This chapter should be cited as follows:
Li B, Glob Libr Women's Med
ISSN: 1756-2228; DOI 10.3843/GLOWM.422263
The Continuous Textbook of Women’s Medicine Series – Gynecology Module
Volume 13
Gynecological cancer
Volume Editors:
Professor Hextan Ngan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong
Professor Karen Chan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong
Chapter
Treatment of Recurrent Ovarian Cancer after First-line Therapy
First published: July 2026
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INTRODUCTION
Recurrent ovarian cancer remains a formidable challenge, with up to 70% of Stage III–IV high-grade cases relapsing within 3 years despite multimodal first-line therapies. Managing recurrence requires a holistic, patient-centered approach, incorporating factors such as BRCA status, treatment-free intervals, prior poly(ADP-ribose) polymerase (PARP) inhibitor use, and the feasibility of secondary cytoreductive surgery. Recent advancements, including targeted therapies like PARP inhibitors and antibody-drug conjugates, as well as innovations in systemic therapy, offer hope but are tempered by inconsistent survival outcomes and significant toxicity. The evolving therapeutic landscape underscores the critical need for personalized strategies that balance disease control with quality of life.
When relapse is suspected, a holistic evaluation of multiple factors is essential to guide therapy choices for individual patients. These factors include the histology of the primary tumor, BRCA status, prior use of PARP inhibitors, number of previous treatment lines, response to prior therapy, treatment-free intervals (particularly the platinum-free interval) and the potential for surgery, especially the likelihood of achieving complete resection balanced against surgical morbidity. Additional considerations include residual toxicity from previous treatments, the patient’s overall fitness and their personal preference.
The initial step in selecting systemic therapy is assessing a patient’s eligibility for platinum-based chemotherapy. Traditionally, patients are classified as platinum-sensitive (recurrence ≥ 6 months after first-line platinum therapy) or platinum-resistant (progression within 6 months). However, factors like follow-up frequency, tumor marker monitoring, histology and BRCA1/2 mutation status can impact the treatment-free interval and response to platinum.1 Not all patients with a platinum-free interval > 6 months respond to platinum (objective response rate 47.2%–66%), and platinum-based combinations have shown efficacy in some patients with a platinum-free interval < 6 months. Clinical judgement is needed on top of the 6-month definition.
CYTOREDUCTIVE SURGERY IN THE RECURRENT SETTING
Patients experiencing a first relapse more than 6 months after completion of first-line platinum-based chemotherapy should be evaluated for secondary cytoreductive surgery in experienced gynecological centers. This approach has been studied in three key randomized trials. The DESKTOP series established the AGO score to identify patients suitable for complete resection (76% success rate), with criteria including complete resection at primary surgery (or FIGO stage I–II), ECOG 0 and < 500 mL ascites. DESKTOP III2 showed improved overall survival (OS) and progression-free survival (PFS) with secondary cytoreductive surgery plus chemotherapy vs chemotherapy alone. The SOC-1 trial3 also showed a PFS benefit using the iModel for patient selection, though OS data remain immature. GOG-02134 found no survival benefit, likely due to lack of proper selection criteria. Complete resection (R0) and appropriate patient selection with surgical expertise are critical for benefit.
While secondary cytoreduction has shown PFS benefit, particularly when complete gross resection is achieved, OS outcomes remain inconsistent. If secondary cytoreductive surgery is performed, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the recurrent setting remains controversial. In the MSK Team Ovary Phase-II study, HIPEC showed no benefit and may have been associated with a detrimental effect in recurrent disease.5 The Phase-3 CHIPOR trial demonstrated that adding HIPEC to cytoreductive surgery after response to six cycles of preoperative platinum-based chemotherapy at first epithelial ovarian cancer recurrence significantly improved OS.6 Median OS was 54.3 months (95% CI, 41.9–61.7 months) with HIPEC, vs 45.8 months (95% CI, 38.9–54.2 months) without HIPEC. However, Grade 3 or worse adverse events within 60 days were higher with HIPEC (49% vs 27%), including anemia (23% vs 14%), hepatotoxicity (11% vs 9%), electrolyte disturbances (14% vs 1%) and renal failure (10% vs 1%). Notably, three deaths occurred within 60 days, all in the no-HIPEC group. Despite this, HIPEC is usually not recommended in international guidelines.
