New frontiers in the management of recurrent epithelial ovarian cancer: a comprehensive review

Chemotherapy

Carboplatin remains the backbone of treatment for ovarian cancer recurrence occurring >6 months after completion of adjuvant therapy. The MITO-8 trial investigated the impact of introducing non-platinum chemotherapy earlier in the treatment of partially platinum-sensitive recurrent ovarian cancer (PFI of 6–12 months). Contrary to expectations, the study demonstrated that delaying platinum re-challenge in favour of initial non-platinum agents did not improve progression-free survival (PFS) and was associated with inferior outcomes compared with immediate platinum-based therapy.9 Similarly, the INOVATYON trial evaluated whether a platinum-free combination of trabectedin and pegylated liposomal doxorubicin (PLD), followed by platinum at progression, could outperform conventional platinum-based chemotherapy. The results confirmed that platinum-based regimens remain the standard of care, as no significant improvement in overall survival (OS) was observed in the experimental arm (patients who had previously received up to two lines of platinum-based therapy).10 These findings reinforce the pivotal role of platinum agents in the treatment of platinum-sensitive ovarian cancer. Several treatment regimens are currently available, including carboplatin (area under the curve (AUC) 5) plus paclitaxel (175 mg/m² intravenously), carboplatin (AUC 4) plus gemcitabine (1000 mg/m² on days 1 and 8) or carboplatin (AUC 5) combined with PLD (30 mg/m² intravenously).

Secondary surgery

The potential benefit of secondary cytoreductive surgery (SCS) in recurrent platinum-sensitive ovarian cancer has been investigated in several phase III trials, yielding mixed results. The DESKTOP III11 and SOC-112 trials demonstrated that, in carefully selected patients in whom complete macroscopic resection is achieved, SCS followed by chemotherapy significantly improves PFS compared with chemotherapy alone (18.4 months vs 14 months (HR 0.66, 95% CI 0.54 to 0.82) in the DESKTOP III and 17.4 months vs 11.9 (HR 0.58, 95% CI 0.45 to 0.74) in the SOC-1). Notably, DESKTOP III also showed a significant improvement in OS11 (53.7 months vs 46.0 months (HR 0.75, 95% CI 0.59 to 0.96)). In contrast, the SOC-1 trial did not demonstrate a statistically significant OS benefit in the intention-to-treat population. However, prespecified sensitivity and subgroup analyses revealed a clinically relevant OS advantage, particularly among patients with fewer than 20 sites of recurrence. Conversely, the GOG-213 trial did not show any OS benefit from SCS when added to chemotherapy and bevacizumab.13 Collectively, these findings suggest that SCS surgery may be beneficial in a subset of patients with recurrent disease, especially when complete resection is feasible, typically in the context of oligometastatic disease.

Hyperthermic intraperitoneal chemotherapy

Hyperthermic intraperitoneal chemotherapy (HIPEC) is an intraoperative treatment modality used in selected cases of advanced ovarian cancer, typically following complete or optimal cytoreductive surgery. During the procedure, heated chemotherapy—commonly cisplatin at 41°C–43°C—is circulated within the peritoneal cavity for 60–90 min. Hyperthermia enhances the cytotoxic effect of the drug, increases tissue penetration and promotes apoptosis, while simultaneously improving drug uptake by cancer cells and impairing DNA repair mechanisms. HIPEC allows for direct exposure of the peritoneal surfaces to high concentrations of chemotherapy, minimising systemic toxicity. In the setting of platinum-sensitive recurrent ovarian cancer, the benefit of adding HIPEC to SCS remains controversial. The CHIPOR trial14 investigated this approach by enrolling women with a first platinum-sensitive relapse of EOC (platinum-free interval ≥6 months) who were eligible for SCS. Patients were randomised 1:1 to undergo SCS followed by intraoperative HIPEC or SCS alone without HIPEC. All patients received six cycles of platinum-based chemotherapy prior to SCS.

