In patients with newly-diagnosed advanced-stage epithelial ovarian cancer (EOC), the combination of cytoreductive surgery and platinum-based chemotherapy has been the cornerstone of treatment for decades now. Since the completeness of surgery—defined as the resection of all macroscopically visible lesions—repeatedly turned out to be independently associated with survival,4 the likelihood of achieving complete gross resection serves, until today, as an essential premise in current treatment algorithms. As such, patients in whom complete resection of tumor burden seems feasible will be triaged to primary cytoreductive surgery, whereas neoadjuvant chemotherapy followed by interval cytoreductive surgery (NACT/ICS) is reserved for patients in whom complete gross resection is not deemed a viable option, due to either the extent of the disease and/or a poor performance status that precludes these patients from undergoing major surgery.5–7

Now that we have increasing access to molecular profiling, the question arises to what extent these longstanding fundamentals of surgical management remain valid. The vast majority of EOCs are represented by high-grade serous ovarian cancers (HGSOCs). The Cancer Genome Atlas revealed that approximately half of these HGSOCs show defects in the homologous recombination repair pathway, of which up to 30% are attributable to distinctive germline or somatic mutations, such as BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, and BARD1.8 9

The presence of a BRCA gene mutation has been shown to impact disease presentation. During laparoscopic assessment, patients with a deleterious BRCA germline mutation presented with a higher tumor load in terms of diffuse peritoneal dissemination (laparoscopic predictive index value >8) and bulky lymph nodes as compared with those who lack a BRCA mutant genotype.10 Interestingly, a unique BRCA mutant phenotype could also be discerned on pre-operative CT scans. In a retrospective observational study conducted by Nougaret and co-workers, two radiologists independently examined pre-operative CT images from patients diagnosed with BRCA mutant and BRCA wild-type HGSOCs.11 They concluded that BRCA-driven HGSOCs more often presented with a nodular peritoneal disease pattern and tumor deposits located on the gastrohepatic ligament, while mesentery involvement as well as enlarged supradiaphragmatic lymph nodes were less frequently observed as compared with their BRCA wild-type counterparts. Furthermore, at a microscopic level, BRCA mutated HGSOCs have been shown to exhibit typical histopathological features, classified as either pushing/circumscribed metastatic patterns that are often accompanied by a solid, pseudo-endometrioid and transitional cell architecture (so-called ‘SET architecture’), or infiltrative metastases exclusively composed of micropapillae.12 By contrast, BRCA wild-type HGSOCs manifested with miscellaneous tumor architectures.

Whether the absence or presence of specific BRCA-associated features has an impact on surgical management and clinical outcome of patients diagnosed with HGSOCs has been the subject of several studies. With respect to patients with BRCA wild-type HGSOCs, more favorable progression-free survival rates were found when patients directly proceeded to primary cytoreductive surgery.10 13 14 On the contrary, the same studies unequivocally demonstrated that patients with BRCA mutant HGSOCs equally benefited from primary cytoreductive surgery versus NACT/ICS, which has been primarily ascribed to their high chemosensitivity. After all, both BRCA1 and BRCA2 are tumor suppressor genes and their corresponding functioning proteins play a vital role in DNA double-strand break repair through the aforementioned homologous recombination repair pathway. In the absence of these BRCA1/2 genes, HGSOCs display unstable genomes that are deficient in this pathway, thereby rendering these entities highly susceptible to DNA-damaging chemotherapeutic agents. On the basis of this mechanism, these tumors also appear exquisitely sensitive to treatment with poly(ADP-ribose) polymerase inhibitors (PARPi).15

