MIRASOL

Several clinical trials investigating novel anticancer drugs such as antibody–drug conjugates and inducers of antitumor-directed immune response for the treatment of platinum-resistant ovarian cancer were presented at ASCO23, including 10 early-phase studies and three phase III trials encompassing one study protocol (Table 1).5 7–22 The advent of antibody–drug conjugates has yielded promising findings in some solid cancers, propelling their clinical development for platinum-resistant ovarian cancer.23 Antibody–drug conjugates possess a distinct advantage of using the principle of immune bioconjugation to selectively administer cytotoxic drugs to cancer cells that express multiple antigens based on specific monoclonal antibodies. This innovative therapeutic class has demonstrated encouraging preliminary evidence of clinical efficacy in platinum-resistant ovarian cancer,23 a cancer type commonly displaying chemotherapy resistance. Mirvetuximab soravtansine is an antibody–drug conjugate that targets folate receptor α (FR-α) and induces cell death in FR-α expressing tumors. Encouraging results were demonstrated in the multi-institutional single-arm SORAYA phase II study (NCT04296890) that investigated mirvetuximab soravtansine in an FR-α-high platinum-resistant ovarian cancer population.24 These findings prompted further exploration of the activity in the MIRASOL (GOG-3045; NCT04209855) phase III confirmatory trial, that randomized 453 patients with high-grade platinum-resistant ovarian cancer to receive mirvetuximab soravtansine or investigator’s choice of chemotherapy including topotecan, pegylated liposomal doxorubicin, or paclitaxel in a 1:1 fashion.5 Progression-free survival as assessed by investigators was the primary endpoint, and overall survival and objective response rate were secondary endpoints. Patient selection was accomplished based on biomarker immunohistochemical analysis for FR-α using FOLR1 assay: patients with platinum-resistant ovarian cancer expressed in at least 75% of viable tumor cells exhibiting ≥2+ level membrane staining intensity, including those with BRCA1/2 mutations. Patients were randomized to receive mirvetuximab soravtansine at a dose of 6 mg/kg on day 1 every 3 weeks (q3w) or investigator’s choice of chemotherapy. Of note, nearly half of enrolled patients (47%) had received three prior lines of therapies. Moreover, prior poly-ADP ribose polymerase (PARP) inhibitors and bevacizumab were allowed as maintenance therapies and had been received by 55% and 62% of enrolled patients, respectively. At the time of data cut-off and after a median follow-up of 13.1 months, progression-free survival was improved, reporting 5.62 months in the mirvetuximab soravtansine arm compared with 3.98 months in the control (HR 0.65, 95% CI 0.52 to 0.81, p<0.0001). In addition, a superior objective response rate was detected in the mirvetuximab soravtansine arm (42.3% vs 15.9%, p<0.0001), including 12 complete responses. In a pre-planned sensitivity analysis, these findings were consistent with those of a blinded independent central review. The interim analysis of overall survival showed a better outcome in patients treated with mirvetuximab soravtansine than those who received the investigator’s choice of chemotherapy (16.46 vs 12.75 months; HR 0.67, 95% CI 0.50 to 0.89, p=0.0046).5 Of note, this was the first study to report an improved overall survival in phase III trials for platinum-resistant ovarian cancer.

In an exploratory subgroup analysis, this clinical activity was more pronounced in bevacizumab-naive patients. The group of patients (n=172) who had no previous exposure to bevacizumab had progression-free survival superior by 34% as compared with the investigator’s choice of chemotherapy (HR 0.66, 95% CI 0.46 to 0.94, p=0.02). Similarly, this group had also a reduced risk of death by 49% (overall survival HR 0.51, 95% CI 0.31 to 0.86, p<0.01). Regarding patients who received prior treatments that included bevacizumab (n=281), progression-free survival only was improved in the mirvetuximab soravtansine subset compared with investigator’s choice of chemotherapy (HR 0.64, 95% CI 0.49 to 0.84, p<0.01) and overall survival was not significantly different between the two arms (HR 0.74, p=0.07).5 Regarding the toxicity profile specific to mirvetuximab soravtansine, grade ≥3 ocular events including 8% blurred vision and 9% keratopathy were remarkable in this trial, which may considerably impair patients’ quality of life (QoL). Ocular toxicities must be carefully screened, promptly diagnosed, and timely treated with this drug.

