ORIGINAL RESEARCH Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study)5 J. A. Perez-Fidalgo1*, A. Cortés2, E. Guerra2, Y. García3, M. Iglesias4, U. Bohn Sarmiento5, E. Calvo García6, L. Manso Sánchez7, A. Santaballa8, A. Oaknin9, A. Redondo10, M. J. Rubio11 & A. González-Martín12 1 Department of Medical Oncology, Hospital Clínico Universitario de Valencia, Valencia; 2Department of Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid; 3Department of Medical Oncology, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònoma de Barcelona, Sabadell; 4Department of Medical Oncology, Hospital Son Llatzer, Palma De Mallorca; 5Department of Medical Oncology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas De Gran Canaria; 6Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla; 7Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid; 8Department of Medical Oncology, Hospital Universitari i Politècnic La Fe, Valencia; 9Department of Medical Oncology, Hospital Universitario Vall d’Hebron, Barcelona; 10Department of Medical Oncology, Hospital Universitario La Paz-IdiPAZ, Madrid; 11Department of Medical Oncology, Hospital Universitario Reina Sofia, Córdoba; 12Department of Medical Oncology Department, Clínica Universidad de Navarra, Madrid, Spain Available online xxx Background: There is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status. Patients and methods: Patients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with 4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) þ intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m2 (PLD40) every 28 days, followed by maintenance with olaparib 300 mg b.i.d. until progression or toxicity. The PLD dose was reduced to 30 mg/m2 (PLD30) due to toxicity. The primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS) by RECIST version 1.1. A proportion of 40% 6m-PFS or more was considered of clinical interest. Results: From 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade 3 treatment-related adverse events occurred in 74% of patients, with neutropenia/ anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%). Conclusions: The PLDeolaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m2 is better tolerated in the combination. Key words: platinum-resistant recurrent ovarian cancer, PARP inhibitor, olaparib, pegylated liposomal doxorubicin, BRCA wild-type INTRODUCTION *Correspondence to: Dr Alejandro Pérez-Fidalgo, Department of Medical Oncology, Hospital Clínico Universitario de Valencia, Avenida de Blasco Ibáñez Ovarian cancer remains the seventh most common cancer no17, Valencia 46010, Spain. Tel: þ34-96-386-26-25 among women worldwide, and accounts for 4.4% of the E-mail: japfidalgo@msn.com (J. A. Perez-Fidalgo). entire cancer-related mortality.1 Primary debulking surgery 5 Note: This clinical trial was conducted in compliance with the International and platinum-based chemotherapy remain the standard of Ethical Guidelines for Biomedical Research Involving Human Subjects, Good care, although w70% of patients experience a relapse Clinical Practice guidelines, and the Declaration of Helsinki, 1964, and local laws. The study was granted ethics approval on 26 October 2017 by the Hospital within the subsequent 3 years.2 Neoadjuvant chemotherapy Clínico y Universitario de Valencia ethics committee (ref. no. 2017-no330). prior to debulking surgery is an alternative option for 2059-7029/© 2021 The Authors. Published by Elsevier Ltd on behalf of Eu- selected patients; nevertheless, there is a lack of consensus ropean Society for Medical Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). about who are the best candidates for this strategy.3 The Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100212 1 ESMO Open J. A. Perez-Fidalgo et al. treatment of ovarian cancer when platinum-based regimens cytotoxic effect, could be of interest in the PROC setting.16 are not a therapeutic option remains challenging.4 The combination of olaparib with pegylated liposomal Inhibition of polyadenosine 50 -diphosphoribose poly- doxorubicin (PLD), an approved treatment for patients with merization (PARP) has emerged as a novel treatment option ovarian cancer that failed to respond to platinum chemo- for tumors with deficiencies in the DNA