After a median follow-up of 6.2 years, HIPEC was associated with a significant improvement in OS (54 vs 46 months) and peritoneal PFS. However, this benefit came at the cost of increased grade ≥3 toxicities, particularly anaemia and renal impairment. Importantly, no detrimental effect on patient-reported quality of life was observed despite the higher toxicity profile. The HORSE/MITO-18 trial, a multicentre Italian study with a similar design, did not demonstrate any PFS benefit in the group that received HIPEC.15 These findings indicate that HIPEC may provide clinical advantages in patients recently exposed to chemotherapy. Nevertheless, the associated rise in post-treatment complications, along with uncertain survival benefits, has made HIPEC a subject of ongoing controversy and debate within the medical community.

Bevacizumab in platinum-sensitive recurrent ovarian cancer

Bevacizumab is used in both frontline and recurrent ovarian cancer, typically in combination with chemotherapy and as maintenance. In the phase III OCEANS trial, patients with platinum-sensitive recurrent ovarian cancer received gemcitabine and carboplatin with either bevacizumab or placebo. The addition of bevacizumab significantly improved PFS (12.4 vs 8.4 months; HR 0.484; p<0.0001), although OS was similar between groups (33.6 vs 32.9 months; HR 0.95; p=0.65).16

A similar benefit was observed in the MITO16b/MANGO–OV2/ENGOT–ov17 trial, a multicentre, open-label, randomised phase III study across Italy, Spain, Israel and the UK. The trial enrolled women with recurrent, platinum-sensitive FIGO stage IIIB–IV EOC who had previously received first-line platinum-bevacizumab therapy. Patients were randomised to a carboplatin-based doublet (carboplatin plus paclitaxel, gemcitabine or PLD) with or without bevacizumab.

Median PFS was significantly improved with the addition of bevacizumab (11.8 vs 8.8 months; HR 0.51, 95% CI 0.41 to 0.65; p<0.0001), confirming the efficacy of continued bevacizumab beyond progression in this setting.17

PARP inhibitors

The role of PARPi in platinum-sensitive relapsed ovarian cancer has evolved significantly, guided by key clinical trials and regulatory changes.

Olaparib demonstrated clinical benefit as maintenance therapy. The phase III SOLO2/ENGOT-Ov21 trial included 295 patients with platinum-sensitive, germline BRCA-mutated, high-grade serous or endometrioid ovarian cancer. Olaparib maintenance significantly prolonged PFS (19.1 vs 5.5 months; HR 0.30) and showed a trend towards improved OS (52 vs 39 months; HR 0.74).18 The SOLO3 trial compared olaparib (300 mg two times per day) with physician’s choice chemotherapy in patients with relapsed, BRCA1/2-mutated ovarian cancer. Olaparib improved objective response rate (ORR) (72% vs 51%) and median PFS (13.4 vs 9.2 months). Based on these findings, olaparib received accelerated Food and Drug Administration approval in 2014 for germline BRCA-mutated (gBRCA+) relapsed ovarian cancer after ≥3 prior lines (3L) of therapy. In 2017, it was approved for maintenance in platinum-sensitive relapsed ovarian cancer after a complete response (CR) or partial response to platinum-based chemotherapy. However, following unfavourable OS data from SOLO3, the ≥3L indication was withdrawn in 2022, and as of 2023, maintenance use is restricted to germline/somatic BRCA-mutated (g/sBRCA+) patients.19

Niraparib was evaluated in the phase III NOVA trial. Among 553 platinum-sensitive, PARP-naïve patients, niraparib maintenance improved PFS in all subgroups, particularly in gBRCA+ patients (21.0 vs 5.5 months; HR 0.27). However, OS benefit was not observed (44 vs 42 months).20 The QUADRA trial showed modest activity in homologous recombination deficiency (HRD)-positive recurrent disease (ORR 27.5%).21 Initially approved in 2017 for maintenance, niraparib’s use was later restricted (November 2022) to gBRCA+ patients only, with the 3L+ HRD-based treatment indication withdrawn in September 2022.