While the effectiveness of biomarker-driven mirvetuximab soravtansine has been confirmed in high-FRα-expressing patients in the MIRASOL trial, ocular toxicity is a worrying adverse event and needs a mitigation plan before infusion.25 The US Prescribing Information (USPI) alerted healthcare providers in a boxed warning about the potential risks associated with mirvetuximab soravtansine ocular toxicity that may lead to significant vision impairment and corneal disorders in addition to pneumonitis and peripheral neuropathy as other considerable safety risks.26 Ocular toxicities likely associated with off-target effects can go unnoticed without symptoms until significant damage occurs. Other important safety risks such as pneumonitis and peripheral neuropathy should also be considered and are included as a warning box for mirvetuximab soravtansine. Therefore, dose optimization strategies could be considered for mirvetuximab soravtansine to improve its safety profile, such as fractionated dosing regimens, as it could achieve a similar efficacy profile as the approved dose/schedule.26

Patients who had primary platinum-refractory disease were excluded from this trial. This also raises concerns about this patient population that has limited treatment options and does not benefit from the recent advances in treating this highly aggressive gynecological cancer, particularly on how the trial mirrors a real-life population. Primary patient-reported outcomes in MIRASOL were not disclosed yet and are awaited in the upcoming meetings. These outcomes are critical patient-centric endpoints to evaluate treatments and support patient-centered care more comprehensively. Globally, only a portion of patients with platinum-resistant ovarian cancer in real-life setting may have similar inclusion criteria than the one used in the MIRASOL study. The financial toxicity of antibody–drug conjugates in general, and particularly of mirvetuximab soravtansine,27 is also an important factor that will limit access to this innovative drug globally as it places a significant financial burden on patients and their families. It is crucial to acknowledge that recognizing these problems holds equal significance as celebrating these wins.

To date, mirvetuximab soravtansine received accelerated approval from the US Food and Drug Administration (FDA) on November 14, 2022, for treating patients with platinum-resistant ovarian cancer who have FR-α-positive tumors and received 1–3 prior lines of systemic treatments. The FDA has also approved the VENTANA FOLR1 (FOLR-2.1) RxDx Assay as a companion diagnostic to identify eligible patients for mirvetuximab soravtansine.26 Doublet-based combination approaches using mirvetuximab soravtansine and other drugs such as bevacizumab may provide improved response and meaningful clinical benefits in the platinum-resistant ovarian cancer population.28 Of course, preventing and optimizing the safety profile is now a priority.

OVAL

The OVAL (GOG-3018) phase III trial investigated ofranergene obadenovec in platinum-resistant ovarian cancer. Ofranergene obadenovec, known as VB-111, is a viral-mediated anti-angiogenic and vascular disrupting agent, based on a non-replicating adenovirus targeted against hypoxic tissue targets to exert endothelial cell killing to the neoangiogenic tumor vasculature.29 Mechanistically, the precise molecular mechanisms by which ofranergene obadenovec acts on ovarian cancer cells are not fully understood. Ofranergene obadenovec was engineered to induce the expression of the Fas-TNFR1 chimeric pro-apoptotic protein exclusively in angiogenic vessels. It is believed that its interaction with tumour necrosis factor α (TNF-α) in the tumor microenvironment of ovarian cancer leads to the apoptosis of endothelial cells.29

Previously, ofranergene obadenovec was studied in a dose-escalation phase I/II study that enrolled 21 patients with platinum-resistant ovarian cancer, including 50% with platinum-refractory disease, to receive ofranergene obadenovec in combination with weekly paclitaxel.29 At a therapeutic dose (1×10¹³ viral particles), ofranergene obadenovec showed superior overall survival as compared with the subtherapeutic dose (16.6 vs 5.8 months) and tolerable toxicities, mainly mild flu-like symptoms. More recently, the OVAL study was designed to confirm these preliminary signals of activity. Four hundred and nine patients with platinum-resistant ovarian cancer were randomly assigned in a 1:1 ratio to receive ofranergene obadenovec at a therapeutic dose every 8 weeks combined with paclitaxel at a dose of 80 mg/m² or placebo with paclitaxel until disease progression, inacceptable toxicity, and per patient preference.7 Progression-free survival and overall survival by blinded independent central review were both co-primary endpoints. Topline mature data presented at ASCO23 showed that the results of the OVAL study were negative. In fact, median progression-free survival was not different between the two arms (5.29 vs 5.36 months, HR 1.03, 95% CI 0.83 to 1.29, p=0.7823). Similarly, median overall survival was not improved in the experimental arm (13.37 vs 13.14 months, HR 0.97, 95% CI 0.75 to 1.27, p=0.8440). The safety profile was similar to that reported in previous early-phase studies.7 These disappointing results were not in line with a futility analysis of this trial, that reported promising interim results.30 A pre-planned interim analysis suggested that the initial response rates based on cancer antigen 125 (CA125) in the OVAL trial were supportive of the study plan.30 Yet, the final OVAL findings raise questions regarding the value of using CA125 to predict response in this perspective, particularly in large phase III trials that enroll an important number of patients without sufficient quality evidence from early-phase studies or interim analyses. This is an important matter to protect patients by avoiding overtreatment in clinical trials with ineffective therapies. Evidence from the OVAL study should be used to pause and reflect on the way we track the disease trajectory in clinical trials to understand the benefit of treatments, and how they may not apply to all treatment types—in this case, with a biological agent.