repair machinery, therapies,17,18 was highly effective in inhibiting ovarian such as those with BRCA1/2 mutations.5 However clinical cancer cell growth in cell-based preclinical models.19 data showed an impact of PARP inhibitors (PARPis) also in Moreover, a phase I trial preliminarily assessed the effi- BRCA1/2 wild-type (wt) patients. cacy of the combination of olaparib and PLD, concluding Recent evidence in ovarian cancer confirmed an important that either continuous or intermittent administration of impact of the use of PARPi for maintenance treatment after olaparib 400 mg b.i.d. (biduum) and PLD 40 mg/m2 was platinum-based chemotherapy in the first-line setting,6-9 effective and tolerable.20 No major pharmacokinetic inter- leading to the approval by the Food and Drug Administra- ference was observed between olaparib and PLD, and the tion (FDA) and the European Medicines Agency (EMA) of study reached an overall ORR of 33%:50% for the ovarian olaparib in BRCA-mutated patients in 2018 and of niraparib cancer subgroup and 25% for the 12 patients with PROC.20 and olaparib in combination with bevacizumab in 2020. We hypothesized that the combination of olaparib with In platinum-sensitive relapsed patients, three phase III the DNA-damaging agent PLD will increase the treatment trials confirmed the efficacy of PARPi as maintenance responses, and will achieve higher efficacy in PROC, even in treatment in patients with previous platinum-sensitive patients who lack the BRCA1/2 mutation. The ROLANDO recurrence. SOLO-2 was a randomized clinical trial in clinical trial aimed to evaluate the efficacy of the olaparibe which BRCA1/2-mutated high-grade serous ovarian cancer PLD combination therapy in patients with platinum- (HGSOC) patients were treated with olaparib in mainte- resistant high-grade serous or endometrioid ovarian nance after platinum-containing chemotherapy, prolonging cancer regardless of their BRCA status. progression-free survival (PFS) and overall survival (OS) when compared with the placebo arm.10 The Phase III PATIENTS AND METHODS randomized SOLO3 trial corroborated a significant and clinically relevant improvement in overall response rate Trial design and treatment (ORR) and PFS in BRCA-mutated platinum-sensitive relapsed The GEICO-1601/ROLANDO study is a single-arm, open-la- patients treated with olaparib monotherapy when bel, nonrandomized, multicenter phase II clinical trial to compared with regular nonplatinum chemotherapy regi- assess the efficacy and safety of the olaparib plus PLD mens.11 In addition, the toxicity was manageable, with the combination in PROC. The clinical trial was conducted in most common adverse events (AEs) being low-grade fa- eight centers in Spain from December 2017 to November tigue, nausea, and vomiting.10,11 2020. This study was sponsored by Grupo Español de In the platinum-resistant ovarian cancer (PROC) setting, Investigación en Cáncer de Ovario (GEICO) and conducted in previous trials of olaparib showed evidence of activity in accordance with the Declaration of Helsinki, the Interna- BRCA-mutated patients. An expansion cohort of a phase I tional Council for Harmonisation of Technical Requirements trial with single-agent olaparib in BRCA-mutated PROC pa- for Pharmaceuticals for Human Use Good Clinical Practices, tients showed an ORR of 33.5% with a clinical benefit rate and the applicable local regulations. The study was of 45.8%, but with no responses in the subgroup of approved by the competent authority in Spain [Agencia platinum-refractory patients.12 In a phase II trial also in Española de Medicamentos y Productos Sanitarios (AEMPS)] BRCA-mutated patients treated with olaparib (single agent) and the Independent Ethics Committee of Hospital Clínico y the ORR was 31.1% among the 193 PROC patients Universitario de Valencia. All patients provided written included.13 informed consent before participation. Conversely, single-agent PARPi activity in PROC with The study comprised two treatment phases. During the BRCA-wt is underwhelming. Two prior studies evaluating induction phase, the enrolled patients received PLD 40 mg/ the activity of olaparib enrolled PROC BRCA-wt patients. The m2 intravenously every 28 days and olaparib tablets 300 mg study