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Impact of homologous recombination status and responses with veliparib combined with first-line chemotherapy in ovarian cancer in the Phase 3 VELIA/GOG-3005 study

Open AccessPublished:December 11, 2021DOI:https://doi.org/10.1016/j.ygyno.2021.12.003

      Highlights

      • The VELIA trial assessed the PARPi veliparib, combined with frontline chemotherapy and continued as maintenance monotherapy.
      • Within the BRCA wild type population, survival outcomes were improved regardless of homologous recombination status.
      • During chemotherapy, radiographic and CA-125 responses were numerically higher with veliparib vs control in all subgroups.
      • PARPi could benefit a broader patient population than those currently eligible based on prior Phase 3 trials.

      Abstract

      Objective

      In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy.

      Methods

      Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks.

      Results

      Of 1140 patients randomized, 742 had BRCA wild type (BRCAwt) tumors (HRP, n = 373; HRD/BRCAwt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCAwt populations (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval [CI] 0.53–1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56–1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCAwt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control.

      Conclusions

      These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials.

      Graphical abstract

      Keywords

      1. Introduction

      Poly (ADP-ribose) polymerase (PARP) enzymes facilitate the repair of deoxyribonucleic acid (DNA) damage [
      • Ame J.C.
      • Spenlehauer C.
      • de Murcia G.
      The PARP superfamily.
      ,
      • Otto H.
      • Reche P.A.
      • Bazan F.
      • Dittmar K.
      • Haag F.
      • Koch-Nolte F.
      In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (pARTs).
      ]. Cancers with defects in genes involved in homologous recombination repair, such as the breast cancer susceptibility genes BRCA1 and BRCA2 (BRCA), are particularly sensitive to PARP inhibition [
      • Farmer H.
      • McCabe N.
      • Lord C.J.
      • Tutt A.N.
      • Johnson D.A.
      • Richardson T.B.
      • et al.
      Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
      ,
      • Jones P.
      • Wilcoxen K.
      • Rowley M.
      • Toniatti C.
      Niraparib: a poly(ADP-ribose) polymerase (PARP) inhibitor for the treatment of tumors with defective homologous recombination.
      ] reflecting reliance of these cancer cells on PARP-mediated replication fork stabilization and alternative end-joining in the absence of homologous recombination. Defining these and other categories of homologous recombination deficiency (HRD) or proficiency (HRP) beyond loss of BRCA function could expand utilization of PARP inhibitors (PARPi) to cancers with related molecular defects. Beyond BRCA mutations, only a few HRD biomarkers have been prospectively tested in PARPi trials and their correlation with PARPi sensitivity has varied across trial design and cancer type [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • DePont Christensen R.
      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer.
      ,
      • Telli M.L.
      • Timms K.M.
      • Reid J.
      • Hennessy B.
      • Mills G.B.
      • Jensen K.C.
      • et al.
      Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer.
      ].
      Veliparib is an oral PARP-1/PARP-2 inhibitor that has demonstrated activity as a monotherapy in patients with ovarian carcinoma associated with germline BRCA mutations [
      • Coleman R.L.
      • Sill M.W.
      • Bell-McGuinn K.
      • Aghajanian C.
      • Gray H.J.
      • Tewari K.S.
      • et al.
      A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - an NRG oncology/gynecologic oncology group study.
      ,
      • Steffensen K.D.
      • Adimi P.
      • Jakobsen A.
      Veliparib monotherapy to patients with BRCA germ line mutation and platinum-resistant or partially platinum-sensitive relapse of epithelial ovarian cancer: a phase I/II study.
      ]. Preclinical studies have shown that PARP inhibition enhances sensitivity of neoplastic cells to DNA-damaging agents [
      • Cheng H.
      • Zhang Z.
      • Borczuk A.
      • Powell C.A.
      • Balajee A.S.
      • Lieberman H.B.
      • et al.
      PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells.
      ,
      • Donawho C.K.
      • Luo Y.
      • Luo Y.
      • Penning T.D.
      • Bauch J.L.
      • Bouska J.J.
      • et al.
      ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.
      ,
      • Hastak K.
      • Alli E.
      • Ford J.M.
      Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin.
      ,
      • Michels J.
      • Vitale I.
      • Senovilla L.
      • Enot D.P.
      • Garcia P.
      • Lissa D.
      • et al.
      Synergistic Interaction Between Cisplatin and PARP Inhibitors in Non-small Cell Lung Cancer.
      ,
      • Yasukawa M.
      • Fujihara H.
      • Fujimori H.
      • Kawaguchi K.
      • Yamada H.
      • Nakayama R.
      • et al.
      Synergetic effects of PARP inhibitor AZD2281 and cisplatin in oral squamous cell carcinoma in vitro and in vivo.
      ]. Combining chemotherapy with a PARPi might, therefore, provide therapeutic benefit and enhance antitumor activity beyond cancers with HRD. The VELIA study (NCT02470585) was an international, placebo-controlled, three-arm Phase 3 study that assessed the efficacy of veliparib when added to first-line chemotherapy with or without continued veliparib maintenance (veliparib-throughout and veliparib-combination only) in patients with previously untreated Stage III or IV high-grade serous ovarian, peritoneal, or fallopian tube carcinoma (HGSC) [
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • Swisher E.M.
      • Steffensen K.D.
      • Friedlander M.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ]. The veliparib-throughout regimen led to significantly longer progression-free survival (PFS) compared with chemotherapy alone, but no improvement in PFS was observed with chemotherapy plus veliparib followed by placebo maintenance [
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • Swisher E.M.
      • Steffensen K.D.
      • Friedlander M.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ]. The PFS benefit with veliparib-throughout was seen in each of the primary analytical cohorts: 1) patients with germline or somatic BRCA mutations; 2) patients with HRD, including BRCA mutated (BRCAm) cases; and 3) intention-to-treat (ITT) population [
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • Swisher E.M.
      • Steffensen K.D.
      • Friedlander M.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ]. Exploratory analyses in the HRP population showed effects on PFS that were smaller, but directionally consistent with those of the primary analysis (hazard ratio 0.81, 95% CI 0.60 to 1.09) [
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • Swisher E.M.
      • Steffensen K.D.
      • Friedlander M.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ].
      Prior studies with other PARPi, as frontline maintenance post chemotherapy selectively enrolled patients with a clinical response to platinum-based chemotherapy, BRCA mutations, or both [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • DePont Christensen R.
      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Coleman R.L.
      • Oza A.M.
      • Lorusso D.
      • Aghajanian C.
      • Oaknin A.
      • Dean A.
      • et al.
      Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Moore K.
      • Colombo N.
      • Scambia G.
      • Kim B.G.
      • Oaknin A.
      • Friedlander M.
      • et al.
      Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.
      ]. In contrast, VELIA enrolled patients at diagnosis and did not select for patients with platinum-sensitive disease or specific biomarkers [
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • Swisher E.M.
      • Steffensen K.D.
      • Friedlander M.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ]. VELIA, therefore, provides a unique opportunity to investigate PARP-inhibition effects on a broader patient population and the opportunity to assess the impact of combining PARP inhibition with chemotherapy.
      To better understand how to utilize this unique regimen to treat newly diagnosed ovarian cancer, we performed an exploratory analysis with two goals: first, to evaluate the contribution of veliparib to first-line chemotherapy (and maintenance) in BRCA wild type (BRCAwt) cancers with various levels of genomic instability as assessed using the Myriad myChoice® CDx assay (Myriad Genetics, Inc., Salt Lake City, UT); and second, to explore whether the addition of veliparib to the chemotherapy phase impacted treatment response. As the number of early (during chemotherapy) PFS events was small in VELIA, analyses of PFS precluded a meaningful comparison between those who only received veliparib with chemotherapy (and not as maintenance) versus chemotherapy alone. Therefore, we conducted analyses exploring the added benefit of veliparib using potentially more sensitive measures (cancer antigen 125 [CA-125] and radiographic responses) during the first six cycles of treatment.

