Update Gynecologic Malignancies 2025 – Expert Opinion on Systemic Therapy for Early and Advanced Gynecological Cancers

Abstract

There have been major changes in the understanding of gynecologic malignancies in recent years, leading to new therapy options and subsequently to greater responsibilities for every professional treating those patients. The most significant therapeutic advances were achieved with checkpoint inhibitors (CPI), especially for endometrial and cervical cancer. In ovarian cancer the dominant and most important new substances are poly (ADP-ribose) polymerase inhibitors (PARPi). This review aims to summarize the latest studies and developments in the therapeutic landscape of endometrial, ovarian, and cervical cancer. The treatment of advanced endometrial cancer has changed significantly with the introduction of CPI such as dostarlimab (RUBY trial), durvalumab (DUO-E trial) and pembrolizumab (Keynote-868 trial). For ovarian cancer PARPi have shown substantial PFS benefits in key approval trials, including PRIMA for niraparib, PAOLA for olaparib, and ATHENA-MONO for rucaparib. These findings have established PARPi as the standard of care in maintenance therapy. Overall survival (OS) data for PRIMA and PAOLA are now available and are analyzed and placed into context in this article. Furthermore, mirvetuximab soravtansine is the first antibody-drug conjugate (ADC) approved in Germany for platinum-resistant ovarian cancer for patients with folate receptor alpha expression. The Keynote-A18 and BEATcc trials have opened new options for the utilization of immuno-oncology in cervical cancer treatment. Along with new therapeutic options, new biomarkers have also become part of daily clinical practice as predictive and prognostic factors as well as forming the basis for targeted personalized medicine.
The use of CPI is revolutionizing the treatment of all gynecologic cancers and offers significant benefits for progression-free survival (PFS) and OS in most therapy regimens. With the increased use of ADCs, this is not the end of these developments. Therapy algorithms from a certified German oncology center are developed and presented in this article.

Zusammenfassung

In den letzten Jahren gab es wichtige Änderungen im Verständnis von gynäkologischen Tumoren, die in neue Therapieoptionen mündeten und eine größere Verantwortung für alle in der Behandlung dieser Patientinnen involvierten medizinischen Fachkräfte bedeuten. Zu den wichtigsten therapeutischen Fortschritten, besonders für die Behandlung von Endometrium- und Gebärmutterhalskrebs, gehören die sog. Checkpoint-Inhibitoren (CPI). Die wichtigsten neuen Substanzen, die zur Behandlung des Ovarialkarzinoms eingesetzt werden, sind Poly(ADP-ribose)-Polymerasen-Inhibitoren (PARPi). Ziel dieses Übersichtsartikels ist, eine Zusammenfassung der neuesten Studien und Entwicklungen in der therapeutischen Landschaft der Endometrium-, Ovarial- und Zervixkarzinome zu geben. Die Behandlung des fortgeschrittenen Endometriumkarzinoms hat sich durch die Einführung von CPI wie Dostarlimab (RUBY-Studie), Durvalumab (DUO-E-Studie) und Pembrolizumab (Keynote-868-Studie) substanziell verändert. Beim Ovarialkarzinom haben wichtige Zulassungsstudien, darunter PRIMA für Niraparib, PAOLA für Olaparib und ATHENA-MONO für Rucaparib, gezeigt, dass PARPi mit wesentlichen Progressionsfreien-Überlebens-(PFÜ-)Vorteilen behaftet sind. Diese Ergebnisse haben PARPi als neuen Therapiestandard bei der Erhaltungstherapie etabliert. Die Gesamtüberlebens-(GÜ-)Daten der PRIMA- und PAOLA-Studien sind jetzt vorliegend und werden hier analysiert und kontextualisiert. Darüber hinaus wurde Mirvetuximab-Soravtansin als erstes Antikörper-Wirkstoff-Konjugat (AWK) für die Behandlung von Patientinnen mit platinresistenten Ovarialkarzinomen, die den Folatrezeptor alpha exprimieren, in Deutschland zugelassen. Die Keynote-A18- und BEATcc-Studien haben neue Möglichkeiten für den Einsatz von Immunonkologie bei der Behandlung von Zervixkarzinomen eröffnet. Zusammen mit diesen neuen therapeutischen Optionen gibt es nun auch neue Biomarker, die als prädiktive und prognostische Faktoren in die klinische Praxis eingegangen sind und nun die Basis einer gezielten individualisierten Medizin bilden.
Der Einsatz von CPI hat die Therapie aller gynäkologischen Karzinome revolutioniert. In den meisten Therapieregimes weisen CPI erhebliche Vorteile beim PFÜ und GÜ auf. Mit der allmählichen Einführung von AWKs ist das Ende dieser Entwicklung noch nicht erreicht. Behandlungsalgorithmen aus einem zertifizierten deutschen Krebszentrum werden entwickelt und in diesem Artikel vorgestellt.