by Gelmon et al.14 included 91 patients (65 ovarian b.i.d. orally for up to six cycles. During the maintenance cancer patients) of whom 17 were BRCA mutated (BRCA- phase, patients were treated with olaparib 300 mg orally mut) and 47 were BRCA-wt patients. The ORR to olaparib b.i.d. as monotherapy until progression or the development was 41% for BRCA-mut and 24% for BRCA-wt patients. of unacceptable toxicity. However when both adverse conditions (BRCA-wt status After the inclusion of 17 patients, the continuous safety and PROC relapse) were considered, ORR was an under- monitoring by the study scientific committee led to an whelming 4%. The CLIO trial was a randomized phase II amendment to the protocol to reduce the PLD dose to study of olaparib versus physician’s choice chemotherapy in 30 mg/m2 due to an unexpected high rate of AEs. PROC patients. ORR in the olaparib arm in this study was 38% in BRCA-mut but only 13% in BRCA-wt patients.15 In this context of lackluster activity, a combination Eligibility criteria for participants strategy of olaparib with chemotherapy in order to block Eligible patients were adults (age 18 years) who were base excision repair, and consequently potentiate the diagnosed with high-grade serous or endometrioid ovarian 2 https://doi.org/10.1016/j.esmoop.2021.100212 Volume 6 - Issue 4 - 2021 J. A. Perez-Fidalgo et al. ESMO Open cancer with platinum-resistant relapse (defined as the physical examinations. The AEs and laboratory values were recurrence which occurred between 28 days and 6 months graded according to the National Cancer Institute Common after the last platinum-containing course). Primary PROC Terminology Criteria for Adverse Events (CTCAE), version was allowed only in BRCA-mut patients. The BRCA muta- 4.03. All patients were followed up until recovery from any tional status was not compulsory at the baseline and could treatment-related AE (TRAE). be determined after patient inclusion. The key inclusion criteria were (i) at least one previous platinum-sensitive Statistical methods and sample size calculation relapse in non-BRCA-mutated patients (no primary plat- inum resistance in BRCA-wt or unknown patients was The sample size was determined on the basis of an exact allowed); (ii) between one and four previous treatment single-stage phase II design. Considering a null hypothesis of lines (up to five in BRCA-mutated patients); (iii) adminis- 15% and a futility threshold of 40% for the 6m-PFS, with tration of at least four cycles of chemotherapy in the 90% power and a 2-sided 0.05 significance level, the study platinum-resistant relapse; (iv) measurable disease as required 27 evaluable patients to be included, and at least 8 defined by RECIST version 1.1 criteria; (v) normal left ven- patients without progression of disease after 6 months to tricular ejection fraction; (vi) an Eastern Cooperative reject the null hypothesis. Factoring in a dropout rate of Oncology Group (ECOG) performance status 2; (vii) life 20%, a total of 32 patients were needed to obtain the expectancy 16 weeks; and (viii) appropriate hematologic, required evaluable number of patients. liver, and renal function. Patients were excluded if they had Summary tables (descriptive statistics and frequency ta- previously received PARPi treatment, had second primary bles) were provided for all baseline, efficacy, and safety malignancies in the last 5 years other than noncutaneous variables, as appropriate. Continuous variables were sum- melanoma, or were immunocompromised. Previous treat- marized with descriptive statistics (mean, standard devia- ment with PLD was allowed as long as the last course was tion, range, and median). Frequency counts and the given >6 months before treatment initiation. percentage of participants within each category were pro- vided for categorical data. The response percentages were Objectives estimated using 95% confidence intervals (CI) or full range intervals. The time-to-event endpoints were estimated us- The primary objective was to assess olaparib efficacy in ing the KaplaneMeier method and Cox regression analysis combination with PLD in platinum-resistance high-grade to obtain hazard ratios and CIs. Patients without docu- serous or endometrioid ovarian