Notoriously, the introduction of PARPi maintenance therapy has impressively changed the treatment paradigm of EOC. According to the current guidelines, these agents can now be offered to patients with International Federation for Obstetrics and Gynecology (FIGO) stage III–IV high-grade serous and endometrioid EOC who have a complete or partial response to first-line platinum-based chemotherapy.16 17 While each of the six randomized double-blind phase III trials conducted in the primary disease setting principally aimed at demonstrating the effect of PARPi maintenance therapy on progression-free survival in these patients,18–23 subgroup analyses now reveal the significance of these agents on surgical outcome. Considering the timing of surgery, a subgroup analysis of the SOLO1 trial showed that patients with BRCA somatic or germline mutations who received olaparib experienced substantially longer progression-free survival when undergoing upfront surgery than when being subjected to NACT/ICS (progression-free survival not reached vs 33.6 months).24 These data meticulously illustrate that targeted therapy with PARPi may considerably influence surgical management: where patients with BRCA mutant tumors prior to the PARPi era had similar progression-free survival outcomes following either primary cytoreductive surgery or NACT/ICS,10 13 14 these patients nowadays seem more likely to benefit from primary cytoreductive surgery when they are expected to receive PARPi maintenance therapy.24

Of further interest in this context is the value of PARPi in the neoadjuvant setting. The NOW trial, a phase I feasibility study, revealed that patients who received olaparib as a single agent for up to two cycles before surgery had an incredible response rate (NCT03943173).25 Thirteen out of a total of 15 patients (86%) proceeded to ICS without any need of additional chemotherapy. Moreover, in 86% of these patients, complete gross resection was achieved. Several other phase I-II trials are still ongoing (Table 1). Should the administration of PARPi in the neoadjuvant setting result in a lower tumor burden and normalization of cancer antigen 125 (CA125) values, then the outcomes of the currently ongoing LANCE trial might be of even greater importance. This trial aims to compare the progression-free survival outcomes following minimally invasive surgery versus open laparotomy in patients with good clinical treatment response after 3–4 cycles of NACT (NCT04575935).26

Clinical trials evaluating PARPi in the neoadjuvant setting in newly-diagnosed advanced EOC

The foregoing triggers the question to what extent PARPi maintenance therapy may affect intra-operative decision-making. Specifically, one may inquire whether the encouraging survival outcomes related to PARPi maintenance therapy may justify less radical surgery in patients in whom major surgical morbidity following complete gross resection cannot be ruled out. In an attempt to formulate a response to this issue, we recently performed a systematic review and meta-analysis.27 This analysis comprised all randomized double-blind phase III trials on first-line PARPi maintenance therapy (ie, SOLO 1,18 PAOLA 1,19 PRIMA,20 PRIME,21 ATHENA-MONO,22 and VELIA).23 Within these trials, the percentage of residual disease following cytoreductive surgery was around 30%. An overview of the effect of PARPi on progression-free survival by residual disease status is shown in Table 2. Regarding the progression-free survival rates, the magnitude of PARPi maintenance therapy in comparison to placebo appeared to be almost equivalent between patients with macroscopic residual disease and patients in whom complete gross resection was achieved (pooled HR 0.55, 95% CI 0.44 to 0.68, vs pooled HR 0.53, 95% CI 0.41 to 0.67, respectively).27 Hence, patients with residual disease following cytoreductive surgery benefit to the same extent from PARPi maintenance therapy as those with complete gross resection. Yet, with the exception of the ATHENA-MONO trial, which reported a higher magnitude of benefit for rucaparib as compared with placebo in the group with macroscopic residual disease treated with bevacizumab,22 all studies demonstrated that PARPi maintenance therapy elicited best survival rates in patients in whom complete gross resection was accomplished. Obviously, the heterogeneity in inclusion criteria and study designs of these trials should not be disregarded when interpreting these results. Nevertheless, it is abundantly clear that also in the PARPi era, the ultimate goal remains to ascertain the absence of any macroscopically visible lesions upon completion of surgery.