Keywords

gynecologic malignancies - endometrial cancer - ovarian cancer - cervical cancer - immune oncology

Schlüsselwörter

gynäkologische Tumoren - Endometriumkarzinom - Ovarialkarzinom - Zervixkarzinom - Immunonkologie

Abbreviations

ADC: antibody-drug conjugate

AHT: anti-hormonal therapy

AML: acute myeloid leukemia

AUC5: area under the free carboplatin plasma concentration versus time curve

CC: cervical cancer

CDK4/6: cyclin-dependent kinase 4/6

CI: confidence interval

CPI: checkpoint inhibitors

CPS: combined positive score

Dato-DXd: datopotamab deruxtecan

dMMR: mismatch repair deficient

EC: endometrial cancer

EMA: European Medicines Agency

ESMO: European Society for Medical Oncology

FDA: Food and Drug Administration

FIGO: Fédération Internationale de Gynécologie et d’Obstétrique

HER2/neu: human epidermal growth factor receptor 2/neural

HR: hazard ratio

HRD: homologous recombination deficiency

IHC: immunohistochemistry

ITT: intention-to-treat

MDS: myelodysplastic syndromes

MMR: mismatch repair

MSI-H: microsatellite instability high

MSI-L: microsatellite instability low

OS: overall survival

OC: ovarian cancer

PARPi: poly (ADP-ribose) polymerase inhibitors

PD-L1: programmed cell death ligand 1

PD-1: programmed cell death 1

PFS: progression-free survival

pMMR: mismatch repair proficient

T-DXd: trastuzumab deruxtecan

TROP2: tumor-associated calcium signal transducer 2

VEGF: vascular endothelial growth factor

Introduction

As the understanding of checkpoint inhibitors (CPI) has increased, new substances and studies are improving the standard of care for all types of gynecological malignancies. PARPi have already been implemented in the standard of care for advanced ovarian cancer, just like pembrolizumab for metastatic, resistant, or recurrent cervical cancer. Apart from these indications, immune oncology was not generally used. Endometrial cancer therapy has gone through major changes with standardized immunohistochemistry and therefore new opportunities for programmed cell death 1 (PD-1) (such as pembrolizumab or dostarlimab) and programmed cell death ligand 1 (PD-L1) antibodies (such as atezolizumab and durvalumab). Similar to the latest studies on breast cancer, antibody-drug conjugates such as trastuzumab deruxtecan (T-DXd) for endometrial cancer and mirvetuximab soravtansine for ovarian cancer seem to be very promising in the second-line therapy and may set new standards in the future. The aim of this review is to summarize recent major developments in the therapy landscape. A compilation of all recently published trials which have led to adjustments in proposed treatment algorithms is presented in [Table 1Table 1].

Table 1 Table 1 Systematic synthesis of the presented studies. The classification was based on entity (ovarian, endometrial, or cervical cancer), line of therapy, the study acronym, and the administered medication.

