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Abstract
Objective Poly (ADP-ribose) polymerase (PARP) inhibitor resistance is problematic in epithelial ovarian cancer management and sequencing strategies may be performed to overcome this issue. In this context, our study evaluated the role of non-platinum doublet pegylated liposomal doxorubicin/trabectedin in ovarian cancer platinum-sensitive patients who experienced disease progression under PARP inhibitor maintenance.
Methods This case–control study includes patients with recurrent epithelial ovarian cancer treated between March 2016 and April 2021 who progressed under PARP inhibitor maintenance. Data of patients treated with pegylated liposomal doxorubicin/trabectedin (experimental group) were matched 1:1 with a series of patients who received platinum-based treatment (control group). The study outcomes were overall clinical benefit (including complete, partial, and stable response), progression-free survival, and overall survival. The safety of both treatments was also evaluated.
Results A total of 26 patients in both groups were analyzed. Clinical benefit was achieved in 15 (57%) patients in the study group and 17 (65%) patients in the control group (p=0.38). Patients receiving pegylated liposomal doxorubicin/trabectedin had 5 months of progression-free survival, compared with 5 months in patients treated with platinum-based treatment (p=0.62). Patients in the experimental group achieved a median overall survival of 16 months compared with 19 months in the control group (p=0.26) There was no difference concerning severe toxicities (G3-G4) between groups, except for hepatic toxicity, which was experienced in 30% of the patients receiving pegylated liposomal doxorubicin/trabectedin and none in the control group (p<0.009).
Conclusions Pegylated liposomal doxorubicin/trabectedin might be an alternative option to platinum-based treatment in patients experiencing disease progression during PARP inhibitor maintenance with an acceptable toxicity profile. This might be a therapeutic option in this setting, sparing platinum compounds for subsequent relapse.
- Ovarian Cancer
- BRCA1 Protein
- BRCA2 Protein
- Neoplasm Recurrence, Local
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
PARP inhibitor resistance is a problematic step in epithelial ovarian cancer. Furthermore, there is a significant overlap between resistance mechanisms to platinum chemotherapy and PARP inhibitors.
WHAT THIS STUDY ADDS
Trabectedin plus pegylated liposomal doxorubicin might overcome this resistance and be considered an option for patients experiencing disease progression while on PARP inhibitor maintenance with comparable efficacy to platinum-based chemotherapy.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
If this hypothesis is confirmed in more extensive data collection, the choice of non-platinum-based treatment could be a good opportunity in this setting.
Introduction
The current optimal therapeutic management in advanced ovarian cancer is still cytoreductive surgery followed by platinum-based chemotherapy plus maintenance treatment, either anti-angiogenic therapy or poly (ADP-ribose) polymerase (PARP) inhibitors, or even both1; regardless, almost 70–80% of patients are expected to develop a relapse within the first 2 years, requiring a subsequent line of treatment. Recurrent ovarian cancer treatment was significantly transformed in 2014 with the first approval of PARP inhibitors as maintenance therapy in patients with partial or complete response after platinum-based chemotherapy.2–4 These agents have also shown excellent progression-free survival results even in the front-line setting,5–7 and nowadays many patients are supposed to receive a PARP inhibitor, sooner or later, during their cancer history. Despite the impact of PARP inhibitors, most patients will experience a relapse, most as a ‘platinum-sensitive’ recurrence.