PLATINUM-SENSITIVE RECURRENCE
For platinum-sensitive recurrence, retreatment with carboplatin combined with paclitaxel, liposomal doxorubicin or gemcitabine, with or without bevacizumab, is recommended. Bevacizumab can also be continued as maintenance therapy if it was not previously used in first-line maintenance settings.
Clinical trials related to conventional chemotherapy choices were primarily conducted in the early 2000s. While there may be slight differences in PFS between regimens, the benefits are generally modest, and improvements in OS were mostly non-significant. The expected PFS is typically around 12 months.
For example, the Phase-III GCIG CALYPSO trial compared carboplatin-liposomal doxorubicin (CD) with carboplatin-paclitaxel (CP) in 976 patients with platinum-sensitive recurrent ovarian cancer who relapsed after more than 6 months. PFS was significantly improved in the CD arm (median 11.3 months vs 9.4 months; HR 0.82; 95% CI, 0.72–0.94; P = 0.005) after a median follow-up of 22 months. However, OS did not differ significantly between the two arms, with median OS of 30.7 months in the CD arm and 33.0 months in the CP arm (HR 0.99; 95% CI, 0.85–1.16; P = 0.94).7
Role of bevacizumab in platinum-sensitive recurrent ovarian cancer
The use of bevacizumab, an anti-VEGF therapy, in combination with chemotherapy for platinum-sensitive recurrent ovarian cancer (PSROC) has shown mixed results, particularly in PFS and OS. Most studies showed that adding bevacizumab to chemotherapy improves PFS compared to chemotherapy alone or with placebo. However, the evidence for OS improvement remains inconclusive. For example, in the GOG-0213 trial,4 the addition of bevacizumab improved PFS (median 13.8 vs 10.2 months; HR 0.63) but did not result in a statistically significant OS benefit (HR 0.87). Similarly, the OCEANS trial8 demonstrated a PFS benefit with bevacizumab (median 12.3 vs 8.6 months; HR 0.45) but no significant OS advantage.
Treatment response rates were also higher with bevacizumab in combination with chemotherapy. The OCEANS trial reported an objective response rate (ORR) of 78.5% with bevacizumab vs 57.4% without it. Non-randomized studies similarly supported improved ORRs and PFS with bevacizumab, although methodological limitations, such as retrospective study design and potential selection bias, limit the strength of these findings. Quality of life (QoL), assessed in the GOG-0213 trial, showed no significant differences between the bevacizumab and control groups, reflecting a neutral impact on patient-reported outcomes.
Safety concerns were consistent with bevacizumab’s established profile, including hypertension, gastrointestinal perforation and proteinuria. Serious adverse events were more frequent in patients receiving bevacizumab, though the overall toxicity was considered manageable.
The AGO-OVAR 2.21/ENGOT-ov 18 trial compared carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) to carboplatin–gemcitabine–bevacizumab (standard group) in 682 patients. Median PFS was significantly longer in the experimental group (13.3 months; 95% CI, 11.7–14.2 months) compared to the standard group (11.6 months; 95% CI, 11.0–12.7 months) with a hazard ratio of 0.81 (95% CI, 0.68–0.96; P = 0.012).9
In conclusion, while bevacizumab has demonstrated PFS and response rate benefits in PSROC, its lack of consistent OS benefit and potential safety risks highlight the need for patient-specific considerations. The evidence supports its role as a treatment option, particularly in improving disease control.