Rucaparib received accelerated approval in 2016 for g/sBRCA+ platinum-sensitive relapsed ovarian cancer after ≥2 prior therapies, based on ORR data from Study 10 (ORR 53.8% (95% CI 43.8 to 63.5)) and ARIEL2 (BRCA-mutated: ORR 45.7% (95% CI 37.2 to 54.3)). However, the ARIEL4 trial failed to show OS benefit, leading to the withdrawal of the 3L+ treatment indication (June 2022) and restriction of maintenance use to gBRCA+ patients (December 2022).22

Recently, the OReO/ENGOT-Ov38 trial evaluated olaparib rechallenge in patients with platinum-sensitive recurrent ovarian cancer previously treated with a PARPi, demonstrating a significant improvement in PFS compared with placebo, both in patients with BRCA mutations (HR 0.57, 95% CI 0.37 to 0.87) and in those without BRCA mutations (HR 0.43, 95% CI 0.26 to 0.71).

In summary, while PARPi remain central in maintenance treatment of platinum-sensitive relapsed ovarian cancer, their use in later lines has been limited due to lack of OS benefit. Current focus is shifting towards earlier-line use in biomarker-selected populations, particularly those with g/sBRCA or HRD positivity.

Immune checkpoint inhibitors

Phase III clinical trials evaluating immune checkpoint inhibitors (ICIs) in ovarian cancer have not demonstrated clinically meaningful activity, irrespective of the line of treatment or combination strategies involving bevacizumab and PARPi. In the first-line setting, studies such as JAVELIN-100 (avelumab),23 IMagyn050 (atezolizumab),24 DUO-O (durvalumab)25 and ATHENA Combo (nivolumab)26 assessed the combination of chemotherapy with ICIs, with or without PARPi, but failed to show significant clinical benefit. In platinum-sensitive recurrent ovarian cancer, phase III trials ATALANTE (atezolizumab)27 and ANITA (atezolizumab),28 investigating combinations of chemotherapies, ICIs and bevacizumab or PARPi, have also failed to show significant clinical benefit. The available evidence underscores the limited role of ICIs in the management of ovarian cancer, questioning their utility regardless of treatment setting or combination strategy.

Platinum rechallenge

According to the 2018 ESMO (European Society of Medical Oncology)-ESGO (European Society of Gynaecological Oncology) consensus, platinum rechallenge may be considered for selected patients with PROC who did not progress during previous platinum therapy and have received an intervening non-platinum regimen. However, supporting evidence is limited.8

Several trials have explored platinum-based combinations in this setting. In a trial by Nagourney et al, cisplatin and gemcitabine yielded a 57% ORR and a median PFS of 6.0 months.30 Another phase II study combining carboplatin, gemcitabine and iniparib reported an ORR of 26% and a PFS of 6.8 months in patients relapsing 2–6 months after prior platinum therapy.31 Brewer et al evaluated gemcitabine and cisplatin in a 28-day cycle, with an ORR of 16% and a PFS of 5.4 months in primary platinum-resistant patients.32 Sharma et al retrospectively analysed a regimen of paclitaxel and carboplatin, achieving an ORR of 60% and a PFS of 7.9 months.33

A multicentre study by Tatsuki et al assessed various platinum-based combinations (including paclitaxel, docetaxel, gemcitabine, PLD and irinotecan) and reported an ORR of 55% and a median PFS of 8.5 months. More recently, a prospective cohort of 30 patients showed an ORR of 27% and a disease control rate (DCR) of 80%. The majority (77%) received carboplatin-based regimens. Median PFS was 5.4 months, with a 6-month PFS rate of 47%.34

These findings suggest that platinum rechallenge is a viable strategy for a subset of patients with PROC, particularly those with an initial platinum response and adequate treatment-free interval. Further research incorporating novel agents and predictive biomarkers is warranted to refine patient selection and optimise outcomes in this setting.