The mechanism of action of PARP inhibitors is, in many ways, complementary to that of platinum agents, and the existence of possible cross-resistance with platinum compounds has been hypothesized.8 Therefore, overcoming platinum and PARP inhibitor resistance remains challenging. At present, after progression on PARP inhibitors, there are no standard approaches, and several key concepts need to be addressed before deciding on subsequent treatment, such as the timing from prior therapy or platinum therapy, the tumor’s histology and biology (BRCA mutational status), and previous (or not) anti-angiogenic therapy. In this context, the association of trabectedin plus pegylated liposomal doxorubicin is still the only non-platinum combination approved to treat platinum-sensitive recurrence.9 This approval comes from the results of the randomized OVA-301 trial, which showed the superiority of trabectedin plus pegylated liposomal doxorubicin over pegylated liposomal doxorubicin alone in relapsed ovarian cancer.10 A subgroup analysis in patients recurring between 6 and 12 months showed that the combination was superior in terms of overall survival, particularly in the subpopulation receiving platinum as the first subsequent line.11
Accordingly, it was hypothesized that the combination of pegylated liposomal doxorubicin/trabectedin could restore platinum sensitivity by selecting cancer cells more responsive to platinum or modifying the microenvironment. This hypothesis has been partially confirmed in the pre-clinical setting,12 but it has been disproved by results from the INOVATYON trial. This trial did not meet its primary endpoint of improving overall survival in partially platinum-treated patients receiving the sequential administration of trabectedin plus pegylated liposomal doxorubicin followed at progression by platinum, compared with carboplatin and pegylated liposomal doxorubicin.13 However, the non-inferior overall survival still indicates a possible role for pegylated liposomal doxorubicin/trabectedin, particularly in patients who cannot receive platinum compounds. Moreover, both trials are outdated, with no patients who had received a PARP inhibitor before pegylated liposomal doxorubicin/trabectedin administration.
The purpose of this retrospective study is to evaluate the efficacy of trabectedin plus pegylated liposomal doxorubicin compared with standard platinum-based chemotherapy in patients who experienced disease progression after PARP inhibitor maintenance.
Methods
This is a retrospective, case–control study evaluating the activity, safety, and tolerability of pegylated liposomal doxorubicin/trabectedin (study group) compared with platinum-based therapy (control group) in partially/fully platinum sensitive recurrent ovarian cancer patients with progression after PARP inhibitor maintenance. Partially platinum sensitive refers to the interval between the last platinum-basd therapy before PARP inhibitor and the end of PARP inhibitor therapy. All patients had provided written informed consent to treatment and to allow the use of their clinical data for scientific purposes at the time of chemotherapy administration. The retrospective collection of clinical data from clinical charts was approved by the Local Ethics Committee and Institutional Review Board. Clinical data were collected between March 2016 and April 2021 at the Division of Gynecologic Oncology of the Catholic University of Rome.
Records were retrospectively reviewed, with particular attention paid to the initial patient history, physical condition, tumor histopathology, residual tumor after cytoreductive surgery, platinum-sensitivity, previous lines of chemotherapy, and previous response to treatments. All included patients had been screened for somatic mutation for BRCA1/2 genes and all patients with tumor BRCA1/2 mutation or variants of uncertain significance had received a blood test to confirm or not the presence of a germline mutation, with subsequent genetic counseling if present.
Pegylated liposomal doxorubicin 30 mg/m2 as a 90-min infusion followed by trabectedin 1.1 mg/m2 as a 3-hour infusion every 3 weeks were administered. Patients received 20 mg of dexamethasone intravenously 30 min before pegylated liposomal doxorubicin administration as anti-emetic prophylaxis and for hepatoprotective effect. All patients had a central venous line placed previously. Platinum-based treatment was given according to international guidelines, without any following possible maintenance (bevacizumab). Cycles were administered as long as re-treatment criteria were met (complete recovery of hematological and non-hematological toxicities, or until disease progression or discontinuation for other reasons).
Patients were defined as partially or fully platinum sensitive if the platinum-free interval was respectively between 6–12 or ≥12 months after their last pre-PARP inhibitor platinum-based chemotherapy. According to national guidelines, patients might have received pegylated liposomal/trabectedin combination if partially platinum sensitive or, if fully sensitive, due to platinum-specific side effects or allergies; platinum-based treatment was given regardless of platinum-free interval. For this reason, cases were matched with controls according to age, BRCA mutational status, and number of previous regimens received, instead of platinum-free interval. Treatment-related toxicity was assessed according to the National Cancer Institute-Common Terminology Criteria criteria (version 5.0).14 We considered all toxicities of grade 3 or 4 to be clinically relevant toxicity.