Effect of PARPi maintenance on progression-free survival by surgical residual tumor status in newly-diagnosed advanced EOC

With respect to the recurrent disease setting, both the SOC-1 and DESKTOP III trial have recently shown that secondary cytoreductive surgery might significantly prolong progression-free survival in patients with platinum-sensitive relapsed EOC.28 29 Especially in the DESKTOP III trial, the eligibility criteria for the identification of patients who mostly benefit from secondary cytoreductive surgery were well defined. These criteria are based on a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, consisting of an Eastern Cooperative Oncology Group (ECOG) performance score of 0, ascites of <500 mL, and complete resection at initial surgery. Although this AGO score led to a fairly adequate patient selection, as complete secondary cytoreductive surgery could be achieved in 75.5% of patients,29 there is still room for some improvement. Indeed, also a negative AGO score occasionally resulted in complete secondary cytoreduction.30 In pursuit of optimizing patient selection for secondary cytoreductive surgery, some researchers therefore endeavored to elucidate the role of BRCA mutational status in this setting. Glajzer and co-workers conducted a large retrospective international multicenter study, in which they found that in patients with BRCA mutant recurrent HGSOCs complete secondary cytoreduction was more often achieved than in patients with BRCA wild-type recurrent HGSOCs (82.1% vs 56.4%, p=0.004).31 This difference was even more pronounced in the second/third relapse setting (75.0% vs 26.8%, p=0.005) and the presence of a BRCA mutation was found to be a significant predictive factor for complete secondary resection (OR 0.214, 95% CI 0.078 to 0.587, p=0.003). These figures were likewise reflected in a significantly longer progression-free survival following secondary resection in BRCA mutant patients as compared with their BRCA wild-type counterparts (22 vs 15 months, p=0.025). Remarkably enough, no differences in peritoneal involvement were observed between these groups. These data are in line with a publication from Gallotta et al, in which the authors described the impact of BRCA mutational status on the outcomes of patients with a platinum-sensitive relapse with liver involvement. Notwithstanding the fact that in this study no differences in disease presentation between the study cohorts were found, patients with BRCA mutant recurrent HGSOC showed significantly better progression-free survival rates at 3 years following hepatic resection than those with BRCA wild-type recurrent HGSOC (81.0% vs 15.2%, p=0.001).32 These results may contribute to the selection of patients for secondary cytoreductive surgery requiring liver resection. Strikingly, in patients with isolated lymph node recurrence, on the other hand, the presence of a BRCA gene mutation had no prognostic impact and has therefore no place in the selection of patients for salvage lymphadenectomy.33 Incidentally, although the presence of a BRCA gene mutation mostly resulted in higher progression-free survival rates, it does not necessarily indicate that patients not harboring a BRCA germline mutation may not benefit from secondary cytoreductive surgery.34

The implementation of PARPi maintenance therapy not only results in a prolongation of the disease-free interval, it also seems to alter the manifestation of disease recurrence. A secondary analysis of the PRIMA trial showed that >75% of patients diagnosed with a relapse under niraparib presented with oligometastatic disease.35 Although stereotactic radiotherapy might be an efficacious treatment option for these patients,36 cytoreductive surgery using a minimally invasive approach needs to be considered. This approach is particularly suitable for patients who present with either single or oligometastatic disease (ie, 2–3 separate nodules) and those being exposed to NACT in the first line setting.37 The oncological outcomes following this approach were found to be roughly equivalent as compared with open laparotomy (3-year recurrence free-survival of 76.0% vs 84.1%, respectively, p=not significant). Besides, the risk of peri-operative complications was considerably lower—33.3% in patients undergoing minimally invasive surgery versus 10.3% in patients who underwent open laparotomy (p=0.004). While this potential advantage of reduced peri-operative complications did not emerge from the study performed by Eriksson et al, their results confirmed that a minimally invasive approach is non-inferior to the open technique in terms of survival outcomes.38 To enable the performance of this minimally invasive approach, a timely diagnosis of recurrent disease is absolutely necessary. Thorough follow-up of these patients is thus warranted, as the monitoring of only CA125 serum levels was found to be insufficient for early detection of disease progression.39 Moreover, research is needed to comprehensively revise the current selection criteria for secondary cytoreductive surgery, as the trials from which these criteria originated were largely performed prior to the PARPi era. The SOCCER-P trial, a randomized phase II study on secondary cytoreductive surgery in patients with relapsed ovarian cancer who have progressed on PARPi maintenance (NCT05704621), is a first step in that direction. Further unraveling of the role of BRCA mutational status within this recurrent disease setting should also definitely be a key point to focus on.