Bevacizumab

The AURELIA trial evaluated the addition of bevacizumab to chemotherapy in patients with platinum-resistant ovarian cancer who had received no more than two prior treatment lines and had no evidence of gastrointestinal complications or rectosigmoid involvement. Participants were randomised to receive either chemotherapy alone or in combination with bevacizumab (15 mg/kg every 3 weeks). The choice of chemotherapy (weekly paclitaxel, topotecan or PLD) was determined by the treating physician.

The combination arm demonstrated a significant improvement in PFS, with a median PFS of 6.7 months compared with 3.4 months in the chemotherapy-only group (HR 0.48, 95% CI 0.38 to 0.60; p<0.001). While OS showed a numerical increase (16.6 vs 13.3 months), the difference was not statistically significant (HR 0.85, 95% CI 0.66 to 1.08; p=0.174). These results support the use of bevacizumab in combination with chemotherapy to improve disease control in the platinum-resistant setting.35

Immune checkpoint inhibitors

In contrast, the integration of ICIs with chemotherapy and bevacizumab has not yielded clinical benefit in this setting. Trials such as JAVELIN-200 (avelumab),36 NRG GY009 (atezolizumab)37 and KEYNOTE-B96 (pembrolizumab)38 failed to demonstrate significant improvements in survival outcomes, suggesting limited efficacy of ICI-based strategies in platinum-resistant ovarian cancer to date.

Mirvetuximab soravtansine

Folate receptor alpha (FRα) is a membrane protein that binds to and transports folate into cells, and it exhibits high overexpression on ovarian cancer cells. In high-grade serous ovarian cancer, approximately 80% of cells show some level of FRα expression. Immunohistochemistry (IHC) assessments indicate that FRα is most highly expressed on the surface of serous EOC cells.39 Mirvetuximab soravtansine (MIRV) is an ADC that selectively binds FRα, delivering the cytotoxic agent DM4 intracellularly. DM4 disrupts microtubule dynamics, inducing mitotic arrest and apoptosis, with potential bystander effects due to its membrane-permeable properties.40

Clinical activity of MIRV has been demonstrated in PROC with high FRα expression. In the phase II SORAYA trial, MIRV achieved an ORR of 32% and a median duration of response (mDOR) of 6.9 months.41 The phase III MIRASOL trial further validated its efficacy in a randomised setting. MIRASOL enrolled patients with FRα-high, platinum-resistant disease (platinum-free interval ≤6 months) and high-grade serous histology. Prior exposure to bevacizumab and PARPi was allowed. Patients (n=453) were randomised 1:1 to MIRV (6 mg/kg every 3 weeks, adjusted ideal body weight) or investigator’s choice chemotherapy (paclitaxel, PLD or topotecan). MIRV significantly prolonged PFS compared with chemotherapy (median 5.6 vs 4.0 months; HR 0.65; p<0.0001) and improved OS (median 16.5 vs 12.8 months; HR 0.67; p=0.0046). ORR was higher with MIRV (42% vs 16%), including 12 CR versus none in the control arm.42

In the FORWARD II trial, MIRV was evaluated in combination with bevacizumab across various FRα expression levels. Among 126 patients, the overall ORR was 44%, with a 12% CR rate. Subgroup analyses showed enhanced activity in patients with higher FRα expression: ORR reached 52% (CR 27%) in those with ≥75% expression and 39% (CR 31%) in those with ≥90%. These findings support FRα as a predictive biomarker, aligning with National Comprehensive Cancer Network (NCCN) recommendations for its assessment in PROC and primary sensitive ovarian cancer.43

Trastuzumab deruxtecan

HER2 overexpression and amplification are identified in approximately 7% of ovarian cancers, although lower than in other tumour types, it presents a therapeutic opportunity in select cases. Pathological evaluation of tumour HER2 protein expression and gene amplification is a critical component of therapeutic decision-making. HER2 IHC testing guidelines from The College of American Pathologists (CAP)/American Society for Clinical Pathology (ASCP)/the American Society of Clinical Oncology (ASCO) define IHC 3+ positivity as circumferential membrane staining that is complete and intense in >10% of tumour cells for breast cancer; strong complete, basolateral or lateral membranous reactivity in ≥10% of tumour cells for surgical gastric specimens and strong complete, basolateral or lateral membranous reactivity in tumour cell clusters (≥5 cells), irrespective of the percentage of tumour cells stained, for gastric biopsy specimens.44