The overall response rate included complete and partial responses, which were classified according to Response Evaluation Criteria in Solid Tumor (RECIST) criteria (version 1.1).15 The clinical benefit included complete and partial response and stable disease. The results of imaging and response evaluations were collected at baseline or the earliest imaging study after the first treatment cycle was considered; imaging was repeated every three cycles or according to the physician’s indication. The final imaging was the assessment performed closest to the follow-up visit and before any other chemotherapy treatment initiation.
Statistical Analysis
This is a case–control study; patients were matched in a 1:1 ratio based on age, BRCA mutational status, and number of previous regimens received. The hypothesis was that the efficacy (estimated as clinical benefit rate) of pegylated liposomal doxorubicin/trabectedin after PARP inhibitor treatment was similar to that of platinum-based therapy. No sample size was estimated, and every association was tested exclusively in a ‘hypotheses generating’ perspective. The χ-quadro of Pearson or Fisher’s exact test for proportion were used to analyze categorical or continuous data distribution.
Progression-free and overall survival were also assessed and were defined as the time elapsed between the start of treatment and progressive disease (progression-free survival) or death or the date of last seen (overall survival). Survival was calculated using the Kaplan-Meier method.16 Log-rank test was used to compare survival between groups.17 All p values were two-sided, and the p value was set at 0.05. Multivariate Cox proportional hazards regression models were used to estimate adjusted hazard ratio (HR) and 95% confidence interval (95% CI) (R function ‘coxph’ and Rpackage ‘forestmodel’). Other risk factors included in the model were age (≤60 vs >60 years), BRCA mutational status, number of previous lines (≤3 vs >3 previous lines of chemotherapy), platinum sensitivity (partially sensitive vs fully sensitive), and treatment received (carboplatinum-based vs pegylated liposomal doxorubicin/trabectedin-based). Statistical analysis was performed using Statistical Package for Social Science (SPSS) 25.0 for Mac (SPSS Inc, Chicago, IL) and the R 0.98.1091 software.
Results
Patient Characteristics
We found 26 recurrent ovarian cancer patients who progressed under PARP inhibitor maintenance and were subsequently treated with pegylated liposomal doxorubicin/trabectedin (study group). They were matched with a historical series of 26 patients (control group) with similar clinical characteristics who received platinum-based treatment instead. The control group included three types of chemotherapy: every 3 weeks carboplatin alone (14 patients), carboplatin-based doublet (eight patients), and weekly carboplatin alone (four patients). Characteristics of the patients enrolled are presented in Table 1.
Distribution of patients’ clinicopathological characteristics according to treatment received
The median age at recurrence was 58 years (range 35–79) for the overall population, with no differences between groups (p=0.14). The most common histotype was serous for both groups (88.5% and 100% for the study and control groups, respectively, p=0.07), and 86% of patients had ovarian cancer at International Federation of Gynecology and Obstetrics (FIGO) stage III at primary diagnosis. The median number of previous chemotherapy lines was three (range 2–5) for both groups (p=0.79). Twenty-four (92.3%) patients in the study group were partially platinum-sensitive at the last treatment of platinum received, while 23 (88.5%) patients in the control group were fully sensitive (p<0.001). Also, the distribution of disease relapse showed four (15%) patients presenting with multiple (≥3) sites of recurrence in the study group compared with two (8%) in the control group.
Toxicity
A total of 269 courses were evaluable for toxicity, with a median number of five cycles (range 2–11) per patient (six cycles, range 2–11) in the treatment group and five cycles (range 2–10) in the control group). No statistically significant differences were found regarding toxicity, except for hepatic toxicity which was more common in the study group. Grade 3–4 neutropenia was documented in 25 patients in both groups (11 patients (42%) in the control group and 14 patients (54%) in the pegylated liposomal doxorubicin/trabectedin group); grade G3-4 anemia was registered in two patients of the control group (8%) and one of the study group (4%; p=0.55), while G3-4 thrombocytopenia was registered in five (19%) patients in the pegylated liposomal doxorubicin/trabectedin group and six (23%) in the platinum-based group. As expected, grade G3-4 hepatic toxicity was typical in pegylated liposomal doxorubicin/trabectedin receiving patients (30% vs 0% in the study and control group, respectively, p<0.009). Also, severe gastrointestinal toxicity occurred more frequently in patients administered pegylated liposomal doxorubicin/trabectedin, but it was not significantly different (19% vs 4% in the control group, p=0.08). No treatment-related deaths or unexpected adverse events occurred in the study group. For toxicity details, see Table 2.
