The present study provides a comprehensive analysis of the clinical characteristics, treatment patterns, and outcomes in a cohort of 400 evaluable women with AOC in Spain between 2013 and 2016. The findings shed light on several aspects of ovarian cancer management, including surgery, neoadjuvant therapy, treatment selection factors, clinical outcomes, and the incorporation of targeted therapies into clinical practice at the time when these patients underwent ovarian cancer treatment.

While most patients with AOC achieve remission with first-line treatment, AOC recurs in 70–85% of all patients [3, 8,9,10,11,12]. Although the patients are rarely cured after recurrence, successive lines of therapies can provide significant clinical responses [13, 14]. In this study, patients with AOC received a median of two lines of treatment. Thus, this cohort did not undergo extensive therapeutic interventions.

The standard front-line treatment for OAC has traditionally involved cytoreductive surgery, aiming for no residual disease (R0), followed by platinum-based chemotherapy. In this study, 24.0% of the patients received cytoreductive surgery followed by platinum-based chemotherapy as first-line treatment, aligning with the prevailing standard for advanced disease treatment at the start of the treatments in this study. Interestingly, those receiving this regimen were more likely to exhibit extended TFI, reaffirming this strategy as the standard of care. However, a potential bias due to the selection of fitter patients for this approach cannot be ruled out.

Additionally, our observations revealed that 39.5% of the patients received IDS combined with NAC, which serves as an alternative treatment strategy for individuals who may not be suitable candidates for PDS [3, 4]. Accordingly, patients presenting a more aggressive FIGO stage (IIIC, IVA, and IVB) at diagnosis were more likely to receive NAC in the first-line treatment.

The results from this study indicate that most of the patients received surgery (84.5%) and platinum-based chemotherapy (95.7%) during first-line treatment, as previously reported in real-world retrospective studies conducted in the USA, France, Italy, Germany, UK, Spain, Greece, Canada, Portugal, South Korea, and Romania in patients diagnosed with AOC between 2012 and 2019 [25,26,27,28,29,30].

The addition of bevacizumab to chemotherapy has emerged as an effective option in the first-line treatment setting [18, 31, 32]. Spanish guidelines at the initiation of the OVOC study already recommended the administration of bevacizumab with the initial chemotherapy followed by a maintenance period of bevacizumab in patients with R0 after standard surgery [24]. However, bevacizumab was the only targeted therapy available for clinical use in OC (approved in Europe in 2011), and some uncertainties about its use were under discussion [24]. In addition, PARP inhibitors were approved in Europe in 2014. In this context, our study shows that targeted agent-based regimens were used in 33.8% of the patients in the first-line setting, with bevacizumab being administered in 92% of the patients receiving targeted therapy. Consequently, bevacizumab was the most consistently used additional agent combined with chemotherapy during the first-line treatment of OC. Similar results were found in a later real-world study using data from the USA and five European countries (France, Germany, Italy, Spain, and UK) from 2017 to 2018, accounting for 26% bevacizumab-containing regimens and 1% a PARP inhibitor-containing regimen as first-line [30]. Another real-world study from 2018 to 2019 found higher proportions of patients treated with angiogenesis inhibitors at first line (47.3% of the patients received chemotherapy and angiogenesis inhibitors) [27]. Overall, this evidence shows the increasing use of targeted therapies in real-world settings as recommended by current guidelines and consensus [3, 33].