Role of PARP inhibitors in the recurrent setting
PARP inhibitors such as olaparib, niraparib and rucaparib have demonstrated significant PFS benefits in patients responding to platinum-based therapy, particularly in those with BRCA mutations. The SOLO2/ENGOT-Ov21 trial evaluated olaparib as maintenance therapy in patients with platinum-sensitive, BRCA-mutated recurrent ovarian cancer and demonstrated a significant improvement in PFS, with a median PFS of 19.1 months vs 5.5 months with placebo (HR 0.30; 95% CI 0.22–0.41; P < 0.0001). Long-term follow-up showed an OS hazard ratio of 0.74 (95% CI 0.54–1.00) in the full analysis set; however, this analysis was not adjusted for crossover, as 38.4% of patients in the placebo group received a PARP inhibitor. Subsequent OS analyses suggested reduced benefit in patients without BRCA mutations, contributing to restricted regulatory approvals of PARP inhibitors in non-BRCA settings.10
The ENGOT-OV16/NOVA trial demonstrated that niraparib maintenance therapy improved PFS after a response to platinum rechallenge in patients with high-grade serous carcinoma (HGSC) and high-grade endometrioid carcinoma (EC), with significant benefits in both germline BRCA1/2-mutated (HR 0.27; 95% CI, 0.17–0.41) and non-germline BRCA1/2-mutated patients (HR 0.45; 95% CI, 0.34–0.61). However, updated OS data, retrieved after addressing missing survival information, revealed no statistically significant differences between niraparib and placebo in either the germline BRCA-mutated cohort (median OS: 40.9 vs 38.1 months; HR 0.85) or the non-germline BRCA-mutated cohort (median OS: 31.0 vs 34.8 months; HR 1.06). Secondary endpoints, including chemotherapy-free interval, time to first and second subsequent therapy and PFS2 (i.e. time from randomization to either disease progression while receiving the next anticancer therapy after the study treatment, or death from any cause), continued to favor niraparib.11
Similarly, the ARIEL3 trial showed that rucaparib maintenance therapy significantly improved PFS after platinum response across multiple cohorts, including the germline or somatic BRCA1/2-mutated group (HR 0.23; 95% CI, 0.16–0.34), the homologous recombinant deficient (HRD) cohort (HR 0.32; 95% CI 0.24–0.42), and the overall intention-to-treat (ITT) population (HR 0.36; 95% CI 0.30–0.45). Median OS from randomization post chemotherapy for rucaparib vs placebo was 45.9 vs 47.8 months (HR 0.83, 95% CI 0.58–1.19) for the BRCA-mutated population; no OS benefit was found with rucaparib in the HRD and ITT populations.12
Patients who have not received a PARP inhibitor as part of their primary treatment should be offered one in the recurrent setting if they are BRCA-positive. For BRCA-negative patients, the benefits of PARP inhibitor maintenance are less well-defined, and individualized risk–benefit discussions are necessary to guide treatment decisions. However, this decision may soon become irrelevant as PARP inhibitors demonstrate clear clinical benefits in first-line settings, meaning most patients will likely have already received them earlier in their treatment course.
Retreatment with a PARP inhibitor following prior failure of PARP maintenance therapy is generally not recommended, as it is unlikely to provide clinically meaningful benefits. OReO/ENGOT-ov38, showed a marginally positive short-lived benefit for some patients retreated with olaparib. Seventy-four BRCA-mutated and 72 non-BRCA-mutated patients were randomized to olaparib, while 38 and 36 patients, respectively, received placebo, with over 85% having undergone ≥ 3 prior lines of chemotherapy. In the BRCA-mutated cohort, olaparib improved median PFS to 4.3 months compared to 2.8 months with placebo (HR 0.57; 95% CI, 0.37–0.87; P = 0.022), with 1-year PFS rates of 19% vs 0%. Similarly, in the non-BRCA-mutated cohort, median PFS was 5.3 months with olaparib vs 2.8 months with placebo (HR 0.43; 95% CI, 0.26–0.71; P = 0.0023), and 1-year PFS rates were 14% vs 0%.13
Notably, single-agent PARP inhibitors should not be used to treat recurrent ovarian cancer; instead, they are intended for use as maintenance therapy after disease control has been achieved with platinum-based chemotherapy.
PLATINUM-RESISTANT RECURRENCE
For platinum-resistant recurrence, sequential single-agent chemotherapy (e.g. weekly paclitaxel, liposomal doxorubicin, topotecan) with or without bevacizumab is advised. In general, the reported response rates of conventional chemotherapy in recent platinum-resistant ovarian cancer (PROC) trials have been 10–15%, with a median PFS of approximately 3–4 months.
Bevacizumab combined with chemotherapy has shown improved PFS in this setting. The AURELIA trial demonstrated that adding bevacizumab to non-platinum chemotherapy improved outcomes in PROC. In this Phase-III study of 361 patients, bevacizumab combined with chemotherapy significantly improved PFS (6.7 vs 3.4 months; HR 0.48, 95% CI, 0.38–0.60) and ORR (27.3% vs 11.8%; P = 0.001), though no significant OS benefit was observed. Toxicities, including a 2% risk of gastrointestinal perforation and exacerbation of chemotherapy-specific side effects like neuropathy or hand–foot syndrome, were consistent with prior findings.14
Antibody-drug conjugates
Recurrent ovarian cancer in the platinum-resistant setting poses particular therapeutic challenges. Traditional systemic treatments, including single-agent chemotherapies such as paclitaxel, liposomal doxorubicin, topotecan and gemcitabine, have been limited by their toxicity and modest efficacy. The recent emergence of antibody-drug conjugates (ADCs) has revolutionized the treatment landscape, providing a novel, targeted approach with improved outcomes and a manageable safety profile.