Worst hematological (G3-G4) and non-hematologic toxicities in the overall series and according to treatment received
Response and Survival
There were no significant differences in response rate between the groups reviewed. Overall, three patients in the control group (11.5%) and none in the study group achieved complete response; five (19%) and four (15%) patients had a partial response in the study and control group, respectively. Overall, clinical benefit was achieved in 15 (57%) patients in the study group and 17 (65%) in the control group (p=0.38) (Table 3).
Clinical response in the overall series and according to treatment received
After a median follow-up of 60 months (range 12–160), 14 (54%) deaths in the pegylated liposomal doxorubicin/trabectedin group and 11 (42%) deaths in control group were recorded (p=0.29). In the entire series, median progression-free survival was 5 months (95% CI 3.4 to 6.5 months); patients receiving pegylated liposomal doxorubicin/trabectedin had 5 months progression-free survival compared with 5 months for the control group (log-rank p=0.62) (Figure 1).
Progression-free survival (PFS). PLD, pegylated liposomal doxorubicin.
Progression-free survival was also similar, 5 months, in both platinum-partially and fully sensitive populations (log-rank p=0.92). Patients in the study group achieved a median overall survival of 16 months, compared with 19 months in the platinum-based group (p=0.26) (Figure 2). In online supplemental figures 1,2 multivariable Cox proportional hazards models, adjusting for established risk factors, including age, BRCA mutational status, number of previous lines, and platinum sensitivity, are summarized, showing that trabectedin-based treatment is not detrimental compared with carboplatinum-based, in terms of both progression-free survival and overall survival. It also appears that BRCA mutational status or the number of previous lines are not related to survival outcomes.
Supplemental material
Supplemental material
Overall survival (OS). PLD, pegylated liposomal doxorubicin.
Discussion
Summary of Main Results
In this study, we found that a combination of pegylated liposomal doxorubicin/trabectedin had similar oncologic outcomes to platinum-based treatment in patients with disease progression while on PARP inhibitor maintenance. The two approaches may be comparable in efficacy and survival, with a median progression-free survival of 5 months, with acceptable toxicity profiles.
Results in the Context of Published Literature
Platinum chemotherapy remains the cornerstone of ovarian cancer treatment, but PARP inhibitors have recently acquired an essential role as maintenance therapy in the first and subsequent lines settings. Unfortunately, many patients develop resistance to PARP inhibitors. Interestingly, it appears quite clear that there is an overlap between resistance mechanisms to platinum chemotherapy and PARP inhibitors. In fact, in both cases, a reactivation of homologous recombination repair18 and an increased DNA repair efficiency (with homologous recombination and nucleotide excision repair being the leading players) have been found.