Therapy setting	Ovarian Cancer		Endometrial Cancer		Cervical Cancer
	Study	Medication	Study	Medication	Study	Medication
Adjuvant			KEYNOTE-B21 trial (phase III)	Carboplatin, Paclitaxel, Pembrolizumab, followed by chemoradiotherapy	INTERLACE trial (phase III)	Carboplatin/Paclitaxel induction followed by standard RCTX
Advanced – 1st line	DUO-O trial (phase III)	Carboplatin, Paclitaxel, Durvalumab, Olaparib	KEYNOTE-868 trial (phase III)	Carboplatin, Paclitaxel, Pembrolizumab	Keynote-A18 trial (phase III)	Standard RCTX plus Pembrolizumab
	TROPION-PanTumor03 (phase II)	Datopotamab deruxtecan	DUO-E trial (phase III)	Carboplatin, Paclitaxel, Durvalumab, Olaparib	BEATcc (phase III)	Carboplatin Paclitaxel Atezolizumab
	ATHENA-MONO trial (phase III)	Rucaparib	RUBY trial (phase III)	Carboplatin, Paclitaxel, Dostarlimab
	PAOLA trial (phase III)	Olaparib and Bevacizumab
	PRIMA trial (phase III)	Niraparib
Recurrence – 2nd line			PALEO trial (phase II)	Palbociclib and Letrozole
			DESTINY-PanTumor02 trial	Trastuzumab deruxtecan

Cervical Cancer

Two studies, the INTERLACE and Keynote-A18 trials, have been published which examine the treatment of advanced cervical cancer (Fédération Internationale de Gynécologie et d’Obstétrique [FIGO] IB1 pN+ to FIGO IVA). Both studies demonstrated improvements in overall survival (OS) and progression-free survival (PFS). However, the patient populations included in each study differ, which may affect their applicability in clinical practice.

The INTERLACE trial investigated the benefits of induction chemotherapy prior to standard radiochemotherapy. Patients with FIGO (2008) IB1 pN+ up to FIGO IVA received induction chemotherapy with weekly carboplatin (AUC) 2 and paclitaxel 80 mg/m² for six weeks, followed by standard radiochemotherapy [11]. OS after five years and PFS after five years are significantly better with induction chemotherapy (PFS hazard ratio [HR] of 0.65 [95% confidence interval (CI) 0.46–0.91]; OS HR of 0.60 [95% CI 0.40–0.91]). In the subgroup analysis smaller tumor stages are more likely to benefit from initial chemotherapy (FIGO I/II HR 0.61 [95% CI 0.39–0.96]; FIGO III/IV HR 0.84 [95% CI 0.42–1.67]).

In contrast, the Keynote-A18 trial examined the effects of pembrolizumab in patients with FIGO (2014) IB2–IIB and pN+ or FIGO (2014) III–IVA in addition to regular radiochemotherapy as a first-line therapy [22]. In this study, patients received 200 mg pembrolizumab every three weeks during radiochemotherapy followed by 400 mg every six weeks for up to 15 cycles. The two-year PFS showed a statistically significant benefit for the patients receiving pembrolizumab with a hazard ratio of 0.70 (95% CI 0.55–0.89). Furthermore, a benefit was also shown for the two-year overall survival, but it was not statistically significant (87% in the pembrolizumab arm vs. 81% in the standard arm, HR 0.73; 95% CI 0.49–1.07). An important aspect here is that significant PFS benefits occurred in patients with FIGO III and IV. Because of this data, the Food and Drug Administration (FDA) approved the utilization of pembrolizumab with radiochemotherapy for patients with FIGO 2014 stage III–IVA in January 2024 [33]. The European Medicines Agency (EMA) followed this recommendation in November [44].

In conclusion, it is recommended to consider adjustments to the standard of care for both patient groups ([Fig. 1Fig. 1]). For patients with FIGO (2014) stages I/II for whom radiochemotherapy is indicated, the inclusion of prior induction chemotherapy should be evaluated. For patients with FIGO stages III–IVA, the addition of pembrolizumab, as indicated by the Keynote-A18 trial, is warranted.