ADCs are composed of three critical components: a monoclonal antibody that specifically targets tumor-associated antigens, a cytotoxic payload and a linker that connects the two. This structure enables selective delivery of potent chemotherapy directly to cancer cells, sparing healthy tissues and reducing systemic toxicity. ADCs have demonstrated significant therapeutic potential in gynecologic malignancies, including ovarian cancer.
Mirvetuximab soravtansine: targeting folate receptor alpha positive tumors
Mirvetuximab soravtansine has emerged as a key therapy for platinum-resistant ovarian cancer with high folate receptor-alpha (FRα) expression. The pivotal Phase-III MIRASOL trial15 demonstrated its efficacy in patients with FRα-positive tumors (≥ 75% of cells with ≥ 2+ staining intensity) who had undergone one to three prior lines of therapy. The trial showed significant improvements in PFS, with a median PFS of 5.62 months for mirvetuximab soravtansine vs 3.98 months for standard chemotherapy (P < 0.001). Objective responses were observed in 42.3% of the mirvetuximab group compared to 15.9% in the chemotherapy group. OS also favored mirvetuximab soravtansine, with a median OS of 16.46 months compared to 12.75 months for chemotherapy (HR for death, 0.67; P = 0.005).
The safety profile of mirvetuximab soravtansine was more manageable than that of chemotherapy, with fewer hematologic toxicities. The most common side effects included blurred vision (40.8%), keratopathy (32.1%), abdominal pain (30.3%) and fatigue (30.3%), making it a well-tolerated option for this patient population. These findings establish mirvetuximab soravtansine as an effective and safer alternative to traditional chemotherapy in platinum-resistant disease.
Trastuzumab deruxtecan (T-DXd): targeting HER2-positive ovarian cancer
HER2 expression is generally low in ovarian carcinoma, particularly in high-grade serous carcinoma, with studies reporting HER2 3+ expression in 6% of unselected cases.16 However, higher expression is observed in certain subtypes, including 23% of mucinous tumors, 11% of endometrioid tumors, 9% of clear cell tumors and 5% of high-grade serous tumors.
Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy in patients with strong HER2 expression (IHC 3+). Data from the DESTINY-PanTumor02 trial showed an ORR of 45% in the ovarian cancer HER2 IHC 2+ and 3+ cohort, with a notably higher response rate of 63–64% in patients with IHC 3+ HER2 expression.17 The median PFS in ovarian cancer patients was approximately 12 months. However, caution is warranted when interpreting these results, as the data are based on a small cohort of patients. Ongoing larger-scale clinical trials aim to validate these findings.
One important toxicity associated with T-DXd is pneumonitis, which requires early detection and prompt intervention with corticosteroids. High-resolution chest CT is recommended for confirming clinical suspicion to ensure patient safety.
Emerging ADCs
The success of mirvetuximab soravtansine and T-DXd has driven the development of additional ADCs targeting novel biomarkers. Promising candidates include luveltamab tazevibulin (STRO-002) for FRα, raludotatug deruxtecan (R-DXd) for cadherin-6, and sacituzumab govitecan for TROP2, all showing encouraging early-phase results. Further research is exploring other targets like B7-H4, mesothelin and tissue factor, with several ADCs in preclinical or early clinical development.
The future of ADCs in ovarian cancer lies in the identification of new targets, the development of next-generation agents, and the exploration of combination therapies to enhance efficacy.