      2. Materials and methods

      2.1 Study design

      Full details of the study design, inclusion and exclusion criteria, treatment, and endpoints have been previously published [
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • Swisher E.M.
      • Steffensen K.D.
      • Friedlander M.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ]. Women aged ≥18 years with a diagnosis of HGSC were randomized 1:1:1 to receive either carboplatin/paclitaxel (C/P) plus placebo, followed by placebo maintenance (control arm); C/P plus veliparib, followed by placebo maintenance (veliparib-combination–only arm); or C/P plus veliparib, followed by veliparib maintenance (veliparib-throughout arm). Stratification factors for randomization have been described previously, and included timing of surgery received and residual disease status after primary surgery [
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • Swisher E.M.
      • Steffensen K.D.
      • Friedlander M.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ]. HRD status (independent of BRCA status) was not a prospective stratification factor.
      The study protocol was approved by all relevant institutional review boards prior to study initiation. The trial was conducted according to International Conference on Harmonisation Good Clinical Practice guidelines, regulations governing clinical study conduct, and the Declaration of Helsinki. All participants provided written informed consent.

      2.2 HRD assessment

      Homologous recombination status was assessed using the Myriad myChoice CDx assay, which combines BRCA tumor mutation sequencing and assessment of three measures of genomic instability: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions [
      • Telli M.L.
      • Timms K.M.
      • Reid J.
      • Hennessy B.
      • Mills G.B.
      • Jensen K.C.
      • et al.
      Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer.
      ,
      • US Food & Drug Administration
      Myriad myChoice® CDx Summary of Safety and Effectiveness Data.
      ]. These three measures are combined into a genomic instability score (GIS). HRD was defined as GIS ≥33 or the presence of deleterious germline or somatic BRCA mutation. HRP was defined as GIS <33 and the absence of a detectable BRCA mutation, consistent with previous analyses [
      • Hodgson D.R.
      • Dougherty B.A.
      • Lai Z.
      • Fielding A.
      • Grinsted L.
      • Spencer S.
      • et al.
      Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.
      ].
      BRCA mutation status was evaluated using the Myriad BRACAnalysis CDx® or myChoice CDx assay for blood (germline) and tissue (somatic and germline) mutations, respectively.

      2.3 PFS assessment

      The data cutoff for this analysis was May 3, 2019. PFS was investigator-assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The current exploratory analysis evaluated PFS in the veliparib-throughout arm and the control arm, in patients with confirmed BRCAwt (wild type) with and without HRD (HRD/BRCAwt and HRP, respectively), for whom a GIS could be obtained (Supplementary Fig. S1).
      PFS was also analyzed in the veliparib-throughout, veliparib-combination only, and control arms, in patients with stable disease (SD) following combination treatment, regardless of BRCA status (Supplementary Fig. S1). The analysis of progression-free survival (PFS) in patients with SD at the end of the combination phase included BRCAm (mutation) and BRCAwt patients with measurable disease assessed by RECIST v1.1 as well as patients with nonmeasurable disease. In patients with nonmeasurable disease, overall response was categorized as complete response (CR), progressive disease (PD), non-CR/non-PD, or not evaluable. Patients undergoing interval surgery had a tumor baseline reassessment after surgery; therefore, response was considered for 3 cycles. PFS since randomization was compared between all 3 treatment arms.