Managing patients with recurrent disease represents a challenge for clinicians, given the inherent heterogeneity of the disease and the diversity of clinical scenarios. Traditionally, the selection of successive lines of treatment has arbitrarily relied on the length of the PFI [3, 16]. According to this approach, most patients with OC have platinum-sensitive disease (PFI ≥ 6 months) after the first recurrence [34]. Indeed, 65.9% of the patients showed platinum-sensitive disease after first-line treatment in the present study. The standard therapy for these patients at the time the study started consisted of retreatment with a platinum-containing regimen [24, 35]. Accordingly, the preferred second-line treatment in this study was platinum-based chemotherapy, administered to 37.0% of the patients with recurrent disease and 50.4% of the patients with platinum-sensitive disease. In agreement, before bevacizumab approval, from 2008 to 2010, 69% of patients with recurrent disease received second-line chemotherapy, according to a Spanish retrospective observational real-world study including 277 patients diagnosed with AOC [36]. In this line, we found that patients with an extended PFI had a higher likelihood of receiving platinum-based chemotherapy as second-line treatment, aligning with the historical recognition of PFI as a leading factor guiding therapeutic decisions in managing recurrent OC. Of note, the use of platinum-based chemotherapy in our study declined as patients relapsed, as previously reported in real-world studies [25, 27]. Since patients with platinum-resistant disease are unlikely to respond to additional platinum-based treatments, platinum rechallenge therapy should not be considered as an option when progression occurs in these individuals [3, 37]. Nevertheless, our findings reveal that approximately 13.5% of the patients with platinum-resistant disease were subjected to retreatment with platinum-based regimens following first recurrence, of whom 60.0% achieved stable disease, 20.0% PR, 10.0% CR, and 10.0% PD after the second-line treatment.

According to the latest recommendations, treatment selection after recurrence should consider tumor-associated characteristics and individual patient-related factors such as clinicopathologic parameters, the nature and severity of symptoms, performance status, molecular results, the type and number of previously administered treatments, or the presence of residual toxicities [3, 4, 17, 33]. Current guidelines acknowledge that platinum-containing regimens can still be the best option for certain patients with recurrent disease [3]. Nevertheless, new evidence supports that platinum-based combination with bevacizumab and platinum-based combination followed by PARPi are optimal options [3]. Thus, targeted agents have emerged as a promising treatment option. For instance, combining bevacizumab with chemotherapy has proven beneficial in terms of PFS and OS in patients with platinum-resistant disease [20, 38]. Indeed, bevacizumab is indicated for the front-line treatment of AOC and in platinum-sensitive recurrent and platinum-resistant recurrent settings for epithelial ovarian cancer, according to its summary of product characteristics (SmPC) [39]. Our study reveals that the combined regimen of chemotherapy with bevacizumab was the second most frequently used second-line treatment, administered to approximately 17.4% of the patients. Chemotherapy followed by any PARP inhibitor was administered to 6.0% of patients. Similar results were reported in the real-world study carried out by Hall et al. [30] for France, Germany, Italy, and Spain, but not for the USA and UK, which had a similar frequency with olaparib monotherapy. Of note in our study, the use of targeted therapy in the second-line setting was similar in patients with platinum-sensitive (25.2%) and platinum-refractory (25.0%) disease but tended to be lower in patients with platinum resistance (16.2%).

Our findings show that the proportion of patients undergoing second-line therapy with a bevacizumab-based regimen (18.0%) represented nearly half of those who received bevacizumab in the first-line setting (30.9%), suggesting that at the time of this study, bevacizumab was preferably used in the first-line setting. These findings align with real-world evidence from the EpOCa study in Greece [27] and from the study carried out by Hall et al. in France, Germany, and Italy [30]. Interestingly, data from Spain from the former study showed a higher prevalence of bevacizumab-containing regimens in the second-line setting (16% versus 31%). However, 39% of the overall population received first-line maintenance therapy, with 73% of those regimens containing bevacizumab [30]. These results highlight the growing recognition of the role of maintenance therapy in delaying disease progression in recent years [12, 40, 41]. In our study, only 2.5% of the patients were retreated with bevacizumab in the second-line setting after receiving first-line bevacizumab-based therapy. It is important to underscore that bevacizumab is approved in recurrent OC for patients who have not previously received this targeted agent.

