TY - JOUR
T1 - Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer
AU - Swisher, Elizabeth M.
AU - Kristeleit, Rebecca S.
AU - Oza, Amit M.
AU - Tinker, Anna V.
AU - Ray-Coquard, Isabelle
AU - Oaknin, Ana
AU - Coleman, Robert L.
AU - Burris, Howard A.
AU - Aghajanian, Carol
AU - O'Malley, David M.
AU - Leary, Alexandra
AU - Welch, Stephen
AU - Provencher, Diane
AU - Shapiro, Geoffrey I.
AU - Chen, Lee may
AU - Shapira-Frommer, Ronnie
AU - Kaufmann, Scott H.
AU - Goble, Sandra
AU - Maloney, Lara
AU - Kwan, Tanya
AU - Lin, Kevin K.
AU - McNeish, Iain A.
N1 - Funding Information:
Medical writing and editorial support were funded by Clovis Oncology and provided by Nathan Yardley and Frederique H. Evans of Ashfield MedComms, an Ashfield Health Company.
Funding Information:
This research was supported by grants from the Department of Defense Ovarian Cancer Research Program (OC12056, EMS, SHK) and a Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant (SU2C-AACR-DT16?15, EMS, RLC, GIS, SHK). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. The current analyses were also funded by Clovis Oncology, Inc., and were designed by the sponsor.Medical writing and editorial support were funded by Clovis Oncology and provided by Nathan Yardley and Frederique H. Evans of Ashfield MedComms, an Ashfield Health Company.
Funding Information:
This research was supported by grants from the Department of Defense Ovarian Cancer Research Program (OC12056, EMS, SHK) and a Stand Up To Cancer - Ovarian Cancer Research Fund Alliance - National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant (SU2C-AACR-DT16–15, EMS, RLC, GIS, SHK). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. The current analyses were also funded by Clovis Oncology, Inc., and were designed by the sponsor.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021
Y1 - 2021
N2 - Objective: To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. Methods: This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. Results: Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10–0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations. Conclusion: Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.
AB - Objective: To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. Methods: This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. Results: Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10–0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations. Conclusion: Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.
KW - Duration of response
KW - Genomics
KW - Ovarian carcinoma
KW - Rucaparib
KW - Safety
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U2 - 10.1016/j.ygyno.2021.08.030
DO - 10.1016/j.ygyno.2021.08.030
M3 - Article
C2 - 34602290
AN - SCOPUS:85116084230
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
ER -