      2.4 CA-125 response endpoints and assessments

      CA-125 levels were measured as a marker of response to therapy [
      • Bottoni P.
      • Scatena R.
      The role of CA 125 as tumor marker: biochemical and clinical aspects.
      ] at baseline and Day 1 of each treatment cycle during the combination phase (Cycles 1–6) using standard methodology at local laboratories. CA-125 response was defined as ≥90% reduction from baseline, in line with previously published studies [
      • Mahdi H.
      • Maurer K.A.
      • Nutter B.
      • Rose P.G.
      The impact of percent reduction in CA-125 levels on prediction of the extent of interval cytoreduction and outcome in patients with advanced-stage cancer of mullerian origin treated with neoadjuvant chemotherapy.
      ,
      • Steiger J.H.
      Structural model evaluation and modification: an interval estimation approach.
      ,
      • Rustin G.J.
      • Vergote I.
      • Eisenhauer E.
      • Pujade-Lauraine E.
      • Quinn M.
      • Thigpen T.
      • et al.
      Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological cancer Intergroup (GCIG).
      ]. A confirmatory value was not required. CA-125 response was calculated in both BRCAm and BRCAwt subgroups using the change in CA-125 levels from baseline to each analysis timepoint. This includes patients with interval cytoreductive surgery (Supplementary Fig. S1).

      2.5 Radiographic response endpoints and assessments

      Radiographic response during treatment Cycles 1–6 was assessed at baseline and then every 9 weeks in all patients. Imaging scans were reviewed by the investigator. Objective response rate (ORR; CR + partial response [PR]) at the end of the combination phase was calculated per RECIST v1.1 only for patients who had measurable residual disease following primary cytoreductive surgery, within the whole population and in subgroups according to BRCA mutation and HRD status. Patients who underwent interval debulking surgery were not included because they were re-baselined at the start of Cycle 4 and generally did not have residual disease after surgery (Supplementary Fig. S1). The end of the combination phase was defined as 30 days after the last dose of carboplatin or paclitaxel, and the last postbaseline tumor assessment within this window was used to determine response.

      2.6 Statistical analysis

      CIs for response rates were calculated using the normal approximation to the binomial distribution. PFS was estimated using the Kaplan−Meier method. Stratified Cox proportional-hazards models were used to estimate hazard ratios and 95% CIs, and treatment arms were compared via stratified log-rank tests. For analysis of PFS by HRD status, stratification factors were International Federation of Gynecology and Obstetrics stage and residual disease status (no visible residual disease vs any [>1 cm] residual disease). Hazard ratios and 95% CIs for the veliparib-throughout versus control arms were calculated for all GIS using generalized additive model with Cox proportional hazards. The analysis of PFS in patients with SD following combination treatment was stratified by residual disease, stage of disease, choice of paclitaxel dosing regimen, and BRCA status. This was a post-hoc subgroup analysis and is potentially biased. Formal hypothesis testing was not performed.
      CA-125 response and radiographic responses were analyzed for the combination phase. During this time, treatment in the veliparib-containing arms was identical; therefore, these arms were pooled for response analysis. The number and percentage of patients having each type of response were summarized for the control arm and for both veliparib arms combined. A proportion test was used to compute the one-sided P-value comparing the ratio of patients with a CA-125 response in the treatment arm with respect to the control arm. No formal comparisons were made for ORR. All analyses were exploratory in nature; statistics are therefore descriptive only.

      3. Results

      3.1 Patients

      A total of 1140 patients were randomized in the VELIA study; baseline demographics and clinical characteristics were broadly balanced between treatment arms and have been previously published, together with PFS in BRCAm and HRD cohorts, as well as the whole (entire) population [
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • Swisher E.M.
      • Steffensen K.D.
      • Friedlander M.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ]. The primary study endpoints evaluated PFS between the veliparib-throughout and control arms.

      3.2 Correlation of PFS and GIS in biomarker-defined subgroups within the BRCAwt population

      BRCAwt patients (N = 742) were grouped according to tumor HRD status: 373 patients had HRP (low GIS, <33) tumors and 329 patients had HRD/BRCAwt (high GIS, ≥33) tumors; there were 40 patients with unknown GIS (Supplementary Fig. S1). Baseline demographic and clinical characteristics for the HRP and HRD/BRCAwt subgroups are listed in Table S1.
      Median PFS was compared between the veliparib-throughout arm and the control arm (as per the primary endpoint analysis) in both HRD/BRCAwt and HRP subgroups (Fig. 1). Overall, median PFS was longer in the HRD/BRCAwt group compared with the HRP subgroup, but HRs between the veliparib-throughout and control arms were similar for both groups (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; HRP: 15.0 vs 11.5 months; hazard ratio 0.765, with veliparib-throughout vs control, respectively; Fig. 1A, Supplementary Fig. S2), suggesting benefits of veliparib treatment were similar in both subgroups.
      Fig. 1
      Fig. 1(A) Kaplan−Meier curves of PFS in HRP and HRD/BRCAwt and patient subgroups. (B) PFS benefit in HRP and HRD/BRCAwt patient subgroups.
      The black line represents hazard ratio and grey shading indicates 95% CI. Abbreviations: BRCAwt, BRCA wild type; CI; confidence interval; GIS, genomic instability score; HRD, homologous recombinant deficient; HR, homologous recombination; HRP, homologous recombinant proficient; PFS, progression-free survival.
      Evaluation of mPFS HRs between the primary study arms across a continuum of GIS in the BRCAwt population revealed similar veliparib treatment effect across all GIS, including HGSC with high GIS as well as those with very low GIS (Fig. 1B). Moving the GIS cutoff from 33 to 42, a GIS cutoff used in other PARPi trials, did not change this observation.