ARTISTRY-7

ARTISTRY-7 (GOG-3063, NCT05092360) is an ongoing phase III trial that is currently recruiting patients with platinum-resistant ovarian cancer to be randomized to receive the engineered cytokine nemvaleukin alfa (ALKS 4230) and pembrolizumab, pembrolizumab monotherapy, nemvaleukin monotherapy, versus protocol-specific investigator’s choice chemotherapy.8 Nemvaleukin was designed to activate antitumor immunity mediated by CD8+T cells and natural killers by binding to interleukin 2 (IL-2) receptor.31 The protocol of this study presented at ASCO23 indicated a study population of 376 patients with platinum-resistant ovarian cancer who will be randomly assigned to one of four arms (3:1:1:3) including intravenous nemvaleukin at a dose of 6 µg/kg on days 1 to 5 and pembrolizumab at a dose of 200 mg as an infusion on day 1 of q3w cycle. The other groups will receive pembrolizumab, nemvaleukin as single agents or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, topotecan, or gemcitabine). To be included, patients may have received up to five prior lines of systemic treatment in a platinum resistant setting and at least one line of therapy containing bevacizumab. Moreover, those with mucinous histology or primary platinum-refractory disease or with platinum-free interval of <3 months from first-platinum, will be excluded.8 Of note, this study will also enroll patients with clear cell ovarian cancer, a rare type that is frequently neglected in major clinical trials. A pre-planned stratification based on PD-L1 status, histology, and chemotherapy was intentional. Progression-free survival by the investigator is the primary endpoint and overall survival and other tumor measures are secondary endpoints.8 The existing data on this novel agent are scarce. In fact, the available conference proceedings showed that nemvaleukin combined with pembrolizumab in the ARTISTRY-1 phase I/II multicohort study (NCT02799095) was active in five subjects of total patients enrolled with heavily pre-treated platinum-resistant ovarian cancer.32 This included one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response. In addition, one patient exhibited stable disease after being on the treatment for approximately 1.5 years.32 However, one can argue that conducting a phase III trial without clear positive results from powered early-phase studies is questionable, as efficacy in early-phase trials can anticipate the overall benefit in later stages of drug development. Moreover, progression-free survival should not be considered the best endpoint in this setting when investigating doublets. In platinum-resistant ovarian cancer, overall survival and QoL outcomes should be the gold standards to objectively assess the benefits of novel agents.33 In fact, progression-free survival as a surrogate endpoint to overall survival is unclear in trials assessing immunotherapy and in gynecological cancers.33