Fig. 1 Fig. 1 Proposed treatment algorithm for advanced cervical cancer (CC) – curative setting. The basis for the treatment approaches were the INTERLACE study for induction chemotherapy and the KEYNOTE-A18 study for the addition of pembrolizumab.

Another new indication for CPI is the utilization of atezolizumab in the BEATcc trial [55]. Unlike pembrolizumab, atezolizumab is a PD-L1 inhibitor and the BEATcc study examined the efficiency of atezolizumab to treat metastatic, persistent or recurrent cervical carcinoma. Inclusion criteria were no other systematic therapy in the recurrent, metastatic, or persistent setting, and no prior therapy with any kind of vascular endothelial growth factor (VEGF) inhibitors or PD-L1 inhibitors. The patients received standard therapy according to GOG250 with duo chemotherapy (cisplatin (50 mg/m²) or carboplatin (AUC5) plus paclitaxel (175 mg/m²/d1 q21d) plus bevacizumab (15 mg/kg) d1 q21d or this regime was expanded by the addition of atezolizumab (1200 mg) d1 q21d. After six cycles both groups received maintenance therapy, either with bevacizumab alone or with atezolizumab plus bevacizumab. An important difference to the current standard of care with pembrolizumab as outlined in the Keynote-826 trial is the lack of stratification based on PD-L1 status or the combined positive score (CPS), and therapy with bevacizumab was mandatory. In this setting PFS ranged from 10.4 months to 13.7 months (HR 0.62, 95% CI 0.49–0.78). The two-year OS data show a statistically significant benefit with an HR of 0.68 (95% CI 0.52–0.88). This regimen provides a new option for immunotherapy in CPS-negative patients with metastatic, persistent, or recurrent cervical carcinoma. Therefore, this new therapeutic option has been incorporated into the proposed first-line therapy algorithm ([Fig. 2Fig. 2]).

Fig. 2 Fig. 2 Proposed treatment algorithm for first-line therapy of persistent, recurrent, metastatic cervical cancer (CC). The basis for the treatment approaches were the Keynote-826 study for the addition of pembrolizumab and the BEATcc study for the addition of atezolizumab.

There are multiple therapeutic options available for the second-line treatment of persistent, recurrent, or metastatic cervical cancer, as illustrated in the proposed algorithm [66]. In line with the study protocols (KEYNOTE-826 and BEATcc, see above), we would not differentiate between histological subtypes (adenocarcinoma or squamous cell carcinoma) and would treat both equally. No significant new data have been recently published regarding this treatment modality ([Fig. 3Fig. 3]). As described above, induction chemotherapy (INTERLACE) and the addition of pembrolizumab (Keynote-A18) for locally advanced but curatively treated cervical cancer have shown impressive effects, establishing immuno-oncology as part of treatment for this indication.

Fig. 3 Fig. 3 Proposed possible treatment algorithm for second-line therapy of persistent, recurrent, metastatic cervical cancer (CC). In this case, prior treatment with a CPI is the decisive factor in determining the treatment pathway.

Endometrial Cancer – Adjuvant

The KEYNOTE-B21 trial investigated the PD-1 antibody pembrolizumab or placebo in combination with adjuvant chemotherapy with or without radiotherapy (carboplatin/paclitaxel/pembrolizumab followed by chemoradiotherapy, then pembrolizumab maintenance at 6 × 400 mg) postoperatively in a high-risk cohort after surgery with no residual tumor. Patients had to undergo curative-intent surgery, including hysterectomy and bilateral salpingo-oophorectomy with no evidence of loco-regional disease or distant metastasis postoperatively, confirmed by imaging [77]. Patients with FIGO stages I–II needed additional risk factors to meet the inclusion criteria (non-endometrioid, or any histological subtype with myometrial invasion and p53 aberration). PFS and OS were the two primary endpoints of the study, as OS data was not yet mature. For PFS, there was no difference between the two groups in the intention-to-treat (ITT) population. However, in the mismatch repair deficient (dMMR) patient group (25% of the total study population), there was a clinically significant benefit for patients receiving pembrolizumab with an impressive HR of 0.3 (95% CI 0.14–0.69), which is comparable to the HR seen in the metastatic setting. OS data and additional PFS updates are awaited. For high-risk patients with early endometrial cancer and mismatch repair (MMR) deficiency, however, the addition of pembrolizumab is already a potential treatment option. It is unfortunate that patients with endometrioid carcinoma and isolated MMR deficiency with p53 wildtype were not included in the study. The presence of both MMR deficiency and a p53 mutation in endometrial cancer is relatively rare (a p53 mutation was not mandatory for type II carcinomas in the trial), meaning that not all patients with MMR deficiency will benefit from this treatment option. However, we have included the option in our proposed algorithm at least with a medication request ([Fig. 4Fig. 4]).