Our results indicate that the use of targeted therapy as second-line treatment varied significantly based on the mutational status of the BRCA gene. While nearly 50% of the patients with platinum-sensitive disease with BRCA gene mutations received targeted therapy as second-line treatment, only 16.9% of those with BRCA wild-type patients received such therapy. Additionally, our findings identified germline BRCA1 mutational status as an independent factor influencing the selection of platinum-based chemotherapy regimens (not containing targeted therapies) as second-line treatment. These results are consistent with current guidelines emphasizing the significance of BRCA1/2 mutations as validated biomarkers guiding the use of PARP inhibitors [3]. The findings underscore the potential impact of genetic factors on treatment choices besides chemotherapy. Indeed, several genes have been found mutated in ovarian cancer [42]. Besides BRCA1/2 mutations, several other genes associated with homologous recombination repair deficiency (HRD), such as CHEK2, RAD51, BRIP1, and PALB2, have been described [42, 43]. In addition, mutations in genes encoding proteins in other pathways, such as the RAS-RAF-MEK-ERK pathway, have also been detected in OC [42, 44]. These molecular insights are directly influencing therapeutic strategies. For instance, patients with positive results for HRD can also benefit from maintenance therapy with PARP inhibitors [43, 45]. Moreover, several therapeutic molecular inhibitors of these pathways have been developed and are currently assessed in clinical trials [44]. The expanding understanding of the molecular landscape of ovarian cancer facilitates the development of personalized treatment approaches.

The median PFS in the first-line setting was 14.2 months. Most patients in this context underwent PDS followed by platinum-based chemotherapy or IDS after neoadjuvant treatment followed by platinum-based chemotherapy. The observed PFS in this real-world study aligned with the data reported in the GOG-0218 study, ranging from 10.3 months in patients treated with paclitaxel and carboplatin to 14.1 months in patients treated with the combination of chemotherapy and bevacizumab [31]. Due to the observational nature of this study, direct comparisons with phase III trials should be regarded as purely descriptive. The observational EpOCa study, conducted in Greece with 154 patients with AOC, reported a PFS of 18.2 months [27]. However, that study had a higher rate of first-line targeted therapy (approximately 50% of patients) than ours (33.8%). Notably, our study revealed a significantly longer PFS (17.4 months) among patients who received targeted therapy in the first-line setting (92% of them received bevacizumab) compared to those who did not (11.55 months; p = 0.039). This observation aligns with the findings of the GOG-0218 and ICON-7 trials, as well as the EpOCa study and the study of Fukuda et al., which demonstrated that the addition of bevacizumab to paclitaxel plus carboplatin resulted in a statistically significantly improvement in PFS or disease-free survival [18, 27, 31, 32].

A median PFS of 8.7 months was observed following initiation of second-line treatment in this study, consistent with the median post-progression survival of 9.7 months observed across 22 phase III randomized controlled trials focusing on second-/third-line chemotherapy treatment for patients with AOC [46]. This finding also aligns with the estimated PFS for the second-line treatment setting in the observational EpOCa study (8.8 months) [27]. As seen in the first-line setting, a significantly longer PFS is achieved among patients receiving targeted therapy after the first relapse (p < 0.001).

Our findings reveal that individuals carrying BRCA1 and BRCA2 mutations experience a diminished probability of disease progression, recurrence, or mortality compared to those with wild-type variants. These results are in line with the outcomes of a meta-analysis including 14 studies in ovarian cancer emphasizing a more favorable prognosis in terms of both PFS and OS in women with BRCA1/2 mutations, irrespective of grade, tumor stage, or histologic subtype [47].

Overall, the discrepancies observed between clinical practice at the start of the study and current guidelines represent a significant opportunity to improve the clinical outcomes of patients with AOC by implementating effective targeted therapies recommended by these guidelines.

This study has limitations that should be acknowledged. The findings need to be interpreted in the context of the targeted agents that were available at the time when the patients underwent OC treatment. It is crucial to acknowledge that the landscape of OC therapy has evolved in recent years with the integration of new targeted agents into the treatment arsenal. In addition, the retrospective design of the study dictated data availability, implying data generation according to routine clinical practices and a lack of systematic collection.