Elodie Coquan, Nicolas Penel, Justine Lequesne, Raphaël Leman, Pernelle Lavaud, Zoé Neviere, Pierre-Emmanuel Brachet, Emeline Meriaux, Aurélien Carnot, Jérémy Boutrois, Marie Castera, Nicolas Goardon, Etienne Muller, Alexandra Leconte, Antoine Thiery-Vuillemin, Bénédicte Clarisse, Florence Joly
{"title":"卡铂用于DNA损伤修复途径发生分子改变的转移性去势抵抗性前列腺癌患者：PRO-CARBO II期试验。","authors":"Elodie Coquan, Nicolas Penel, Justine Lequesne, Raphaël Leman, Pernelle Lavaud, Zoé Neviere, Pierre-Emmanuel Brachet, Emeline Meriaux, Aurélien Carnot, Jérémy Boutrois, Marie Castera, Nicolas Goardon, Etienne Muller, Alexandra Leconte, Antoine Thiery-Vuillemin, Bénédicte Clarisse, Florence Joly","doi":"10.1177/17562872241229876","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>DNA damage repair genes are altered in 20-35% of metastatic castration-resistant prostate cancer (mCRPC). Poly-ADP (Adénosine Diphosphate)-ribose polymerase inhibitors (PARPi) showed significant activity for these selected tumors, especially with homologous recombination repair (HRR) deficiency. These alterations could also predict platinum sensitivity. Although carboplatin was inconclusive in unselected mCRPC, the literature suggests an anti-tumoral activity in mCRPC with HHR gene alterations. We aimed to assess the efficacy of carboplatin monotherapy in mCRPC patients with HRR deficiency.</p><p><strong>Methods: </strong>This prospective multicenter single-arm two-stage phase II addressed mCRPC men with HRR somatic and/or germline alterations, pretreated with ⩾2 taxane chemotherapy regimens and one androgen receptor pathway inhibitor. Prior PARPi treatment was allowed. Enrolled patients received intravenous carboplatin (AUC5) every 21 days for 6-9 cycles. The primary endpoint was the best response rate according to adapted PCWG3 guidelines: radiological response (RECIST 1.1 criteria) and/or biological response [⩾50% prostate-specific antigen (PSA) decline].</p><p><strong>Results: </strong>A total of 15 out of 16 enrolled patients started carboplatin treatment. Genomic alterations were identified for <i>BRCA2</i> (<i>n</i> = 5), <i>CDK12</i> (<i>n</i> = 3), <i>ATM</i> (<i>n</i> = 3) <i>CHEK2</i> (<i>n</i> = 2), <i>CHEK1</i> (<i>n</i> = 1), and <i>BRCA1</i> (<i>n</i> = 1) genes. Objective response (partial biological response + stable radiological response) was achieved in one patient (6.7%), carrying a BRCA2 mutation and not pre-treated with PARPi; stable disease was observed for five patients (33.5%). Among seven patients (46.7%) with previous PARPi treatment, four patients (57.1%) had a stable disease. The median progression-free and overall survivals were 1.9 [95% confidence interval (95% CI), 1.8-9.5] and 8.6 months (95% CI, 4.3-19.5), respectively. The most common severe (grade 3-4) treatment-related toxicities were thrombocytopenia (66.7%), anemia (66.7%), and nausea (60%). Overall, 8 (53.3%) patients experienced a severe hematological event.</p><p><strong>Conclusion: </strong>The study was prematurely stopped as pre-planned considering the limited activity of carboplatin monotherapy in heavily pre-treated, HHR-deficient mCRPC patients. Larger experience is needed in mCRPC with BRCA alterations.</p><p><strong>Trial registration: </strong>NCT03652493, EudraCT ID number 2017-004764-35.</p>","PeriodicalId":23010,"journal":{"name":"Therapeutic Advances in Urology","volume":null,"pages":null},"PeriodicalIF":2.6000,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903225/pdf/","citationCount":"0","resultStr":"{\"title\":\"Carboplatin in metastatic castration-resistant prostate cancer patients with molecular alterations of the DNA damage repair pathway: the PRO-CARBO phase II trial.\",\"authors\":\"Elodie Coquan, Nicolas Penel, Justine Lequesne, Raphaël Leman, Pernelle Lavaud, Zoé Neviere, Pierre-Emmanuel Brachet, Emeline Meriaux, Aurélien Carnot, Jérémy Boutrois, Marie Castera, Nicolas Goardon, Etienne Muller, Alexandra Leconte, Antoine Thiery-Vuillemin, Bénédicte Clarisse, Florence Joly\",\"doi\":\"10.1177/17562872241229876\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>DNA damage repair genes are altered in 20-35% of metastatic castration-resistant prostate cancer (mCRPC). Poly-ADP (Adénosine Diphosphate)-ribose polymerase inhibitors (PARPi) showed significant activity for these selected tumors, especially with homologous recombination repair (HRR) deficiency. These alterations could also predict platinum sensitivity. Although carboplatin was inconclusive in unselected mCRPC, the literature suggests an anti-tumoral activity in mCRPC with HHR gene alterations. We aimed to assess the efficacy of carboplatin monotherapy in mCRPC patients with HRR deficiency.