cancer patients regardless mented progression or death at the time of the analysis of BRCA status. Secondary objectives included safety and were censored at the last date of tumor evaluation. All tolerability of the treatment schedule. statistical analyses were performed with R (version 3.6.3 [2020-02-29] “Holding the Windsock,” The R Foundation for Efficacy analysis Statistical Computing, Vienna, Austria) and SPSS (IBM SPSS The primary efficacy endpoint was the 6-month PFS (6m- Statistics Version 26, Armonk, NY). Figures and tables were PFS) rate. generated using RStudio (Version 1.2.5033 2009-2019 The secondary efficacy endpoints were ORR and disease RStudio, Inc., Boston, MA, USA). All statistical tests were control rate (DCR) according to RECIST version 1.1 criteria, considered two-tailed, and results with P < 0.05 were CA-125 response, PFS, OS, and the patient’s quality of life considered significant. (QoL). PFS was defined as the time between the initiation of RESULTS treatment and the first objective evidence of radiological progression on computed tomography (CT) scanning or Patient characteristics death from any cause. OS was defined as the time from the Between December 2017 and November 2020, 35 patients initiation of treatment to the date of death from any cause. were screened and 31 (ITT analysis set) received at least Efficacy was evaluated in all patients who received at one cycle of treatment. Among these patients, 20 complied least a single dose of study medication [the intention-to- with all protocol procedures and received at least two cy- treat (ITT) analysis set] and in all patients who fulfilled all cles of study treatment and were included in the PP analysis of the protocol specifications in terms of eligibility, in- set (Figure 1). The most frequent reasons for exclusion from terventions, and outcome assessment and received at least the PP analysis set were lack of previous platinum-sensitive two cycles of olaparib þ PLD [per-protocol (PP) analysis relapse in non-BRCA-mutated patients (n ¼ 4), no previous set]. platinum-resistance treatment (n ¼ 3), or patients who had premature treatment discontinuation (less than two cycles Safety analysis of olaparibePLD; n ¼ 3). Secondary endpoints include safety and tolerability of ola- In the ITT set, the median age was 58 years; deleterious parib in combination with PLD and as monotherapy evalu- BRCA1/2 mutations were found in five patients (16%), ated in all patients who received at least one dose of whereas 77% were BRCA-wt and 7% had unknown muta- olaparib or PLD (ITT analysis set) based on the assessment tional status. The ECOG status was 1 in 68% of patients and of AEs, clinical laboratory test results, vital signs, and 87% had HGSOC (Table 1). The median number of previous Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100212 3 ESMO Open J. A. Perez-Fidalgo et al. 35 patients enrolled 3 screening failure 1 died before receiving treatment 31 patients complied with eligibility criteria and received at least one dose of Olaparib + PLD 4 no previous platinum-sensitive treatment 2 no previous platinum-resistant treatment 2 no two cycles of PLD + Olaparib received 1 no measurable target lesions at baseline 1 previous platinum-resistant treatment only 3 cycles 1 refractory 20 patients complied with all protocol procedures 31 included in the ITT analysis set 20 included in the PP analysis set Figure 1. CONSORT patient flowchart. ITT, intention to treat; PLD, pegylated liposomal doxorubicin; PP, per protocol was 5 (range: 2-6) and the median duration of olaparib Table 1. Patient characteristics treatment was 5 months (range 1.4-19.5 months). ITT (n [ 31) PP (n [ 20) Age, years, mean (SD) 58 (10) 59.8 (10) Efficacy ECOG, % 0 32 25 After a median follow-up of 10.2 months (range 2.2-25.2 1 68 75 months), the 6m-PFS (primary endpoint) surpassed the fu- Serous subtype, n (%) Serous 27 (87) 17 (85) tility threshold of 40%, reaching 47% (95% CI 32% to 69%) in Endometrioid 3 (10) 2 (10) the ITT analysis set (Figure 2A), with a median PFS of 5.8 Mixed histology 1 (3) 1 (5) months (95% CI 4.4-9.7 months). For patients who were BRCA, n (%) Mutated 5 (16) 3 (15) administered PLD30 and PLD40, the median PFS was 5.8 Wild type 24 (77) 16 (80) months (95% CI 4.4-NA) and 5.4 months (95% CI 4.03-13.16 Unknown 2 (7) 1 (5) months), respectively (Figure 2B). The OS at 6 months CA-125, n (%) <2 Upper limit normal 7 (23) 3 (15) reached an estimated cumulative survival ratio of 87%, and >2 Upper limit normal 24 (77) 17 (85) the median OS was 14.5 months (95% CI 9.9-NA; Figure 2C). Previous lines, median (range) The stratified analysis of PFS and OS according to BRCA Total previous lines 2 (1-5) 2.0 (1-4) status found no statistically significant differences with a Platinum previous lines 2 (1-4) 2.0 (1-4) Initial dose of PLD, n (%) median PFS of 5.4 months (95% CI 4-12 months) and 6.5 40 mg/m2 17 (55) 12 (60) months (95% CI 5.3-NA; P ¼ 0.64); and median OS of 12.2 30 mg/m2 14 (45) 8 (40) months (95% CI 10.6-NA) and 21.3 months (95% CI 12.5-NA; ECOG, Eastern Cooperative Oncology Group; ITT, intention to treat; PLD, pegylated P ¼ 0.68) for BRCA-wt and BRCA-mut, respectively liposomal doxorubicin; PP, per protocol. (Supplementary Figure S1, available at https://doi.org/10. 1016/j.esmoop.2021.100212). treatment lines was 2 (range 1-5). No relevant differences Similarly, the 6m-PFS in the PP analysis set was 50% (95% were observed in the PP set, with three (15%) patients CI 32% to 77%) with a median PFS of 5.8 months (95% CI 5- having deleterious BRCA1/2 mutations (Table 1). 12 months; Figure 2D). In the PP analysis set, the median OS was 20 months (95% CI 9.6-NA), and the OS at 6 months reached an estimated cumulative survival ratio of 95% Treatment (Figure 2E). In the ITT set, 17 patients received PLD at a starting dose of The median ORR in the ITT population was 29% (95% CI 40 mg/m2 (PLD40). Because of the high toxicity observed at 15% to 48%), all of them with partial response (PR). Another this dosage, the protocol was amended and the subsequent 48% of patients achieved a stable disease (SD), with a DCR 14 patients received PLD at a starting dose of 30 mg/m2 of 77% (Table 2). The median duration of response was 18.5 (PLD30). The median number of cycles administered for PLD months (range 4.2-38.3 months). 4 https://doi.org/10.1016/j.esmoop.2021.100212 Volume 6 - Issue 4 - 2021 J. A. Perez-Fidalgo et al. ESMO Open A D B E PLD doses 30 mg/m2 40 mg/m2 PLD doses C Figure 2. Progression free and overall survival. (A) Progression-free survival (PFS) in the intention-to-treat (ITT) analysis set. (B) PFS in the ITT analysis set that was clustered according to the pegylated liposomal doxorubicin (PLD) dose administration: 30 mg/m2 (PLD30) and 40 mg/m2 (PLD40). (C) Overall survival (OS) in the ITT analysis set. (D) PFS in the pegylated liposomal doxorubicin (PLD) þ olaparib (per-protocol [PP]) analysis set. (E) OS in the PP analysis set. CI, confidence interval; HR, hazards ratio. In the PP population, the ORR reached 25%, all of them increased at week 16 after treatment initiation (P ¼ 0.02 and with PR and 65% of patients achieved SD as the best response 0.037, respectively) and returned to baseline levels by with a DCR of 90% (Table 2). The CA-125 response was ach- week 32. ieved by 32% and 50% of patients in the ITT and PP analysis cohorts, respectively (Table 2). QoL was not significantly Safety reduced during the first 32 weeks of study treatment All 31 patients from the ITT set were evaluated for safety. (Supplementary Figure S2, available at https://doi.org/10.1 The most common AEs of any grade in patients who 016/j.esmoop.2021.100212). At the individual level, nausea/ received olaparibePLD were nausea (n ¼ 22; 71%), fatigue vomiting and constipation parameters were significantly (n ¼ 21; 68%), and anemia (n ¼ 18; 58%). Twenty-five (81%) Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100212 5 ESMO Open J. A. Perez-Fidalgo et al. 40% (Figure 2A) in a heavily pretreated population among Table 2. Treatment response which >75% were BRCA1/2-wt patients. Regarding the Response Treatment response Treatment response secondary endpoints, ORR, CA-125 response, and OS were ITT (n [ 31) PP (n [ 20) also meaningful. The combination could be of potential 40 mg/m2 30 mg/m2 All dose 40 mg/m2 30 mg/m2 All dose interest for further development. n ¼ 17 n ¼ 14 n ¼ 31 n ¼ 8 n ¼ 12 n ¼ 20 Symptom control is a classical objective in OC when RECIST version 