Trastuzumab deruxtecan (T-DXd) is an ADC designed to target HER2-expressing tumours. It consists of a humanised anti-HER2 monoclonal antibody linked to deruxtecan, a potent topoisomerase I inhibitor, via a cleavable linker. This structure allows for selective intracellular release of the cytotoxic payload within the tumour microenvironment, facilitating a bystander effect even in tumours with heterogeneous HER2 expression.

The DESTINY-PanTumor02 trial evaluated T-DXd in advanced solid tumours, including a cohort of patients with previously treated ovarian cancer and HER2 expression (IHC 1+ to 3+). Patients were heavily pretreated, with a substantial proportion receiving three or more prior lines of therapy. In ovarian cancer, the confirmed ORR was 45.0% in IHC 3+ tumours, 63.6% in IHC 2+ tumours, 36.8% in IHC 1+ tumours and 20.0% in IHC 0 tumours. mDOR ranged from 8.3 to 22.1 months across HER2 expression levels. Patients with HER2-amplified tumours also showed encouraging activity, with an ORR of 60%. These findings support the potential of T-DXd in HER2-expressing ovarian cancer, particularly in IHC 2+ and 3+ subgroups. Current NCCN guidelines recognise T-DXd as a therapeutic option in select cases of HER2-positive ovarian cancer (IHC 2+/3+), following prior lines of therapy.44

Ongoing investigation includes the DESTINY-Ovarian01 trial, a phase III study evaluating T-DXd combined with bevacizumab as first-line maintenance therapy in patients with epithelial ovarian, fallopian tube or primary peritoneal cancer with confirmed HER2 expression (IHC 1+ to 3+). Eligible patients must have achieved disease control following carboplatin-paclitaxel-bevacizumab induction and are not candidates for PARPi maintenance. The trial will stratify patients by HER2 IHC status, surgical outcomes and histology. The primary end point is PFS, with secondary end points including OS, response rates and safety outcomes. The study aims to clarify the role of HER2-directed therapy in the maintenance setting for HER2-expressing ovarian cancer.45

Novel ADCs in ovarian cancer

Several investigational agents targeting FRα, cadherin-6 (CDH6) and trophoblast cell-surface antigen 2 (TROP2) are under evaluation for relapsed or PROC, with promising efficacy observed across early and late-phase clinical trials.

The REFRaME-O1 study (GOG 3086/ENGOT-OV79) is a phase II/III randomised trial investigating luveltamab tazevibulin, an FRα-targeting ADC, in patients with FRα-positive PROC. Eligible participants must have received one to three prior treatment lines and exhibit at least 25% FRα expression, with platinum-refractory disease excluded. In part 1 of the study, patients were randomised to receive either 5.2 mg/kg or 4.3 mg/kg intravenously every 3 weeks. An optimised dose (5.2 mg/kg) was selected for part 2, comparing luveltamab tazevibulin against investigator’s choice chemotherapy. Interim results demonstrated an ORR of 32% and a DCR of 96% at the 5.2 mg/kg dose, supporting continued evaluation in this population.46

The RainFOL trial (ENGOT-OV86/GOG 3107) is a phase III evaluating rinatabart sesutecan (Rina-S), an ADC consisting of a human monoclonal antibody that selectively binds FRα and a topoisomerase 1 inhibitor payload, exatecan, in patients with relapsed PROC. Eligible patients include those with high-grade serous or endometrioid histology who have progressed after standard-of-care therapies, including platinum, bevacizumab, PARPi (if BRCA-mutant) and MIRV (if FRα-positive). Participants are randomised to receive either Rina-S or investigator-selected chemotherapy. The primary end point is PFS, with secondary end points including OS, ORR, DOR and quality of life.47

