients, CONFIDENCE intervals, DNA repair, DRUG efficacy, IMMUNOTHERAPY, LONGITUDINAL method, MEDICAL cooperation, MEDICAL records, METABOLIC disorders, GENETIC mutation, PROSTATE tumors, RESEARCH, SURVIVAL, TUMOR markers, PROSTATE-specific antigen, TREATMENT effectiveness, RETROSPECTIVE studies, SEQUENCE analysis, ACQUISITION of data methodology, PROGRAMMED cell death 1 receptors, IMMUNE checkpoint inhibitors, THERAPEUTICS
Abstract

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. Biomarkers of immune checkpoint inhibition sensitivity are needed. This article reports on genomic biomarkers that may predict response to anti‐PD1 therapy in prostate cancer. [ABSTRACT FROM AUTHOR]

Published
2021
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29. Co-occurring BRCA2/SPOPMutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-resistant Prostate Cancer

Author

Orme, Jacob J., Taza, Fadi, De Sarkar, Navonil, Tewari, Alok K., Arsalan Naqvi, Syed, Riaz, Irbaz B., Childs, Daniel S., Omar, Noha, Adra, Nabil, Ashkar, Ryan, Cheng, Heather H., Schweizer, Michael T., Sokolova, Alexandra O., Agarwal, Neeraj, Barata, Pedro, Sartor, Oliver, Bastos, Diogo, Smaletz, Oren, Berchuck, Jacob E., McClure, Heather, Taplin, Mary-Ellen, Aggarwal, Rahul, Sternberg, Cora N., Vlachostergios, Panagiotis J., Alva, Ajjai S., Mehra, Niven, Nelson, Peter S., Hwang, Justin, Dehm, Scott M., Shi, Qian, Fleischmann, Zoe, Sokol, Ethan S., Elliott, Andrew, Huang, Haojie, Bryce, Alan, Marshall, Catherine H., and Antonarakis, Emmanuel S.

Abstract

Presence of BRCA2mutations helps identify a subset of patients with prostate cancer who are likely to benefit from poly (ADP-ribose) polymerase (PARP) inhibitors, but additional biomarkers are needed to better refine patient selection. This study found that concurrent SPOPmutations predict enhanced PARP inhibitor sensitivity and durable progression-free survival in BRCA2-altered castration-resistant prostate cancer.

Published
2023
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30. Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer.

Author

Su CT, Nizialek E, Berchuck JE, Vlachostergios PJ, Ashkar R, Sokolova A, Barata PC, Aggarwal RR, McKay RR, Agarwal N, McClure HM, Nafissi N, Bryce AH, Sartor O, Sayegh N, Cheng HH, Adra N, Sternberg CN, Taplin ME, Cieslik M, Alva AS, and Antonarakis ES

Subjects
Male, Humans, Retrospective Studies, Treatment Outcome, Taxoids therapeutic use, BRCA2 Protein genetics, Ataxia Telangiectasia Mutated Proteins genetics, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology
Abstract

Background: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions., Methods: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy., Results: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35)., Conclusions: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy., (© 2022 The Authors. The Prostate published by Wiley Periodicals LLC.)

Published
2023
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