Luveltamab Tazevibulin

Luveltamab tazevibulin (STRO-002) is an FR-α-targeting antibody–drug conjugate with a drug-to-antibody ratio of 4 that was investigated in ovarian cancer settings with the advantages of no reported ocular toxicities.34–36 This antibody–drug conjugate uses the anti-tubulin payload 3-aminophenyl hemiasterlin to induce cytotoxic and immunologic cell death.37 Luveltamab tazevibulin received fast-track approval by the FDA in August 2021. An interim analysis of recent safety data of this agent used in patients at a higher dose (5.4 mg/kg once q3w) showed grade ≥3 neutropenia requiring pegfilgrastim treatment but without ocular adverse events.37 Of note, pegfilgrastim is a pegylated granulocyte-colony stimulating factor (G-CSF) used to enhance white blood cell production and is commonly used to prevent neutropenia in patients with cancer.38 A higher dose of luveltamab tazevibulin was associated with superior benefits including an objective response rate of 43.8%. Based on this, the phase II/III REFRaME trial (NCT05200364) will be initiated to investigate luveltamab tazevibulin in platinum-resistant ovarian cancer.35 At ASCO23, Oaknin et al reported recent updated data on luveltamab tazevibulin which was studied for relapsed patients with ovarian cancer in the global STRO-002-GM1 phase I trial.9 The study enrolled patients with platinum-sensitive and platinum-resistant ovarian cancer and this latter group had progressive disease after 1–3 prior lines of treatments. These patients were assigned to receive intravenous q3w luveltamab tazevibulin at doses of 4.3 or 5.2 mg/m² (1:1 ratio) until disease progression. Biomarker analysis in this trial was not planned and it was provided as a post-hoc review of archived tissues. Objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST, v1.1) was the primary endpoint, and progression-free survival and duration of response were secondary objectives. The majority of enrolled patients had prior exposure to bevacizumab and PARP inhibitors. The objective response rate was 31.7% in the overall population and 37.5% in FR-α >25%. In addition, the objective response rate was more pronounced (43.8%) in the higher starting dose in patients with FR-α >25% tumors. Yet, data regarding the impact of platinum sensitivity is lacking. The most frequent grade ≥3 adverse events included neutropenia, arthralgia, and anemia (70.5%, 18.2%, and 13.6%, respectively). These emerging adverse events were associated with a dose delay and reduction in 80% and 61% of the study participants, respectively, particularly in those who received a higher therapeutic dose (5.2 mg/kg).9 However, this novel antibody–drug conjugate may provide new therapeutic perspectives for platinum-resistant ovarian cancer if demonstrated in large trials, particularly given the early response seen in patients with a broader expression of FR-α. Currently, a phase I study (NCT05200364) evaluating the combination of luveltamab tazevibulin with bevacizumab is recruiting patients with advanced refractory or relapsed ovarian cancer after progression on available standard chemotherapies, and it is expected to release early findings in January 2024. Moreover, the REFRaME-O1 phase II/III trial investigating the efficacy and safety of luveltamab tazevibulin in patients with platinum-resistant ovarian cancer with FR-α >25% is currently open for enrollment (NCT05870748).

Fostamatinib

Fostamatinib is an orally available inhibitor of spleen tyrosine kinase (SYK). SYK has been found to be involved in conferring resistance to paclitaxel in ovarian cancer by modulating the stability of microtubules and has been correlated with poor overall survival in ovarian cancer patients.39 Preclinical models have shown that the use of fostamatinib sensitizes resistant cells to paclitaxel, thereby inducing cytotoxic effects.39 Based on these findings, the toxicity and early efficacy of fostamatinib were investigated in a recent phase I study presented at ASCO23.12 This trial enrolled patients with recurrent platinum-resistant ovarian cancer in a dose-escalation manner to determine the maximum tolerated dose and recommended phase II dose. Response rates were evaluated using RECIST v1.1 criteria. Eligible patients (n=27) received fostamatinib orally twice a day at three dose levels (100, 150, and 200 mg) in combination with intravenous paclitaxel (80 mg/m², on days 1, 8, and 15, q4w). Adverse events attributed to the treatment included diarrhea, fatigue, anemia, neutropenia, nausea, dysgeusia, and hypertension. Grade 3 or 4 toxicities observed were neutropenia (37%), anemia (26%), and thromboembolic events (22%). The determined dose for the expansion cohort will be 200 mg when combined with paclitaxel.12 The efficacy data provided in the available abstract showed 39% of partial and complete responses; the study is still ongoing (NCT03246074).

SL-172154

SL-172154, also known as SIRPα-Fc-CD40L, is a fusion protein that incorporates the extracellular domains of signal regulatory protein α (SIRPα) and CD40L linked by an Fc domain.40 This complex molecule functions by blocking CD47, thereby increasing the capacity of macrophages to enhance phagocytosis and promoting CD40-based processing of antigens, leading to their presentation on antigen-presenting cells to CD8+T lymphocytes. A first-in-human phase I trial (NCT04406623) with a dose escalation design investigated the toxicity and pharmacokinetics of SL-172154 in patients with platinum-resistant ovarian cancer through intravenous administration of five different doses (0.1, 0.3, 1.0, 3.0, 10 mg/kg).13 The available results from a cohort of 27 patients with advanced platinum-resistant ovarian cancer showed one dose-limiting toxicity of grade 3 alanine aminotransferase increase. Grade 3/4 adverse events included aspartate aminotransferase elevation and lymphopenia (7% each). Infusion-related reaction rates increased with higher doses. The best response observed was stable disease in 22% (n=6) of evaluable patients.13 A maximum tolerated dose was not reached in this study. Combination therapies that target the CD47-SIRPα axis have shown higher response rates in solid tumors, as indicated by a recent meta-analysis.41