Immunotherapy combinations
The randomized, double-blind, Phase-III ENGOT-ov65/KEYNOTE-B9618 study investigated the integration of immune checkpoint inhibition into the management of platinum-resistant disease, enrolling 643 adult patients with epithelial ovarian, Fallopian tube or primary peritoneal carcinoma who progressed within 6 months of completing one to two prior systemic lines. Participants were assigned 1 : 1 to receive open-label intravenous paclitaxel (80 mg/m2 on days 1, 8 and 15 of a 21-day cycle) paired with either intravenous pembrolizumab (400 mg every 6 weeks for up to 18 cycles) or a placebo, with concomitant bevacizumab permitted at the investigator's discretion. The study successfully met its primary endpoint, demonstrating a statistically significant improvement in investigator-assessed PFS at the first interim analysis for both the PD-L1 combined positive score (CPS) ≥ 1 population (median 8.3 vs 7.2 months; HR 0.72; 95% CI 0.58–0.89; P = 0.0014) and the overall population (median 8.3 vs 6.4 months; HR 0.70; 95% CI 0.58–0.84; P < 0.0001). This benefit translated into a significant OS advantage, with the second interim analysis showing a median OS of 18.2 vs 14.0 months in the PD-L1 CPS ≥ 1 cohort (HR 0.76; 95% CI 0.61–0.94; P = 0.0053) and the final analysis confirming an overall population OS benefit (median 17.7 vs 14.0 months; HR 0.82; 95% CI 0.69–0.97; P = 0.011).
Selective glucocorticoid receptor antagonists
The randomized, controlled, open-label Phase-III ROSELLA (GOG-3073/ENGOT-ov72)19 trial investigated whether modulating cortisol signaling with relacorilant, a selective glucocorticoid receptor antagonist, could enhance chemotherapy sensitivity in 381 adult patients with platinum-resistant epithelial ovarian, Fallopian tube or primary peritoneal cancer who had received up to three prior therapies and mandatory prior bevacizumab. Participants were assigned 1 : 1 to receive either relacorilant (150 mg orally the day before, of and after chemotherapy) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the same schedule). The trial met its dual primary endpoints, showing a statistically significant improvement in PFS by blinded independent central review (median 6.54 vs 5.52 months; HR 0.70; 95% CI 0.54–0.91; P = 0.0076) and a clinically meaningful OS benefit at a planned interim analysis (median 15.97 vs 11.50 months; HR 0.69; 95% CI 0.52–0.92; P = 0.0121) with the addition of relacorilant. Adverse events were similar across both arms when adjusted for nab-paclitaxel exposure, revealing no new safety signals.
TARGETED THERAPY FOR LOW-GRADE SEROUS OVARIAN CARCINOMA
Low-grade serous ovarian carcinoma (LGSOC) frequently exhibits estrogen and progesterone receptor expression and is strongly influenced by the MAPK signaling pathway. Unlike high-grade serous ovarian carcinoma, which is characterized by p53 mutations, DNA repair defects and copy number abnormalities, LGSOC has a high prevalence of MAPK pathway mutations. KRAS mutations are found in 16–44% of LGSOCs, BRAF mutations in 2–20% and NRAS mutations in up to 26%.20
The GOG 281/LOGS trial, an international, randomized Phase-2/3 study, compared trametinib to standard care in patients with recurrent LGSOC.21 The median PFS was significantly longer in the trametinib group at 13.0 months (95% CI, 9.9–15.0 months) compared to 7.2 months (95% CI, 5.6–9.9 months) in the standard-care group (conventional second-line chemotherapy) (HR 0.48; 95% CI, 0.36–0.64; P < 0.0001). The most common Grade-3 or -4 adverse events with trametinib were skin rash (13%), anemia (13%), hypertension (12%), diarrhea (10%), nausea (9%) and fatigue (8%). In contrast, standard care was associated with abdominal pain (17%), nausea (11%), anemia (10%) and vomiting (8%).
The ENGOT-OV60/GOG-3052/RAMP 201 trial evaluated the efficacy of avutometinib and defactinib in 57 adults with KRAS-mutated recurrent LGSOC who had received at least one prior systemic therapy, including platinum-based regimens.22 Patients received avutometinib (a MEK inhibitor) and defactinib (a FAK inhibitor) until disease progression or unacceptable toxicity. The confirmed ORR was 44% (95% CI, 31%–58%), with response durations ranging from 3.3 to 31.1 months. Common adverse reactions (≥ 25%) included increased creatine phosphokinase, nausea, fatigue, rash, diarrhea, musculoskeletal pain and elevated liver enzymes. The recommended dosing schedule involves maintaining both drugs until progression or intolerable side effects. This combination of MEK and FAK inhibitors represents a promising advancement in targeted therapy for KRAS-mutated LGSOC.