Fig. 4 Fig. 4 Proposed treatment algorithm for first-line therapy of endometrial cancer (EC). Depending on MMR status, three CPIs are now available that can be combined with carboplatin and paclitaxel. If conventional chemotherapy is contraindicated, hormone receptor and HER2neu status can already be assessed in the first-line setting.

Endometrial Cancer – Advanced – First Line

In recent years, there have been regular breakthroughs in treatment options for patients with endometrial carcinoma, with impressive new study data emerging [88]. Central to these developments are CPI, specifically PD-1 and PD-L1 antibodies, which, like in other cancers, have demonstrated strong efficacy, and highlight the crucial role of an activated immune system in cancer treatment. In first-line advanced endometrial carcinoma (FIGO 2009 III, IV), OS data from the RUBY trial on dostarlimab (a monoclonal PD-1 antibody)/placebo combined with carboplatin and paclitaxel (6 cycles) followed by maintenance with dostarlimab/placebo were published [99]. The results showed significant improvements in PFS and OS, with particularly strong effects in the dMMR/microsatellite instability high (MSI-H) group, but also clinically meaningful effects in the mismatch repair proficient (pMMR)/microsatellite instability low (MSI-L) group. OS at 24 months was 71.3% (95% CI 64.5–77.1) with dostarlimab and 56.0% (95% CI 48.9–62.5) with placebo (HR, 0.64; 95% CI 0.46–0.87) in the overall population. The HR for PFS was similarly 0.64 (0.51–0.8), corresponding to the OS. These updated data led to a positive opinion from EMA for pMMR patients as well, improving future therapeutic options for this patient group, therefore the combination of dostarlimab with chemotherapy can be used in all patients independent of MMR status.

The DUO-E trial evaluated durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab +/− olaparib as first-line treatment for advanced or recurrent endometrial cancer [1010]. Randomization was 1 : 1 : 1 (standard, + durvalumab, + durvalumab and olaparib). PFS was clinically significantly improved with durvalumab and with durvalumab plus olaparib in both groups compared to the standard therapy with carboplatin and paclitaxel. The effect was strongest with the combination of durvalumab and olaparib, and more pronounced in the dMMR group (HR [durvalumab + olaparib versus control], 0.41 [95% CI 0.21–0.75]) compared to the pMMR group (HR [durvalumab + olaparib versus control] 0.57; [95% CI 0.44–0.73]). While OS data indicate an OS advantage as well, maturity is still awaited. However, the EMA has already approved the treatment for pMMR patients in the first-line metastatic or recurrent/advanced setting.

In the KEYNOTE 868 trial, patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer endometrial carcinoma or recurrent endometrial carcinoma were treated with pembrolizumab or placebo in combination with paclitaxel plus carboplatin [1111]. The treatment consisted of six cycles chemotherapy plus pembrolizumab/placebo every three weeks, followed by up to 14 maintenance cycles pembrolizumab/placebo every six weeks. PFS was significantly improved in both the pMMR (HR, 0.54; 95% CI, 0.41–0.71) and dMMR (HR 0.3; 95% CI 0.19–0.48) group. OS data are still pending.