In this context, the role of pegylated liposomal doxorubicin/trabectedin is of interest. First, both drugs penetrate and are retained within cells using transport systems different from those used by platinum compounds, thus avoiding known resistance mechanisms. In addition, the interaction of trabectedin with DNA is different from that of other drugs, and, unlike platinum and PARP inhibitors, it has been suggested to be particularly effective even in nucleotide excision repair-proficient cells.19
On these bases, we hypothesized that pegylated liposomal doxorubicin/trabectedin might overcome resistance mechanisms and be effective after PARP inhibitor progression, similar to a platinum compound. The 5 months of progression-free survival found in our series is shorter than what we would expect in a platinum-sensitive population. However, our data are in line with others recently published8–20 according to which, following progression from maintenance PARP inhibitors in the recurrent setting, the efficacy of subsequent platinum-based chemotherapy seems to be reduced. Therefore, we further confirm that progression while on PARP inhibitors is challenging to treat. Moreover, it should be underscored that in our series, patients with the fully-platinum sensitive disease, who received a platinum-based treatment in most cases, did not achieve a more prolonged survival compared with the partially sensitive disease, disproving what is usually suggested by the literature.21
It should be underlined that pegylated liposomal doxorubicin/trabectedin is currently the only non-platinum combination approved by the European Medicines Agency to treat recurrence in patients with platinum-sensitive disease.9 This is a possibility for those ‘partially’ or ‘fully’ platinum-sensitive patients who have residual toxicity or contraindications to further platinum treatment. Finally, data from multicenter Italian trials in the ovarian cancer MITO-15 trial have confirmed, in the real-life setting, that platinum sensitivity identifies patients highly responsive to trabectedin.22
In light of the INOVATYON trial, platinum rechallenge seems to be weaker than before,13 as overall survival was not improved with a non-platinum therapy and progression-free survival was worse in the group with pegylated liposomal doxorubicin/trabectedin; nonetheless, in this study, progression-free survival after the subsequent line was longer in the pegylated liposomal doxorubicin/trabectedin group, when platinum was administered at progression. This reaffirms the hypothesis that the study combination may lead to platinum sensitivity. Therefore, we believe that, in a sequence strategy, pegylated liposomal doxorubicin/trabectedin might be a reasonable choice after a PARP inhibitor progression to restore platinum sensitivity, especially but not limited to patients with multiple prior lines of platinum, who may need a stronger recovery from platinum toxicities. Conversely, pegylated liposomal doxorubicin/trabectedin would be utterly missing as an option (in the entire history of the disease) if we prefer to administer platinum after a PARP inhibitor progression; this is because patients are expected to recur briefly, often before 6 months (platinum-resistant), and data on the effectiveness of pegylated liposomal doxorubicin/trabectedin in this subgroup are few and controversial.
Strengths and Weaknesses
This is the first series to investigate the role of a non-platinum doublet in ovarian cancer patients who recurred during PARP inhibitor administration. Although unconfirmed, results raise new thoughts on overcoming PARP inhibitor resistance with ‘conventional’ approaches. We recognize the limitations of our work due to its retrospective nature and the small number of patients. Moreover, we did not match our population based on platinum-free interval because we consider that the importance of a platinum-free interval after PARP inhibitors seems questionable and the number of previous regimens received would have been a better comparator.
Implications for Practice and Future Research
Unfortunately, our understanding of resistance mechanisms to drugs such as platinum and PARP inhibitors, and how to overcome them, is still limited. Therefore, whether those combinations show substantial clinical efficacy and improve overall survival remains to be seen. Incorporating translational objectives into clinical trial protocol design will further elucidate these critical questions. Until the already approved non-platinum-based combination could be an alternative to extend the survival of patients, it would be helpful to confirm our data with other real-world experiences. A more extensive data collection is currently underway within the MITO group (MITO 39 trial) with the same objective.
Conclusions
We confirm that PARP inhibitor resistance is a problematic step in ovarian cancer, and sequencing strategies should be carried out to overcome it. While waiting for ongoing trials to address this issue, the choice of non-platinum-based treatment could be a good opportunity in this setting and might prolong survival expectations, sparing platinum compounds for subsequent relapse. We believe our preliminary results might be hypothesis-generating and help with other and larger study designs.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Ethics Committee of Fondazione Policlinico Universitario A. Gemelli. Number of protocol approval: DIPUSVSP-PD-03-2210 Participants gave informed consent to participate in the study before taking part.
Acknowledgments
All authors have written parts of and have reviewed the whole manuscript.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @annafagottimd
Contributors LV: conceptualization, investigation, writing - review and editing, guarantor. SMB: conceptualization, investigation, writing - review and editing. GT: investigation and data curation. GA: investigation. GC: investigation. AF: conceptualization, supervision and project administration. GS: supervision and project administration. CM: conceptualization, formal analysis, writing - review and editing and project administration, guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests Some authors report competing interest but outside the submitted work.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.