IMMUNOTHERAPY AND ANTI-ANGIOGENIC THERAPY FOR CLEAR CELL OVARIAN CARCINOMA
Clear cell ovarian carcinoma (CCOC) is significantly more common in Asian women. In the USA, its incidence is nearly five times higher in Asian women compared to white women, and in Japan, CCOC accounts for up to 25% of epithelial ovarian cancers, a proportion much higher than in Western countries. CCOC is genomically distinct23 and frequently associated with mutations in ARID1A (~49%) and PIK3CA (~48%), as well as alterations in KRAS, PTEN and MET. Unlike other ovarian cancer subtypes, CCOC has a low incidence of BRCA1/2 mutations and is strongly linked to endometriosis. Due to its distinct molecular profile, immunotherapy, with or without anti-angiogenic agents, has shown particular relevance in its treatment.
The INOVA trial evaluated sintilimab combined with bevacizumab in 41 patients with relapsed or persistent CCOC, with response data available for 37 patients.24 The ORR was 40.5% (95% CI, 24.8–57.9%), including 14% complete responses and 27% partial responses. Adverse events observed were consistent with those expected from the agents used.
The PEACOCC trial, a single-arm Phase-2 study conducted across five UK centers, investigated pembrolizumab in PD-1 inhibitor-naive patients with clear cell gynecological cancers, 85% of which were ovarian.25 The median patient age was 58.5 years, with 54% having an ECOG PS of 0 and 46% an ECOG PS of 1. Patients had a median of three prior therapies, with 40% receiving anti-angiogenic therapy and 40% having a platinum-free interval exceeding 12 months. Most tumors (98%) were mismatch repair (MMR)-proficient. The ORR was 25% (95% CI, 14–40%), including 12 partial responses, while the 12-week PFS rate was 42% (95% CI, 28–57%). Grade-3 treatment-related adverse events occurred in 19% of patients, with no Grade-4 or -5 events reported.
The DOVE trial is an ongoing global Phase-2 study evaluating dostarlimab alone or in combination with bevacizumab compared to standard chemotherapy in patients with recurrent or persistent clear cell gynecological cancers (rGCCC). Patients are randomized into three groups, with crossover to dostarlimab + bevacizumab allowed in cases of progression.26 The trial is actively recruiting.
METRONOMIC CHEMOTHERAPY AND HORMONAL THERAPY
Oral metronomic chemotherapy involves delivering low doses of chemotherapy drugs continuously over a prolonged period, rather than in high-dose short cycles. This treatment works through both anti-angiogenic and cytotoxic effects while minimizing toxicity and side effects. It is often used as a palliative option for patients with indolent, treatment-resistant disease who remain fit and wish to pursue further therapy.
For instance, a Phase-2 study demonstrated that continuous oral cyclophosphamide at a dose of 50 mg daily resulted in stable disease lasting over 6 months in 15–20% of patients, with a partial response observed in 4%. However, the median PFS was only 2 months. Side effects, including nausea, vomiting and abdominal pain, were generally well-tolerated.27
Hormonal therapy with tamoxifen or aromatase inhibitors like letrozole may serve as a palliative option for patients with refractory disease who are estrogen receptor-positive. Although large-scale prospective clinical trial data are lacking, retrospective reviews suggest this approach has modest activity. For example, a retrospective study of 81 ovarian cancer patients found that endocrine therapy achieved a 35% disease control rate, 10% symptom improvement and stable disease for over 6 months in 23.5% of patients, with a median overall survival of 62.6 months.28 Factors significantly improving PFS included platinum sensitivity (P = 0.021), complete surgical resection (P = 0.020) and endocrine therapy as maintenance (P = 0.002).
PALLIATIVE CARE
Despite advancements in therapeutic options, long-term survival remains achievable for only a small subset of patients, while the majority experience short PFS and OS. Many advanced treatments, particularly in late-line settings, fail to demonstrate an OS benefit despite their high costs. Palliative care plays a crucial role in managing the physical symptoms caused by disease complications, as well as addressing the psychological, social, spiritual and emotional distress experienced by patients and their families. Ultimately, when prolonging survival is not a realistic goal, prioritizing quality of life becomes essential.