      3.3 Veliparib in combination with chemotherapy: CA-125 response analysis

      The main CA-125 response analysis included all patients (BRCAm and BRCAwt) with evaluable CA-125 measurements and pooled data from patients in the veliparib-containing arms because they received the same treatment for the first 6 cycles. Table 1 shows the baseline characteristics for the pooled veliparib-containing (N = 765) and control arms (N = 375), including 213 and 107 patients in each arm, respectively, who received interval surgery; molecular characteristics were balanced, and CA-125 was elevated (according to local laboratory definitions) at baseline in the majority of patients.
      Table 1Key patient characteristics in the veliparib-containing pooled arms and control arm of the VELIA study (CA-125 and radiographic response analysis).
      CharacteristicVeliparib-containing arms (pooled) (n = 765)Control arm (n = 375)
      Age, median (range), years62 (22–88)62 (33–86)
      Age distribution, n (%)
       <65 years454 (59.3)233 (62.1)
       ≥65 years311 (40.7)142 (37.9)
      Geographic region, n (%)
       North America528 (69.0)266 (70.9)
       Japan55 (7.2)23 (6.1)
       Rest of world182 (23.8)86 (22.9)
      ECOG status, n (%)
       0434 (57.6)226 (60.9)
       ≥1319 (42.4)145 (39.1)
       Unknown124
      Stage of disease, n (%)
      Status unknown for 1 patient in each arm.
       Stage III583 (76.3)292 (78.1)
       Stage IV181 (23.7)82 (21.9)
      Surgery received,
      68% of all primary surgeries were gross resection.
      70% of all interval surgeries were gross resection.
      n (%)
       Primary514 (67.2)250 (66.7)
       Interval213 (27.8)107 (28.5)
       None38 (5.0)18 (4.8)
      Residual disease after primary surgery, n/N (%)
       No residual disease242/514 (47.1)116/250 (46.4)
       Microscopic residual disease only100/514 (19.5)58/250 (23.2)
       Any macroscopic residual disease172/514 (33.5)76/250 (30.4)
      Residual disease after interval surgery, n/N (%)
       No residual disease91/206 (44.2)50/103 (48.5)
       Microscopic residual disease only54/206 (26.2)22/103 (21.4)
       Any macroscopic residual disease61/206 (29.6)31/103 (30.1)
       Unknown74
      Biomarker status,
      BRCA status unknown for 71 patients (veliparib pooled) and 29 patients (control).
      HRD status unknown for 97 patients (veliparib pooled) and 44 patients (control).
      n (%)
      BRCAm206 (29.7)92 (26.6)
      BRCAwt (includes HRD and HRP)488 (70.3)254 (73.4)
       HRD (includes BRCAm and BRCAwt)420 (62.9)207 (62.5)
       HRD/BRCAwt214 (32.0)115 (34.7)
       HRP248 (37.1)124 (37.5)
      CA-125 status, n (%)
       Baseline CA-125 > ULN
      All evaluable, status unknown for 12 patients (veliparib pooled) and 6 patients (control).
      642 (85.3)316 (85.6)
      Abbreviations: CA-125, cancer antigen 125; BRCAm, BRCA mutation; BRCAwt, BRCA wild type; ECOG, Eastern Cooperative Oncology Group; HRD, homologous recombination deficient; HRP, homologous recombination proficient; ULN, upper limit of normal.
      All percentages are calculated on nonmissing values.
      a Status unknown for 1 patient in each arm.
      b 68% of all primary surgeries were gross resection.
      c 70% of all interval surgeries were gross resection.
      d BRCA status unknown for 71 patients (veliparib pooled) and 29 patients (control).
      e HRD status unknown for 97 patients (veliparib pooled) and 44 patients (control).
      f All evaluable, status unknown for 12 patients (veliparib pooled) and 6 patients (control).
      By Day 1 of Cycle 3 in the combination phase, the proportion of patients with a CA-125 response defined as ≥90% reduction (regardless of surgery type) was higher in the pooled veliparib arm relative to the control arm (34% vs 23% of patients, respectively; P = 0.0004; Supplementary Fig. S3A). CA-125 response rates were similar between the pooled veliparib and control arms for the remainder of the combination phase (56% vs 51% on Day 1 of Cycle 7; P = 0.179). For the subgroup of patients undergoing neoadjuvant chemotherapy, CA-125 responses up to interval surgery (Day 1 of Cycle 3) were 51% (95/187) and 37% (37/100) in the pooled veliparib and control arms, respectively (P = 0.017) (Fig. 2A ).
      Fig. 2
      Fig. 2CA-125 response during the combination phase in (A) BRCAm and BRCAwt patients receiving interval debulking surgery, and in (B) BRCAm and (C) BRCAwt subgroups regardless of surgery type. Abbreviations: BRCAm, BRCA mutated; BRCAwt, BRCA wild type; CA-125, cancer antigen 125.
      *P < 0.05. CA-125 was measured on Day 1 of each cycle, thereby reflecting the previous cycle.
      CA-125 responses in biomarker-defined subgroups according to BRCA mutation status and HRD status are shown in Fig. 2 and Supplementary Fig. S3. The proportion of patients achieving CA-125 responses was generally higher in the pooled veliparib arms compared with the control arm. Of note, this difference was most evident at Cycle 3 in the BRCAwt and HRP subgroups (pooled veliparib vs control arm: 31% vs 22% and 28% vs 14%, respectively; Figs. 2C and S3D) as compared with more similar proportions in the biomarker-selected subgroups, i.e., those with HRD and BRCAm tumors (pooled veliparib vs control arm: 35% vs 30% and 36% vs 27%, respectively; Figs. S3B and 2B).