Debio-0123

Debio-0123 is a WEE1 inhibitor that has been studied in a phase I trial (Debio 0123–101; NCT03968653). WEE1 is a tyrosine kinase that regulates the cell cycle to prevent entry into the mitotic process.42 It has been identified as a prognostic biomarker of poor overall survival in patients with serous ovarian carcinomas treated with chemotherapy (reviewed elsewhere, see Schutte et al42). Targeting WEE1 by Debio-0123, which is an orally available, ATP-competitive WEE1 inhibitor, is being studied as a single agent or in combination with carboplatin in various solid tumors.17 Currently, no comprehensive data on this agent, including preclinical studies, are available to the public. During ASCO23, a poster presentation provided insights into the toxicity and preliminary activity of Debio-0123. The authors of a phase I trial (n=38) reported on the pharmacokinetics, pharmacodynamics, and anticancer activity of combining carboplatin with Debio-0123 in patients who had recurred or progressed following prior platinum-based therapy.17 The study followed a two-arm dose escalation design, administering Debio-0123 as a single agent and in combination with carboplatin. The maximum tolerated dose was found to be 520 mg, and the majority of adverse events were grade 1 or 2. In terms of clinical benefits, four out of the 12 enrolled patients with platinum-resistant ovarian cancer achieved partial responses.17

PRGN-3005 Autologous UltraCAR-T Cells

Chimeric antigen receptor (CAR)-T has recently attracted significant attention and has rapidly progressed to enhance the arsenal of cancer treatments, particularly in blood cancers, where it has shown remarkable results. CAR-T cell strategies involve targeting specific tumor cell antigens expressed in cancer. In ovarian cancer, proof of concept evidence on therapeutic targeting of various antigens, such as CA125 and mesothelin, has yielded promising T cell infiltration in both primary and recurrent disease.43 In mouse models, treatment using CAR-T cells was found to control the dissemination of ovarian cancer in vivo.44 Recently, an investigational phase I/Ib clinical trial (NCT03907527) evaluated PRGN-3005 UltraCAR-T cells, manufactured overnight and targeting CA125, in a population of patients with platinum-resistant ovarian cancer.14 In the phase I part of this trial, heavily pre-treated patients were infused intraperitoneally with PRGN-3005 without lymphodepletion or intravenously at three dose levels. Dose level 3 of intravenous injection was further assessed in patients who also received cyclophosphamide. PRGN-3005 was found to be well-tolerated at up to 65.5×10⁵ cells/kg, and no dose-limiting toxicity was reported, including known adverse events of CAR-T cells such as grade ≥3 cytokine-release syndrome and on-target/off-target toxicities. Regarding clinical response, evaluated by RECIST v1.1, 20% of enrolled patients had a response to at least one target lesion. The group treated with intravenous doses had an 85.7% disease control rate, including a decrease in target tumor burden in four of the seven enrolled women.14 The phase Ib part of this trial is currently recruiting more patients, and final results are expected to be delivered in November 2028 (NCT03907527).

Raludotatug Deruxtecan

Raludotatug deruxtecan (DS-6000) is a novel antibody–drug conjugate containing a stable linker and a topoisomerase I inhibitor targeting cadherin 6 (CDH6). CDH6 is frequently expressed in primary and relapsed ovarian cancer of all histotypes, particularly in high-grade serous tumors.45 Early findings from an ongoing phase I trial (NCT04707248) demonstrated premature efficacy signals in heavily pretreated ovarian cancer patients, including those with platinum-resistant disease.22 In this study, patients who had received prior taxane and platinum treatments were enrolled to receive raludotatug deruxtecan as a single agent, without CDH6 preselection, at various dose-escalating levels. The maximum tolerated dose was determined to be 8 mg/kg. A subgroup analysis of this trial (n=40 with platinum-resistant ovarian cancer), presented at ESMO23, reported a 50% incidence of grade ≥3 adverse events, including nausea, fatigue, diarrhea, vomiting, anemia, and decreased neutrophil and platelet counts. These events were all manageable and consistent with previous reports on similar antibody–drug conjugates using the same payload.22 The assessment of response based on RECIST v1.1 revealed a 38% objective response rate at 4.8 mg/kg, 33% at 6.4 mg/kg, and 31% at 8 mg/kg. The encouraging activity observed in heavily pretreated platinum-resistant ovarian cancer supports the continuation of this ongoing phase I trial.