SUMMARY
The key characteristics of the main trials informing treatment of recurrent ovarian cancer are provided in Table 1. Treatment hinges on individualized approaches guided by disease biology, previous therapy and patient-specific factors. Platinum-sensitive recurrence often benefits from chemotherapy combinations, with or without bevacizumab, while PARP inhibitors offer significant PFS benefits, particularly in BRCA-mutated patients. Secondary cytoreductive surgery improves outcomes when complete resection is achievable, though HIPEC’s role remains controversial. For platinum-resistant disease, emerging therapies like ADCs and targeted agents have shown promise. Despite advancements, many treatments fail to significantly prolong OS, highlighting the importance of palliative care to prioritize quality of life in advanced stages.
1
Summary of key clinical trials.
Trial | Setting | Key findings | Outcomes | Comments |
DESKTOP III2 | Secondary cytoreductive surgery in platinum-sensitive recurrence | Secondary cytoreductive surgery plus chemotherapy improved PFS and OS compared to chemotherapy alone in patients with positive AGO scores. | OS and PFS benefit seen with complete resection (R0). | Complete resection and appropriate patient selection are critical. |
SOC-13 | Secondary cytoreductive surgery | PFS benefit observed using the iModel for patient selection. OS data are immature. | Improved PFS but no conclusive OS data yet. | Highlights the importance of patient selection using predictive models. |
GOG-02134 | Secondary cytoreductive surgery | No significant survival benefit from secondary cytoreductive surgery in recurrent settings. | PFS and OS outcomes did not favor surgery. | Likely confounded by lack of objective selection criteria for surgery. |
CHIPOR6 | HIPEC in first recurrence after chemotherapy | Adding HIPEC to cytoreductive surgery improved OS (54.3 vs 45.8 months) but increased ≥ Grade 3 adverse events (49% vs 27%). | OS improved, but with higher toxicity rates, including anemia, hepatotoxicity and renal failure. | HIPEC is not routinely recommended in international guidelines due to toxicity concerns. |
CALYPSO7 | Platinum-sensitive recurrence | Compared carboplatin-liposomal doxorubicin (CD) vs carboplatin-paclitaxel (CP). CD improved PFS but no OS difference was found. | PFS: 11.3 months (CD) vs 9.4 months (CP); OS: 30.7 months (CD) vs 33.0 months (CP). | CD regimen associated with fewer toxicities compared to CP. |
GOG-02134 | Bevacizumab in platinum-sensitive recurrence | Adding bevacizumab to chemotherapy improved PFS but did not significantly improve OS. | PFS: 13.8 months (bevacizumab) vs 10.2 months (control); OS: not significantly different. | Bevacizumab combination therapy improves disease control but not OS. |
OCEANS8 | Bevacizumab in platinum-sensitive recurrence | Bevacizumab improved PFS but did not show an OS benefit. | PFS: 12.3 months (bevacizumab) vs 8.6 months (control); OS: no significant difference. | Higher objective response rate (ORR) with bevacizumab (78.5% vs 57.4%). |
SOLO2/ | PARP inhibitor (olaparib) maintenance | Olaparib maintenance therapy significantly improved PFS in BRCA-mutated patients. OS benefit was limited in non-BRCA patients. | PFS: 19.1 months (olaparib) vs 5.5 months (placebo). OS: HR 0.74 (BRCA-mutated). | Long-term benefit primarily in BRCA-mutated patients. |
ENGOT-OV16/ | PARP inhibitor (niraparib) maintenance | Niraparib improved PFS in both BRCA-mutated and non-BRCA patients but showed no significant OS benefit. | PFS: HR 0.27 (BRCA-mutated) and HR 0.45 (non-BRCA-mutated). OS: no significant difference. | Continued benefit in chemotherapy-free intervals and PFS. |
ARIEL312 | PARP inhibitor (rucaparib) maintenance | Rucaparib improved PFS across BRCA-mutated, HRD-positive, and overall populations but showed no OS benefit. | PFS: HR 0.23 (BRCA-mutated), HR 0.32 (HRD-positive), HR 0.36 (ITT population). OS: no benefit for HRD or ITT populations. | Best outcomes observed in BRCA-mutated patients. |
AURELIA14 | Bevacizumab in platinum-resistant recurrence | Bevacizumab with chemotherapy improved PFS and response but did not improve OS. | PFS: 6.7 months (bevacizumab) vs 3.4 months (control); ORR: 27.3% (bevacizumab) vs 11.8% (control). OS: no significant difference. | Bevacizumab offers disease control but has risks like GI perforation. |