      3.4 Veliparib in combination with chemotherapy: Radiographic response analysis

      Baseline characteristics for patients with measurable disease after primary surgery (n = 290) were generally similar to the overall population and between treatment arms (Table S2; Table 1). At the end of the combination phase, CRs were seen in 24% (95% CI 18.4 to 30.4) of patients in the pooled veliparib arms and 18% (95% CI 10.4 to 26.1) of patients in the control arm in the overall population. Response rates per RECIST v1.1 for each of the biomarker-selected and -unselected subgroups are shown in Fig. 3; ORR in the HRP subgroup was generally lower than in biomarker-positive subgroups and the whole population.
      Fig. 3
      Fig. 3ORR at the end of the combination phase in (A) all patients with primary surgery and measurable disease and in the (B) all HRD, (C) BRCAm, (D) HRD/BRCAwt, and (E) HRP subgroups.
      Abbreviations: BRCAm, BRCA mutated; BRCAwt, BRCA wild type; CR, complete response; HRD, homologous recombination deficient; HRP, homologous recombinant proficient; ORR, objective response rate; PR, partial response

      3.5 PFS in patients with stable disease following combination treatment

      At the end of the combination phase, 28% (n = 104) of patients in the control arm, 23% (n = 89) in the veliparib-combination–only arm, and 21% (n = 82) in the veliparib-throughout arm had SD for those with measurable disease, or non-CR/non-PD for those with only nonmeasurable disease (Fig. S4). These patients are typically not eligible for PARPi maintenance therapy, but were allowed to continue maintenance in this study. Baseline characteristics for these patients are shown in Table S3. Notably, fewer patients in the veliparib combination-only arm have Stage IV disease than in the control and veliparib-throughout arms, and fewer patients in the control arm had a BRCA mutation than in the veliparib arms. A waterfall plot illustrating the change in tumor size from baseline in each arm is shown in Fig. S4A. Median PFS in patients with SD following combination treatment was 13 months for the control arm, 14 months for the veliparib-combination–only arm (hazard ratio 1.03; 95% CI 0.72 to 1.47 vs control), and 16 months for the veliparib-throughout arm (hazard ratio 0.79; 95% CI 0.54 to 1.16 vs control; Fig. S4B). At Month 10, the PFS rate was 83% for the veliparib-throughout arm, 78% in the veliparib-combination–only arm, and 73% in the control arm.