Cobimetinib

Cobimetinib is an orally available small molecule that inhibits mitogen-activated protein kinase (MEK) within the mitogen-activated protein kinase (MAPK)/ERK pathway.19 This signaling pathway is commonly over-activated in human tumors, including certain histotypes of ovarian cancer.46 The BOUQUET study (NCT04931342), presented at ESMO23, is a phase II trial evaluating various treatments in biomarker-selected patients with rare ovarian cancer who exhibit lower responsiveness to standard treatments.19 The interim analysis of this study, which investigated cobimetinib in women with BRAF/KRAS/NRAS or NF1 alterations compared with atezolizumab and bevacizumab in ineligible patients, reported an objective response rate of 16% in the cobimetinib arm and 14% in the combination arm. Notably, patients with low-grade serous tumors and mesonephric-like adenocarcinoma showed an improved response rate of 33%, supporting further enrollment of these patients with these rare histotypes.19

IN10018

IN10018 selectively inhibits focal adhesion kinase (FAK), a non-receptor tyrosine kinase with a primary role in regulating adhesion, migration, and cell survival.47 In ovarian cancer, FAK has been found to be overexpressed and associated with prognostic features such as stage and overall survival.47 Additionally, FAK orchestrates immunosuppression, lymphangiogenesis, and metastasis in ovarian cancer.48 49 The targeting of FAK is now fully explored as a therapeutic strategy in ovarian cancer, particularly in low-grade serous carcinomas.50 Recently, survival data from the phase Ib trial of IN10018 (n=61; NCT05551507) were presented at ESMO23.20 The study investigated the preliminary efficacy of IN10018 in combination with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer, focusing specifically on high-grade serous tumors. The primary endpoint, objective response rate, was 46.3%, and secondary objectives, including progression-free survival at 7.3 months and overall survival at 20.9 months, were achieved. The safety profile was manageable, primarily associated with known toxicities of pegylated liposomal doxorubicin.20 A phase II trial comparing this combination to a placebo is currently in the planning stages.

Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC)

Treating recurrent ovarian cancer with peritoneal metastases poses a challenge as it is often associated with suboptimal debulking and resistance to intravenous platinum-based chemotherapy. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) was developed as an alternative method to deliver chemotherapy as aerosol compounds while maintaining high pressure in the peritoneum. Trials using various PIPAC procedures have shown encouraging objective response rates and improvements in QoL. Therefore, PIPAC has been proposed as a therapeutic option for patients with refractory peritoneal disease of various origins, including ovarian cancer. Previously, prospective case series and early evidence on the use of PIPAC in platinum-resistant ovarian cancer showed positive objective tumor response in a setting that poses important clinical challenges.51 52 A recent first-in-US phase I multicohort study communicated as a poster session investigated the role of PIPAC in seven pretreated patients with platinum-resistant ovarian cancer using a combination of cisplatin and doxorubicin.18 Eligible patients had recurrent ovarian cancer with peritoneal involvement and possible extraperitoneal metastases. Dose limiting toxicity was the primary endpoint, and progression-free survival and QoL were secondary objectives. A total of 71.4% of the participants in the study successfully completed PIPAC without encountering any surgical complications. The median decrease in peritoneal cancer index was −1.4% (from cycle 1 to cycle 2) and −2.8% (from cycle 1 to cycle 3). The clinical benefits of PIPAC were seen in a subset of patients with low-grade serous histology treated with six cycles and showed a partial response according to RECIST criteria.18

To date, this study is the only one to assess PIPAC efficacy as a palliative therapeutic option in selected platinum-resistant ovarian cancer patients, and merits further investigations compared with conventional chemotherapy. Of course, the evidence is insufficient to recommend any clinical implementation now. Other findings from negative and ongoing early-phase trials for patients with platinum-resistant ovarian cancer are summarized in Table 1.