MIRASOL15 | ADC (mirvetuximab soravtansine) in platinum-resistant recurrence | Mirvetuximab improved PFS and OS in FRα-positive tumors versus chemotherapy. | PFS: 5.62 months (mirvetuximab) vs 3.98 months (chemotherapy). OS: 16.46 months (mirvetuximab) vs 12.75 months (chemotherapy). | Safer and more effective than traditional chemotherapy for FRα-positive platinum-resistant disease. |
DESTINY-PanTumor0217 | ADC (trastuzumab deruxtecan) in HER2-positive ovarian cancer | High response rates and PFS of ~12 months in HER2-positive ovarian cancer. | ORR: 45% overall; ORR: 63–64% in HER2 IHC 3+ tumors. PFS: ~12 months for HER2-positive patients. | Promising results, but data based on small patient cohort. |
GOG 281/ | MEK inhibitor (trametinib) in low-grade serous ovarian cancer | Trametinib improved PFS compared to standard chemotherapy in recurrent low-grade serous ovarian cancer. | PFS: 13.0 months (trametinib) vs 7.2 months (standard care). | Targeting the MAPK pathway offers significant benefits for low-grade serous ovarian cancer. |
INOVA24 | Immunotherapy (sintilimab + bevacizumab) in clear cell ovarian cancer | Sintilimab plus bevacizumab achieved a 40.5% ORR with manageable toxicity in relapsed clear cell ovarian cancer. | ORR: 40.5% (14% complete responses, 27% partial responses). | Promising combination for a molecularly distinct and challenging subtype. |
AGO, Arbeitsgemeinschaft Gynäkologische Onkologie (German 'Gynecological Oncology Working Group'); ADC, antibody-drug conjugate; HIPEC, hyperthermic intraperitoneal chemotherapy; HRD, homologous recombinant deficient; ITT, intention-to-treat; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
PRACTICE RECOMMENDATIONS
- High relapse rate. Up to 70% of patients with Stage-III–IV high-grade ovarian cancer relapse within 3 years despite multimodal first-line therapies.
- Holistic evaluation for recurrence. Treatment decisions in recurrent ovarian cancer require consideration of factors like BRCA status, platinum-free interval, histology, prior therapies, fitness and surgery feasibility.
- Platinum sensitivity. Patients are traditionally classified as platinum-sensitive (recurrence ≥ 6 months after platinum therapy) or platinum-resistant (< 6 months), but clinical judgment is critical as not all patients fit these categories.
- Role of secondary cytoreductive surgery. Trials like DESKTOP III and SOC-1 show PFS and OS benefits when complete resection (R0) is achieved, emphasizing patient selection and surgical expertise. HIPEC remains controversial, with CHIPOR showing OS benefits but increased toxicity.
- Platinum-sensitive recurrence therapies. Platinum-based combinations (e.g. carboplatin with paclitaxel, liposomal doxorubicin or gemcitabine) are standard, with or without bevacizumab. Bevacizumab improves PFS but shows limited OS benefits.
- PARP inhibitors. Olaparib, niraparib and rucaparib significantly improve PFS in BRCA-mutated patients. OS benefits are limited, and their use is evolving as most patients may receive them in first-line settings.
- Platinum-resistant disease. Sequential single-agent chemotherapy with or without bevacizumab is standard, offering modest benefits (PFS ~3–4 months). Bevacizumab improves PFS and response rates but not OS (e.g. AURELIA trial).
- Emerging therapies. Antibody-drug conjugates (ADCs): mirvetuximab soravtansine (FRα-positive tumors) and trastuzumab deruxtecan (HER2-positive tumors) show significant efficacy in specific subgroups. Targeted agents in low-grade serous ovarian cancer: MEK inhibitors like trametinib and combination therapies (e.g. avutometinib + defactinib) offer promising results.
- Immunotherapy in clear cell ovarian cancer. Combinations like sintilimab and bevacizumab demonstrate potential, particularly in molecularly distinct subtypes like clear cell ovarian carcinoma.
- Palliative and supportive care. Many advanced therapies fail to significantly improve OS, highlighting the importance of prioritizing quality of life and integrating palliative care for symptom management and emotional support.
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