1.1 criteria best response platinum-based regimens are not a therapeutic option and PR, % 35 21 29 42 d 25 SD, % 41 57 48 42 100 65 achieving a response in this context could be critical. The PD, % 18 21 19 17 d 10 ORR shown by the combination of olaparib þ PLD in our NE, % 6 d 3 d d d trial was 29% with a DCR of 77%. When compared with DCR (PR/SD) Yes, % 77 79 77 83 100 90 previous trials in PROC, our ORR was similar to the studies No, % 18 21 19 17 d 10 by Fong et al.,12 Kaufman et al.,13 and Vanderstichele NE, % 6 d 3 d d d et al.14 in which single-agent olaparib achieved 33.5%, CA-125 level responsea 31.1%, and 38% ORR, but in a cohort of BRCA-mutated Yes, % 35 29 32 50 50 50 No, % 47 43 45 33 38 35 patients. In our trial only 16% harboured a BRCA mutation; NEb, % 18 29 23 17 13 15 in this context the ORR of our study is far higher than that DCR, disease control rate; ITT, intention to treat; NE, not evaluable; PP, per protocol; reported previously in PROC BRCA-wt patients (4%-13%) for PR, partial response; SD, stable disease. a Patients that have baseline CA-125 <2 upper limit of normal, without taking into single-agent olaparib.14,15 However, a separate spectrum of account if it was obtained within 2 weeks prior to starting the treatment. genetic abnormalities related to the homologous recombi- b Seven patients in ITT and three patients in PP cannot be evaluated according to nation pathway sensitizes BRCA-wt cancers to PARPi and CA-125 because they did not have a pretreatment sample that is at least two times the upper limit of normal. this was not addressed in our study. Additional reliable markers need to be validated in clinical trials to select pa- tients potentially responsive to PARPi, who cannot be patients had an AE of grade 3, with the most common identified solely on the basis of deleterious BRCA mutations being neutropenia (n ¼ 12; 39%) followed by anemia (n ¼ or platinum responsiveness.21 7; 23%) (Figure 3A and Supplementary Table S1, available at Regardless of the indirect comparison limitations of https://doi.org/10.1016/j.esmoop.2021.100212). single-arm design, the efficacy in the ROLANDO trial was in TRAEs, which were assessed according to the investigator line with those described for the combination of chemo- criteria, were reported in 30 (97%) patients, and 23 (74%) therapy and bevacizumab, the current standard of care in had at least a grade 3 TRAE. The most frequent TRAEs PROC. The phase III AURELIA trial reported an ORR of 27% were nausea (n ¼ 18; 58%), fatigue (n ¼ 17; 55%), and for PROC patients treated with bevacizumab and PLD, anemia (n ¼ 17; 55%); and the most common grade 3 weekly paclitaxel, or topotecan, which was similar to the TRAEs were neutropenia (n ¼ 15; 48%; including three 29% observed in our trial.22 cases of febrile neutropenia) and anemia (n ¼ 7; 23%) The strategy of combining olaparib with other agents has (Figure 3B and Supplementary Table S1, available at https:// gained interest in order to overcome the primary resistance doi.org/10.1016/j.esmoop.2021.100212). The reduction of to PARPi in PROC. Initial attempts to combine olaparib in this the PLD dose to 30 mg/m2 achieved a reduction of AEs and advanced setting with hypoxia-inducing drugs, such as TRAEs, especially neutropenia, leukocytopenia, and throm- vascular endothelial growth factor inhibitors, failed to show a bocytopenia (Figure 3). statistically significant improvement over standard chemo- The evaluation of the related serious AEs of PLD, ola- therapy.23 Immunotherapy has been used more recently in parib, or both was less frequent in patients who received combination with PARPi in a phase I/II clinical trial (TOPACIO) PLD 30 mg/m2 (n ¼ 1; 7%) than in those who received PLD with promising results in advanced or metastatic ovarian 40 mg/m2 (n ¼ 3; 18%) (Supplementary Table S2, available cancer.24 Patients with recurrent PROC who were treated at https://doi.org/10.1016/j.esmoop.2021.100212). Simi- with a combination of niraparib and pembrolizumab (pro- larly, PLD delays were less frequent for those who received grammed cell death 1 inhibitor) reached an ORR of 25%.24 30 mg/m2 (n ¼ 14; 32%) than for those who received 40 Apart from the effect of targeting DNA repair system, mg/m2 (n ¼ 17; 39%) (PLD30: n ¼ 5; 16%; PLD40: n ¼ 7; another potential rationale for combining olaparib and PLD 23%; Supplementary Table S1, available at https://doi.org/ is that PLD has immunomodulatory effects that induces a 10.1016/j.esmoop.2021.100212) (ITT set). The most com- highly immunogenic apoptosis that enhances the tumor mon reasons for PLD delays and reductions were neu- antigen presentation by myeloid dendritic cells and pre- tropenia (n ¼ 26; 54% and n ¼ 5; 16%) and anemia (n ¼ 7; sentation to T cells.25,26 Preclinical data suggest that PARP 15% and n ¼ 2; 7%), respectively. inhibition with olaparib also triggers antitumor immunity through a STING-dependent antitumor immune response in mice with BRCA-1-deficient tumors.27 Independent immune DISCUSSION modulation mediated by PLD and PARP inhibition could be The ROLANDO study met its primary endpoint showing behind the high response rates reported in our trial. promising efficacy of the olaparibePLD combination, with a The main limitation of this study was toxicity. With the 6m-PFS surpassing the pre-established futility threshold of initial dose of PLD 40 mg/m2 plus olaparib 300 mg the 6 https://doi.org/10.1016/j.esmoop.2021.100212 Volume 6 - Issue 4 - 2021 J. A. Perez-Fidalgo et al. ESMO Open A PLD30 TOTAL PLD40 n = 17 n = 31 n = 14 Nausea (22) Fatigue (21) Vomiting (17) Anemia (18) Neutropenia (16) Diarrhea (11) AEs Constipation (12) All grades Mucositis oral (10) Grade ≥ 3 Thrombocytopenia (7) Anorexia (8) White blood cell decrease (6) Intestinal obstruction (7) Abdominal pain (6) Headache (4) Pyelonephritis (1) 14 12 10 8 6 4 2 0 0 2 4 6 8 10 12 14 Number of events Number of events B PLD30 TOTAL PLD40 n = 17 n = 31 n = 14 Nausea (18) Fatigue (17) Vomiting (14) Anemia (17) Neutropenia (15) Diarrhea (9) TRAEs Constipation (0) All grades Mucositis oral (9) Grade ≥ 3 Thrombocytopenia (6) Anorexia (6) White blood cell decrease (5) Intestinal obstruction (0) Abdominal pain (0) Headache (0) Pyelonephritis (1) 14 12 10 8 6 4 2 0 0 2 4 6 8 10 12 14 Number of events Number of events Figure 3. Safety analysis in the intention-to-treat (ITT) set. (A) Bar plot representation of adverse event frequencies clustered by type and pegylated liposomal doxorubicin 30 mg/m2 (PLD30) and 40 mg/m2 (PLD40). (B) Bar plot representation of treatment-related adverse event (TRAE) frequencies clustered by type and PLD30 and PLD40. toxicity was high with an important number of patients thrombocytopenia and prolonged neutropenia and leading having a TRAE, among which 74% experienced grade 3 to reduced veliparib dose.33 Conversely, a previous phase I TRAEs. Despite the unexpected increase in the frequency of trial studied the olaparibePLD combination in two regimens TRAEs, the toxicity profile was similar to that described (continuous and intermittent) in 44 patients, among which previously for the combination of olaparib with carboplatin 28 were ovarian cancer patients.20 Olaparib 400 mg b.i.d. or PLD, with the most common TRAEs being neutropenia (capsule formulation) and PLD 40 mg/m2 were tolerable (39%) and anemia (23%).20,28 with no dose-limiting toxicities and this was the recom- In the platinum-sensitive relapse, PARPi in combination mended phase II dose. In fact, the maximum tolerated dose with platinum-based chemotherapy has also shown of olaparib was not reached in this study. Stomatitis, increased toxicity and doubtful benefit that has led to nausea, and asthenia were the most frequent AEs in the subtherapeutic recommended doses of olaparib.29-32 In a cohort with this dose level. Neutropenia was the most phase I dose-escalation trial that combined PDL with car- frequent grade 3 AE and occurred in 20% of patients. In boplatin, bevacizumab and veliparib, six patients experi- our study the combination of olaparib 300 mg b.i.d. (tablet enced dose-limiting toxicities, including grade 4 formulation) and PLD 40 mg/m2 lead to almost a 60% grade Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100212 7 ESMO Open J. A. Perez-Fidalgo et al. 3 neutropenia and an unexpected high rate of serious AEs. as a speaker and received travel and accommodation grants One of the potential reasons for this adverse toxic profile from AstraZeneca and GSK. MI has participated