As a consequence of these new study data, we have incorporated therapies dependent on the existing MMR status (proficient or deficient) into our proposed algorithm starting from FIGO III, with varying strengths of recommendation ([Fig. 4Fig. 4]). While the RUBY study has already reported significantly positive OS data (hence, strength of recommendation ++), the results of the DUO-E and KEYNOTE 868 studies are still pending (hence, strength of recommendation +).

Endometrial Cancer – Advanced – Second Line

With the current data on CPI in the first-line setting, the benefit of CPI after CPI in the second line setting remains still unclear, even though a clinical benefit might be conceivable. Future studies will provide guidance on this. However, after CPI therapy, it is still possible to administer chemotherapy like pegylated doxorubicin monotherapy [1212]. In any case, testing for hormone receptors and human epidermal growth factor receptor 2/neural (HER2/neu) status in the second-line setting is advisable. This is supported by two phase II studies that have demonstrated the benefit of the ADC T-DXd and the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib.

In the PALEO trial (phase II), patients received palbociclib and letrozole in a double-blind, placebo-randomized design [1313]. The primary endpoint PFS demonstrated significantly longer outcomes with the study medication at 8.3 months versus 3.1 months, with an HR of 0.57 (95% CI 0.32–0.99). A limitation of the trial are small group sizes (36 patients in the intervention group versus 37 patients in the placebo group). A phase III study is currently in planning.

In the DESTINY-PanTumor02 study, patients with various advanced malignancies were included, including those with endometrial, cervical, and ovarian cancer [1414]. In this phase II study, T-DXd was administered once every three weeks for HER2/neu-expressing (immunohistochemistry (IHC) 3+/2+) tumors. The objective response rate was highest in IHC 3+ tumors and was pronounced across all three cancer types (endometrial > cervical > ovarian cancer). T-DXd is therefore a potential and significant treatment option for patients, not only in endometrial cancer but also in other gynecological tumors.

The new study data have led to the inclusion of palbociclib in combination with anti-hormonal therapy (AHT) and T-DXd, both following a cost approval request, in our proposed treatment algorithm ([Fig. 5Fig. 5]).

Fig. 5 Fig. 5 Proposed treatment algorithm for endometrial cancer (EC) in second-line therapy. Prior treatment with a CPi is crucial for guiding further therapy. New treatment options such as T-DXd and palbociclib are now also available for this patient group.

Ovarian Cancer

Also, in the case of ovarian cancer, there are updates related to immunotherapies following initial challenges with the DUO-O and TROPION-PanTumor03 trials. Additionally, last year brought exciting updates on the PRIMA [1515], PAOLA [1616], and ATHENA-MONO [1717] trials, providing new insights into the three approved PARPi.

In the DUO-O trial, patients with advanced ovarian carcinoma (FIGO III–IV) were included in the first-line setting and received carboplatin, paclitaxel, and bevacizumab in combination with the monoclonal PD-L1 antibody durvalumab [1818]. Durvalumab was then continued in the maintenance phase with olaparib and bevacizumab. Last year, the final PFS data were presented as an abstract at European Society for Medical Oncology (ESMO) congress, while the final publication is still pending. In the population with positive homologous recombination deficiency (HRD) status, PFS in the arm with triple maintenance therapy was significantly better than maintenance in the control arm with bevacizumab alone and the arm B with bevacizumab combined with durvalumab, with an HR of 0.46 (0.33–0.65). It must be noted that the comparator arm olaparib plus bevacizumab as maintenance therapy is missing. The HR regarding PFS is comparable to the one for olaparib and bevacizumab in the PAOLA-1 trial (indirect comparison), which might suggest that the effect is primarily driven by olaparib. Nevertheless, at this point, the DUO-O study is a positive trial. The full publication and OS data should still be awaited. Approval is currently not foreseeable.

In the TROPION-PanTumor03 study (NCT 05489211), a novel ADC, datopotamab deruxtecan (Dato-DXd), was evaluated. The monoclonal antibody datopotamab binds to the tumor-associated calcium signal transducer 2 (TROP2)-receptor, and after binding, the drug deruxtecan is released – a mechanism that we already know with sacituzumab govitecan from breast cancer [1919]. The results of the full publication are still pending and highly awaited.