      4. Discussion

      VELIA is the first Phase 3 trial to evaluate PARP inhibition in newly diagnosed patients with advanced HGSC regardless of BRCA status, surgical management, or response to platinum therapy. This distinguishes VELIA from other reported primary maintenance trials in HGSC in that it enrolled a broader patient population. The results of these exploratory analyses of PFS within the BRCAwt population suggest that veliparib provided a similar improvement in PFS compared with placebo regardless of tumor HRD status. Median PFS was also generally longer for patients with BRCAwt/HRD cancers relative to those with HRP cancers, regardless of study arm. Taken together, these data indicate that the GIS may be a prognostic marker of PFS regardless of treatment arm; however, GIS is not a predictive marker of response to veliparib. That GIS is not a predictive marker represents an important finding because patients with HRP cancers may still derive benefit from the veliparib-throughout regimen. A PFS benefit with the veliparib-throughout regimen versus control was observed across a range of GIS, including patients whose cancers had a GIS as low as 0–10. The lack of a difference between the hazard ratios across treatment arms for HRD/BRCAwt and HRP cancers is unique to VELIA, differing from other PARPi maintenance trials of HGSC both in the recurrent and frontline settings [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • DePont Christensen R.
      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Mirza M.R.
      • Monk B.J.
      • Herrstedt J.
      • Oza A.M.
      • Mahner S.
      • Redondo A.
      • et al.
      Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.
      ]. In previous studies of PARPi as maintenance therapy [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • DePont Christensen R.
      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer.
      ], a GIS cutoff of 42 was used. The rationale for using a cutoff of 33 in VELIA was based on findings reported by Hodgson et al., [
      • Hodgson D.R.
      • Dougherty B.A.
      • Lai Z.
      • Fielding A.
      • Grinsted L.
      • Spencer S.
      • et al.
      Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.
      ] wherein the threshold of 33 aimed to exclude patients who were least likely to benefit from PARPi. Because we found no GIS cutoff that separated those in whom a veliparib treatment benefit was not seen (i.e., to define HRD and HRP subgroups), we conclude that using a cutoff of 33 was not responsible for the lack of predictive ability for the test within VELIA.
      To explore whether the addition of veliparib to chemotherapy contributed to eliminating the difference in hazard ratios between HRD and HRP cancers, we used CA-125 as a sensitive measure of tumor regression in BRCAm and BRCAwt cases. CA-125 responses occurred earlier in the veliparib-containing treatment arms compared with the control arm. Likewise, in the neoadjuvant setting a higher proportion of patients in the veliparib arms than in the control arm had CA-125 responses after the first two cycles of chemotherapy (prior to interval debulking surgery). CA-125 responses have been previously associated with improved surgical and response outcomes [
      • Mahdi H.
      • Maurer K.A.
      • Nutter B.
      • Rose P.G.
      The impact of percent reduction in CA-125 levels on prediction of the extent of interval cytoreduction and outcome in patients with advanced-stage cancer of mullerian origin treated with neoadjuvant chemotherapy.
      ]; however, in our analysis the placebo arm caught up in CA-125 response by the end of chemotherapy and the clinical significance of this CA-125 decrease is uncertain.
      Notably, the CA-125 analyses showed a trend toward a higher response rate with the addition of veliparib primarily in HRP cancers, with a smaller benefit seen in the HRD/BRCAwt subgroup. One hypothesis is that HRD cancers are already highly sensitive to platinum-based chemotherapy [
      • Pennington K.P.
      • Walsh T.
      • Harrell M.I.
      • Lee M.K.
      • Pennil C.C.
      • Rendi M.H.
      • et al.
      Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
      ], and their response is not further augmented by adding veliparib, whereas the addition of veliparib produces a more prominent effect in HRP cancers. While higher CA-125 responses have been reported in HRD/BRCAwt HGSC treated with PARPi or chemotherapy [
      • Swisher E.M.
      • Lin K.K.
      • Oza A.M.
      • Scott C.L.
      • Giordano H.
      • Sun J.
      • et al.
      Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial.
      ], VELIA uniquely combined chemotherapy with a PARPi inhibitor. These results provide rationale for further exploration of veliparib in combination with chemotherapy in patients with HRP cancers.
      To corroborate the CA-125 response findings, we assessed radiographic ORR after the chemotherapy combination phase in BRCAm and BRCAwt patients, acknowledging the limitations associated with volumetric analysis and the application only to patients with measurable disease after primary surgery. We demonstrate that during the combination phase, addition of veliparib to chemotherapy led to numerically higher radiographic response rates relative to chemotherapy alone. The higher rates of CR observed across the ITT population support a potential benefit of veliparib added to chemotherapy in higher risk patients with measurable disease after primary cytoreductive surgery. In addition, patients without disease progression at the end of the combined therapy phase were eligible to receive veliparib (or placebo, according to randomization) in the maintenance setting in VELIA; this resulted in an extra 21%–28% of patients in each arm being eligible for maintenance treatment, in contrast to other PARPi maintenance trials.
      It should be noted that these analyses were exploratory in nature and hypothesis-generating; sample sizes also preclude a conclusive interpretation of the data. Furthermore, a lack of PFS difference for the veliparib arm without maintenance calls into question the clinical significance of these findings. However, these findings may explain the similar PFS hazard ratios in VELIA for HRD/BRCAwt and HRP HGSC. The veliparib combination phase may have improved the overall outcomes specifically for the HRP patients, including those who would not have qualified for other PARPi maintenance trials because of inadequate platinum response. Alternative explanations for the different behavior of the HRD biomarker in VELIA relative to other studies include differences in selection criteria between trials, differences in the design of the control arms in the maintenance phase (eg, the PAOLA study used bevacizumab in combination with chemotherapy) [
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • DePont Christensen R.
      • Graybill W.
      • Mirza M.R.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • Perol D.
      • Gonzalez-Martin A.
      • Berger R.
      • et al.
      Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer.
      ], the very low event rate during chemotherapy in general, or variation in the mode of action of different PARPi [
      • Zandarashvili L.
      • Langelier M.F.
      • Velagapudi U.K.
      • Hancock M.A.
      • Steffen J.D.
      • Billur R.
      • et al.
      Structural basis for allosteric PARP-1 retention on DNA breaks.
      ].
      Overall, HRD has some utility in terms of relative risk and prognostic expectations, but its use to inform who to treat or not treat with veliparib is limited.

      5. Conclusion

      Our data demonstrate that the VELIA regimen is effective in various subgroups of HGSC, obviating the question of when and whether to use HRD testing before PARPi maintenance, and potentially broadening the application of PARPi therapy in HGSC that would not have been sufficiently chemo-responsive to qualify for maintenance in other frontline PARPi trials.

      Data sharing statement

      AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
      This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html

      Financial support

      This work was supported by AbbVie . AbbVie participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.