in advisory could be the different formulations of olaparib. Although and consultancy boards for Roche, GSK, Tesaro (A GSK the tablet formulation dose was established as 300 mg Company), and PharmaMar; participated in the speakers b.i.d.,34 this dose cannot be considered biologically equiv- bureau for AstraZeneca, Roche, GSK, Tesaro (A GSK Com- alent to 400 mg b.i.d. in capsule formulation. pany), Eisai, Clovis, and PharmaMar; and received travel/ To improve the toxicity profile, the PLD dose was reduced accommodation expenses from Novartis, AstraZeneca, to 30 mg/m2. Although our study was not designed for MSD, Tesaro (A GSK Company), PharmaMar, Roche, GSK, making comparisons between two different groups, given Pfizer, and Eisai. AC reports consulting or advisory role for that the initial dose modification of PLD was not foreseen, Lilly, Clovis; is on the speaker bureau for GSK, Roche Gen- and that dose modification occurred after 17 patients had entech, AstraZeneca, Eisai, MSD, Pfizer; and has received been enrolled, we presented the data on tolerability and research funding from Pfizer; travel, accommodation, and efficacy in the two different PLD dose levels. With obvious other expenses were covered by Pfizer and Roche Gen- limitations due to the small sample size in the context of an entech. EG has received advisory/consultancy honorarium unexpected dose modification, efficacy seemed apparently from AstraZeneca-MSD, Clovis Oncology, GSK- Tesaro (A unaffected with the PLD 30 mg/m2 dose level, whereas GSK Company), PharmaMar, and Roche; has received toxicity seemed to be improved. Thus, some severe TRAEs speaker bureau/expert testimony honorarium from Astra- such as neutropenia grade 3 were 59% in PLD 40 and 36% Zeneca, PharmaMar, Roche, and GSK; and has received in PLD 30, whereas anemia grade 3 was quite similar in travel/accommodation/expenses from Roche, Tesaro (A GSK both dose levels (24% and 21%, respectively). Company), and Baxter. AR reports receiving honoraria from Of note, QLQ-C30 data showed that QoL was sustained and plays advisory/consultancy roles for MSD, AstraZeneca, throughout the study and from baseline, indicating that the Roche, GSK, Clovis, PharmaMar, Lilly, and Amgen; research treatment did not significantly worsen the QoL throughout grant/funding to his institution from Eisai, PharmaMar, and the exposure to the combination. Roche; travel/accommodation/expenses from AstraZeneca, In conclusion, the ROLANDO trial provided evidence that Tesaro (A GSK Company), PharmaMar, and Roche; and continuous administration of olaparib 300 mg b.i.d. in serves on the speakers bureau of MSD, AstraZeneca, Roche, combination with PLD 30 mg/m2 would be suitable for GSK, Clovis, and PharmaMar, outside the submitted work. investigation in further research and offers a potential All other authors have declared no conflicts of interest. therapeutic alternative in patients with ovarian cancer when platinum-based regimens are not a therapeutic op- DATA SHARING tion regardless of the BRCA mutation status. The results from this clinical trial are available at clinicatrials.gov (NCT03161132). ACKNOWLEDGEMENTS This work was sponsored by Grupo Español de Investigación CONSENT TO PARTICIPATE en Cáncer de Ovario (GEICO). Olaparib was provided by All patients signed the informed consent form prior to their AstraZeneca under a cooperative research agreement with inclusion in the study. the Sponsor, Grupo Español de Investigación en Cáncer de Ovario (GEICO). This research was supported by AstraZe- REFERENCES neca. Pau Doñate, Ph.D., and Jordi Curto, M.Sc., both from 1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: MFAR Clinical Research (Barcelona, Spain), contributed to GLOBOCAN estimates of incidence and mortality worldwide for 36 medical writing and statistical analysis, respectively. cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. Authors specially thank Laura Vidal, Carlota de Blas, and 2. Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and Carmen Marques for their contributions to this study. relapsed epithelial ovarian carcinoma: ESMO clinical practice guide- lines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):24-32. 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