However, these are phase II data, and regulatory approval has not (yet) been granted. Further large-scale studies must be awaited. Nevertheless, data are now available for a new ADC in addition to the approved miretuximab soravtansine, and the path for ADCs in OC appears to be paved. Regarding PARPi, the PRIMA study revealed unexpected findings on niraparib. Here the final OS data were presented [1515]. Although PFS data were highly positive in both the HRD-positive (HRD+) and HRD-negative (HRD−) population, these data were not confirmed in terms of OS. On one hand, these were disappointing news, on the other hand, it is worth taking a closer look at the study population and the following therapies after disease progression. 35.1% presented with stage IV disease at diagnosis, 66.7% received neoadjuvant chemotherapy (not a standard in Germany), 47.5% with postoperative visible residual disease or without a debulking surgery. After all a study collective with a bad prognosis from the start. Furthermore, there was an unbalanced cross-over to a PARPi after progress. While 38/48% (ITT population/HRD+ population) of the placebo group received a PARPi in the next therapy lines (olaparib had already been approved at this time), only 16/12% (ITT population/HRD+ population) of the niraparib group did. Long-term safety data were consistent with the already known adverse events of niraparib, the myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) rate remained low (niraparib: 2.3% versus placebo: 1.6%). In conclusion, we continue to assume a significant benefit of niraparib.

Which brings us to the second PARPi rucaparib. Data from the ATHENA-MONO study are convincing and support the use and benefit of rucaparib as maintenance therapy in the first line treatment for advanced ovarian cancer (FIGO III–IV) [2020]. Inclusion criteria were similar to those of the PRIMA study, the actual study population was less high-risk and closer to the mean ovarian cancer population compared to the PRIMA trial. While the ATHENA combo (rucaparib + nivolumab vs. rucaparib + placebo) study with a negative PFS may be remembered as a negative study (full publication with final PFS data still pending), rucaparib mono maintenance therapy showed clinically and statistically significant benefits concerning PFS with meaningful HR in favor of rucaparib: 0.47 (95% CI 0.31–0.72) in the HRD positive population, 0.65 (95% CI 0.45–0.95) in the HRD negative population and 0.52 (95% CI 0.40–0.68) in the ITT population [1717]. Final OS data are yet to be reported, which places rucaparib in the range of niraparib, both with positive PFS data also in the HRD negative population, albeit with higher HR compared to the HRD positive population.

For the third PARPi olaparib, final OS data was already presented last year [1616]. For the sake of completeness, the HR of PFS and OS in the HRD positive group are reported here. The patients received bevacizumab and olaparib in maintenance therapy. In the HRD positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45–0.85), updated PFS in the HRD positive group remained longer (HR 0.41, 95% CI 0.32–0.54) compared to placebo. The effect in the HRD negative group was not significant for PFS or OS. This leaves olaparib as the only one of the three PARPi with an OS advantage in the pivotal studies. However, olaparib was also the first and thus only PARPi at the time the study patients progressed. A cross-over to other PARPi was therefore not possible, which may partly explain the OS benefits of olaparib compared to the other two PARPi.

Head-to-head comparisons with other PARP inhibitors as maintenance therapy, such as olaparib (we will discuss the new data below), are challenging due to differences in study objectives, patient populations, treatment duration, and cross-over (PARPi after PARPi) [2121]. Efforts for direct comparison although have been made in the past at least for the recurrent setting, without finding meaningful differences between the three PARPi in the HRD positive subgroup and between niraparib and rucaparib in the HRD negative subgroup regarding PFS [2222].