The REJOICE-Ovarian01 study (ENGOT-OV77/GOG 3096) is a phase II/III trial evaluating raludotatug deruxtecan (R-DXd), a CDH6-targeted ADC, in PROC. Patients must have received one to three prior lines of therapy, including bevacizumab, and must not have received prior CDH6-directed agents or topoisomerase I inhibitor ADCs. Phase II involves dose escalation (4.8–6.4 mg/kg intravenously every 3 weeks), while phase III randomises patients to R-DXd at the recommended dose versus investigator’s choice chemotherapy. Primary end points include ORR and PFS, with secondary assessments of OS, DOR and quality of life.48

Datopotamab deruxtecan, a TROP2-directed ADC, is being explored in the TROPION-PanTumor03 study (substudy 4) for advanced ovarian cancer. This agent combines a topoisomerase I payload with a cleavable tetrapeptide linker, enabling a bystander effect. Patients with high-grade serous or endometrioid tumours who have progressed after one or two prior lines of platinum therapy are treated with 6 mg/kg intravenously every 3 weeks. Primary outcomes include ORR and safety; secondary end points assess PFS, DOR, DCR, pharmacokinetics and OS. The study includes biomarker evaluations to refine patient selection.49

These agents represent emerging strategies to improve outcomes in PROC through biomarker-directed therapy, and ongoing randomised trials will determine their definitive clinical utility.

Relacorilant

Cortisol-mediated activation of the glucocorticoid receptor (GR) suppresses apoptosis, contributing to resistance to cytotoxic agents such as nab-paclitaxel. GR is frequently overexpressed in ovarian cancer and is associated with adverse clinical outcomes. Relacorilant, a selective GR modulator, blocks the anti-apoptotic effects of cortisol and may enhance chemotherapy sensitivity.50

The ROSELLA trial (GOG-3073/ENGOT-ov72; NCT05257408) is a phase III, open-label, randomised study evaluating relacorilant plus nab-paclitaxel in patients with high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer. Eligible patients have disease progression within 6 months of their last platinum-based therapy, excluding primary platinum-refractory cases and have received one to three prior treatment lines. Patients are randomised 1:1 to receive either oral relacorilant (150 mg) with intravenous nab-paclitaxel (80 mg/m²) or investigator’s choice of chemotherapy: PLD, paclitaxel, topotecan (weekly or 5-day regimen) or nab-paclitaxel (100 mg/m²). The primary end point is PFS assessed by blinded independent central review. Secondary end points include OS, investigator-assessed PFS, ORR, best response, duration of response, clinical benefit rate, CA-125 response and composite response by Response Evaluation Criteria In Solid Tumors (RECIST) and Gynecological Cancer Intergroup (GCIG) criteria. Safety, quality of life, pharmacokinetics and pharmacodynamics are also evaluated.51

WEE1 inhibition

The G2/M checkpoint ensures genomic stability by arresting the cell cycle in response to DNA damage, thereby allowing repair before mitosis. In tumours with p53 dysfunction—where the G1/S checkpoint is compromised—cells increasingly rely on the G2/M checkpoint, leading to replication stress and susceptibility to checkpoint inhibition. WEE1 kinase is a critical regulator of this checkpoint, and its inhibition disrupts cell cycle control, inducing mitotic catastrophe in DNA repair-deficient tumours.52

Adavosertib, an oral WEE1 inhibitor, has shown preclinical activity both alone and in combination with PARPi in models of PARP-resistant ovarian cancer. A phase II randomised, double-blind trial evaluated adavosertib plus gemcitabine in platinum-resistant or refractory ovarian cancer. The combination demonstrated a significant improvement in PFS (HR 0.55; 95% CI 0.35 to 0.90; p=0.015) and OS (HR 0.56; 95% CI 0.35 to 0.91; p=0.017), supporting its therapeutic potential in this population.53