      Disclosures

      Elizabeth M. Swisher: Speaker/advisory role: Ideaya Biosciences.
      Carol Aghajanian: Consulting/advisory role for Tesaro, Eisai/Merck, Mersana Therapeutics, Roche/Genentech, AbbVie, AstraZeneca/Merck, and Merck. Research funding (to institution) from Genentech, AbbVie, Clovis Oncology, and AstraZeneca.
      David M. O'Malley: Consulting and/or advisory role for AstraZeneca, Tesaro/GSK, Immunogen, Ambry, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance Biotherapeutics, Inc., Myriad Genetics, Eisai, Agenus, Tarveda, Merck, SeaGen, Novartis, Mersana, Clovis, Rubis, Elevar. Research funding to institution from AstraZeneca, Tesaro/GSK, Immunogen, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, VentiRx Array Biopharma EMD Serono, Ergomed, Ajinomoto Inc., Ludwig Cancer Research Stemcentrx, Inc., CERULEAN PHARMA, GOG Foundation, NCI, Bristol-Myers Squibb Co, Serono Inc., TRACON Pharmaceuticals, Yale University, New Mexico Cancer Care Alliance, INC Research, Inc., inVentiv Health Clinical, Iovance Biotherapeutics, Inc., PRA Intl, Eisai, Agenus, Merck, GenMab, SeaGen, personal fees from Mersana, Clovis.
      Gini F. Fleming: Research funding to institution from Corcept Therapeutics, AbbVie, Genentech, Tesaro, Sermonix, Syndax, Forty-Seven, Iovance, Syros, Astex, Merck. Research funding and advisory board fees from GSK. Speaker fees from Vaniam Group, Wolters Kluwer. Author fees from Wolters Kluwer.
      Scott H. Kaufmann: Research funding to institution from Eli Lily, Takeda, and Cyteir.
      Douglas A. Levine: Consulting/advisory role for Tesaro/GSK, Merck. Research funding to institution from Merck, Tesaro, Clovis Oncology, Regeneron, Agenus, Takeda, Immunogen, VBL Therapeutics, Genentech, Celsion, Ambry, Splash Pharmaceuticals, Founder of Nirova BioSense, Inc.
      Michael J. Birrer: Advisory role for Clovis, Astra Zeneca, GSK, and Mersana.
      Kathleen N. Moore: Consulting/advisory role for Aravive, Astra Zeneca, AbbVie, Eisai, Elevar, GSK/Tesaro, Genentech/Roche, Immunogen, Myriad, Merck, Mersana, OncXerna, Sorrento, VBL Therapeutics. Research funding from PTC Therapeutics, Lilly, and Merck.
      Mark S. Shahin: Consultant/speaker for GSK/Tesaro, Astra Zeneca, Merck, and Aspira. Consultant for GSK/Tesaro, Astra Zeneca, Merck, and Novocure. Leadership/ fiduciary role for GSK/Tesaro, Astra Zeneca, Merck, and Novocure.
      Michael Friedlander: Consulting/advisory role for Astra Zeneca, Lilly, Takeda, MSD, GSK, Novartis. Research funding to institution from Astra Zeneca, Novartis, Beigene. Steering Committee member, VELIA trial. Speaker fees/honoraria from Astra Zeneca; GSK, and ACT Genomics. Support for attending meetings and/or travel from Astra Zeneca. Data Safety Monitoring Board or Advisory Board for AGIGTG IDSMB.
      Karina Dahl Steffensen: Steering Committee member, VELIA trial.
      Aikou Okamoto: Consulting/advisory role for AstraZeneca, Chugai. Honoraria: from AstraZeneca, MSD, Chugai. Grant/research funding from Kaken, Mochida, Kissei, Pfizer.
      Vasudha Sehgal, Peter J. Ansell, Minh H. Dinh: Employees of AbbVie, may own stocks or shares.
      Michael A. Bookman: Advisory role for Merck Sharp & Dohme, Genetech-Roche, and Seattle Genetics. Protocol Steering Committee member for AbbVie (VELIA, GOG3005) and Aravive. Chair of Data and Safety Monitoring Board for Immunogen.
      Robert L. Coleman: Consulting/advisory role for Clovis Oncology, Genentech/Roche, Esperance, NCCN, AstraZeneca/MedImmune, Genmab, GamaMabs Pharma, OncoMed, Sotio, Oncolytics, GSK, AbbVie. Research funding for AstraZeneca/MedImmune, Esperance, OncoMed, Array, Clovis, Johnson & Johnson, Merck, Roche/Genentech, Abbott/AbbVie.
      All remaining authors have declared no conflicts of interest.

      Acknowledgments

      AbbVie and the authors thank all the trial investigators, the patients who participated in this clinical trial, and Brenden Chen (former AbbVie employee) and Mark Brady (formerly of the NRG Oncology Statistical and Data Center, Roswell Park Cancer Institute) for their contributions to this manuscript. Medical writing support was provided by Laura Fullerton-Batten, PhD, of Fishawack Communications, Inc., funded by AbbVie .