</p><p><strong>Methods: </strong>This prospective multicenter single-arm two-stage phase II addressed mCRPC men with HRR somatic and/or germline alterations, pretreated with ⩾2 taxane chemotherapy regimens and one androgen receptor pathway inhibitor. Prior PARPi treatment was allowed. Enrolled patients received intravenous carboplatin (AUC5) every 21 days for 6-9 cycles. The primary endpoint was the best response rate according to adapted PCWG3 guidelines: radiological response (RECIST 1.1 criteria) and/or biological response [⩾50% prostate-specific antigen (PSA) decline].</p><p><strong>Results: </strong>A total of 15 out of 16 enrolled patients started carboplatin treatment. Genomic alterations were identified for <i>BRCA2</i> (<i>n</i> = 5), <i>CDK12</i> (<i>n</i> = 3), <i>ATM</i> (<i>n</i> = 3) <i>CHEK2</i> (<i>n</i> = 2), <i>CHEK1</i> (<i>n</i> = 1), and <i>BRCA1</i> (<i>n</i> = 1) genes. Objective response (partial biological response + stable radiological response) was achieved in one patient (6.7%), carrying a BRCA2 mutation and not pre-treated with PARPi; stable disease was observed for five patients (33.5%). Among seven patients (46.7%) with previous PARPi treatment, four patients (57.1%) had a stable disease. The median progression-free and overall survivals were 1.9 [95% confidence interval (95% CI), 1.8-9.5] and 8.6 months (95% CI, 4.3-19.5), respectively. The most common severe (grade 3-4) treatment-related toxicities were thrombocytopenia (66.7%), anemia (66.7%), and nausea (60%). Overall, 8 (53.3%) patients experienced a severe hematological event.</p><p><strong>Conclusion: </strong>The study was prematurely stopped as pre-planned considering the limited activity of carboplatin monotherapy in heavily pre-treated, HHR-deficient mCRPC patients. 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Carboplatin in metastatic castration-resistant prostate cancer patients with molecular alterations of the DNA damage repair pathway: the PRO-CARBO phase II trial.
Introduction: DNA damage repair genes are altered in 20-35% of metastatic castration-resistant prostate cancer (mCRPC). Poly-ADP (Adénosine Diphosphate)-ribose polymerase inhibitors (PARPi) showed significant activity for these selected tumors, especially with homologous recombination repair (HRR) deficiency. These alterations could also predict platinum sensitivity. Although carboplatin was inconclusive in unselected mCRPC, the literature suggests an anti-tumoral activity in mCRPC with HHR gene alterations. We aimed to assess the efficacy of carboplatin monotherapy in mCRPC patients with HRR deficiency.
Methods: This prospective multicenter single-arm two-stage phase II addressed mCRPC men with HRR somatic and/or germline alterations, pretreated with ⩾2 taxane chemotherapy regimens and one androgen receptor pathway inhibitor. Prior PARPi treatment was allowed. Enrolled patients received intravenous carboplatin (AUC5) every 21 days for 6-9 cycles. The primary endpoint was the best response rate according to adapted PCWG3 guidelines: radiological response (RECIST 1.1 criteria) and/or biological response [⩾50% prostate-specific antigen (PSA) decline].
Results: A total of 15 out of 16 enrolled patients started carboplatin treatment. Genomic alterations were identified for BRCA2 (n = 5), CDK12 (n = 3), ATM (n = 3) CHEK2 (n = 2), CHEK1 (n = 1), and BRCA1 (n = 1) genes. Objective response (partial biological response + stable radiological response) was achieved in one patient (6.7%), carrying a BRCA2 mutation and not pre-treated with PARPi; stable disease was observed for five patients (33.5%). Among seven patients (46.7%) with previous PARPi treatment, four patients (57.1%) had a stable disease. The median progression-free and overall survivals were 1.9 [95% confidence interval (95% CI), 1.8-9.5] and 8.6 months (95% CI, 4.3-19.5), respectively. The most common severe (grade 3-4) treatment-related toxicities were thrombocytopenia (66.7%), anemia (66.7%), and nausea (60%). Overall, 8 (53.3%) patients experienced a severe hematological event.
Conclusion: The study was prematurely stopped as pre-planned considering the limited activity of carboplatin monotherapy in heavily pre-treated, HHR-deficient mCRPC patients. Larger experience is needed in mCRPC with BRCA alterations.
Trial registration: NCT03652493, EudraCT ID number 2017-004764-35.
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Therapeutic Advances in Urology delivers the highest quality peer-reviewed articles, reviews, and scholarly comment on pioneering efforts and innovative studies across all areas of urology.
The journal has a strong clinical and pharmacological focus and is aimed at clinicians and researchers in urology, providing a forum in print and online for publishing the highest quality articles in this area. The editors welcome articles of current interest across all areas of urology, including treatment of urological disorders, with a focus on emerging pharmacological therapies.
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