      Appendix A. Supplementary data

      References

        • Ame J.C.
        • Spenlehauer C.
        • de Murcia G.
        The PARP superfamily.
        Bioessays. 2004; 26: 882-893
        • Otto H.
        • Reche P.A.
        • Bazan F.
        • Dittmar K.
        • Haag F.
        • Koch-Nolte F.
        In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (pARTs).
        BMC Genomics. 2005; 6: 139
        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • Tutt A.N.
        • Johnson D.A.
        • Richardson T.B.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Jones P.
        • Wilcoxen K.
        • Rowley M.
        • Toniatti C.
        Niraparib: a poly(ADP-ribose) polymerase (PARP) inhibitor for the treatment of tumors with defective homologous recombination.
        J. Med. Chem. 2015; 58: 3302-3314
        • Gonzalez-Martin A.
        • Pothuri B.
        • Vergote I.
        • DePont Christensen R.
        • Graybill W.
        • Mirza M.R.
        • et al.
        Niraparib in patients with newly diagnosed advanced ovarian cancer.
        N. Engl. J. Med. 2019; 381: 2391-2402
        • Ray-Coquard I.
        • Pautier P.
        • Pignata S.
        • Perol D.
        • Gonzalez-Martin A.
        • Berger R.
        • et al.
        Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer.
        N. Engl. J. Med. 2019; 381: 2416-2428
        • Telli M.L.
        • Timms K.M.
        • Reid J.
        • Hennessy B.
        • Mills G.B.
        • Jensen K.C.
        • et al.
        Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer.
        Clin. Cancer Res. 2016; 22: 3764-3773
        • Coleman R.L.
        • Sill M.W.
        • Bell-McGuinn K.
        • Aghajanian C.
        • Gray H.J.
        • Tewari K.S.
        • et al.
        A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - an NRG oncology/gynecologic oncology group study.
        Gynecol. Oncol. 2015; 137: 386-391
        • Steffensen K.D.
        • Adimi P.
        • Jakobsen A.
        Veliparib monotherapy to patients with BRCA germ line mutation and platinum-resistant or partially platinum-sensitive relapse of epithelial ovarian cancer: a phase I/II study.
        Int. J. Gynecol. Cancer. 2017; 27: 1842-1849
        • Cheng H.
        • Zhang Z.
        • Borczuk A.
        • Powell C.A.
        • Balajee A.S.
        • Lieberman H.B.
        • et al.
        PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells.
        Carcinogenesis. 2013; 34: 739-749
        • Donawho C.K.
        • Luo Y.
        • Luo Y.
        • Penning T.D.
        • Bauch J.L.
        • Bouska J.J.
        • et al.
        ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.
        Clin. Cancer Res. 2007; 13: 2728-2737
        • Hastak K.
        • Alli E.
        • Ford J.M.
        Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin.
        Cancer Res. 2010; 70: 7970-7980
        • Michels J.
        • Vitale I.
        • Senovilla L.
        • Enot D.P.
        • Garcia P.
        • Lissa D.
        • et al.
        Synergistic Interaction Between Cisplatin and PARP Inhibitors in Non-small Cell Lung Cancer.
        12. 2013: 877-883
        • Yasukawa M.
        • Fujihara H.
        • Fujimori H.
        • Kawaguchi K.
        • Yamada H.
        • Nakayama R.
        • et al.
        Synergetic effects of PARP inhibitor AZD2281 and cisplatin in oral squamous cell carcinoma in vitro and in vivo.
        Int. J. Mol. Sci. 2016; 17: 272
        • Coleman R.L.
        • Fleming G.F.
        • Brady M.F.
        • Swisher E.M.
        • Steffensen K.D.
        • Friedlander M.
        • et al.
        Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
        N. Engl. J. Med. 2019; 381: 2403-2415
        • Coleman R.L.
        • Oza A.M.
        • Lorusso D.
        • Aghajanian C.
        • Oaknin A.
        • Dean A.
        • et al.
        Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet. 2017; 390: 1949-1961
        • Moore K.
        • Colombo N.
        • Scambia G.
        • Kim B.G.
        • Oaknin A.
        • Friedlander M.
        • et al.
        Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.
        N. Engl. J. Med. 2018; 379: 2495-2505
        • US Food & Drug Administration
        Myriad myChoice® CDx Summary of Safety and Effectiveness Data.
        2019
        • Hodgson D.R.
        • Dougherty B.A.
        • Lai Z.
        • Fielding A.
        • Grinsted L.
        • Spencer S.
        • et al.
        Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.
        Br. J. Cancer. 2018; 119: 1401-1409
        • Bottoni P.
        • Scatena R.
        The role of CA 125 as tumor marker: biochemical and clinical aspects.
        Adv. Exp. Med. Biol. 2015; 867: 229-244
        • Mahdi H.
        • Maurer K.A.
        • Nutter B.
        • Rose P.G.
        The impact of percent reduction in CA-125 levels on prediction of the extent of interval cytoreduction and outcome in patients with advanced-stage cancer of mullerian origin treated with neoadjuvant chemotherapy.
        Int. J. Gynecol. Cancer. 2015; 25: 823-829
        • Steiger J.H.
        Structural model evaluation and modification: an interval estimation approach.
        Multivar. Behav. Res. 1990; 25: 173-180
        • Rustin G.J.
        • Vergote I.
        • Eisenhauer E.
        • Pujade-Lauraine E.
        • Quinn M.
        • Thigpen T.
        • et al.
        Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological cancer Intergroup (GCIG).
        Int. J. Gynecol. Cancer. 2011; 21: 419-423
        • Mirza M.R.
        • Monk B.J.
        • Herrstedt J.
        • Oza A.M.
        • Mahner S.
        • Redondo A.
        • et al.
        Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.
        N. Engl. J. Med. 2016; 375: 2154-2164
        • Pennington K.P.
        • Walsh T.
        • Harrell M.I.
        • Lee M.K.
        • Pennil C.C.
        • Rendi M.H.
        • et al.
        Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
        Clin. Cancer Res. 2014; 20: 764-775
        • Swisher E.M.
        • Lin K.K.
        • Oza A.M.
        • Scott C.L.
        • Giordano H.
        • Sun J.
        • et al.
        Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2017; 18: 75-87
        • Zandarashvili L.
        • Langelier M.F.
        • Velagapudi U.K.
        • Hancock M.A.
        • Steffen J.D.
        • Billur R.
        • et al.
        Structural basis for allosteric PARP-1 retention on DNA breaks.
        Science. 2020; 368