As discussed above, we still consider niraparib to be effective as maintenance therapy and in the recurrent setting and have integrated it into our proposed algorithm for the HRD negative population ([Fig. 6Fig. 6]). Our proposed algorithm for the second line therapy, including two ADCs is shown in [Fig. 7Fig. 7]. In second-line therapy, there are strong recommendations for the use of chemotherapeutic agents or mirvetuximab soravtansine in cases of platinum-resistant recurrence with folate receptor positivity. Regarding the use of trastuzumab deruxtecan (T-DXd), we would favor treatment options with a more robust evidence base – namely chemotherapy and mirvetuximab soravtansine. Beyond this (third-line and beyond), or in cases with a contraindication to conventional chemotherapy, treatment with T-DXd should be considered if there is evidence of HER2 overexpression. With data from the TROPION-Pan Tumor 03 study on the horizon new ADCs will likely enter our second-line algorithm in the future.

Fig. 6 Fig. 6 Proposed treatment algorithm for ovarian cancer (OC) in first-line therapy. The foundation is standard chemotherapy with carboplatin and paclitaxel. Depending on BRCA and HRD status, bevacizumab and a PARP inhibitor should be added, starting from FIGO stage III. The prerequisite is prior surgery, as radical as possible, ideally with no residual tumor.

Fig. 7 Fig. 7 Proposed treatment algorithm for ovarian cancer (OC) in second-line therapy. The decision is made based on whether the recurrence is platinum-sensitive or platinum-resistant. If there is a contraindication to further conventional chemotherapy, T-DXd can be considered as early as the second-line setting in HER2-positive cases.

Outlook

While subtype-specific therapy is already standard of care in breast cancer, specific therapy is also emerging even in early endometrial cancer. In the future, treatment for early and advanced endometrial cancer will become still more diverse, guided by MMR, HER2/neu, and hormone receptor status. Further subdivisions and increasingly targeted therapies are expected. For the first time, a CDK4/6 inhibitor, palbociclib, and the first ADC, T-DXd, have made their way into treatment algorithms, although phase III studies are still pending. New ADCs are certainly on the horizon, as well as new therapeutic concepts involving vaccinations, bispecific antibodies, personalized big-data approaches, CAR-T cell therapies and the combination of those approaches. Treatment strategies will develop to a more targeted approach. Therefore, some patients can benefit from a more deescalated therapy regime while high-risk patients can benefit from a more specific and maintained combination therapy.

In ovarian cancer, three PARPi are currently approved for maintenance therapy. The direct comparison of the three drugs is pending, so that recommendations can be made analogous to the approval studies. The question of PARPi after PARPi also remains unresolved, as no conclusions on its efficacy can be drawn at this time. Both tasks will mainly involve studies in the real-world setting. One of these studies, which is active in Germany, is the BZKF-OVAR1 study. The prospective collection of the necessary clinical and molecular data for patients receiving PARPi after PARPi will provide an opportunity to better understand the mechanisms of progression and may even be able to give an answer about the best efficacy of PARPi after PARPi and could at least allow a retrospective data analysis for comparison in the first line maintenance setting.

In cervical cancer, the adjuvant vaccination study, for example with Gardasil-9 in combination with a CPI, is still pending and could represent an innovative therapeutic concept. The evaluation of indication for conisation prior to the final operation is a wildly discussed issue and may be answered in the future with many studies planned and executed around this issue. The problem of using CPI after CPI arises in cervical cancer as in other entities and needs more clinical research. Real-world registry studies will also provide valuable insights here.

It is also important not to overlook the established role of HPV vaccination with the nonavalent vaccine, which has demonstrated a 99.8–100% seroconversion rate in month 7 after vaccination, along with a more than 95% reduction in preinvasive and invasive lesions of the cervix, vulva, and vagina—and all without the need for new clinical studies. Given the persistently low vaccination rates, including in Germany, this comment nevertheless deserves its place in the outlook section.

Immuno-oncology and targeted therapies are on the rise across all entities of gynecological cancers and will provide us with a diverse, personalized, and improved approach to cancer therapy.

Funding: This research received no external funding.

Institutional Review Board Statement: An ethics committee approval was not necessary for this review article.

Contributorsʼ Statement

J.E. and P.P. made substantial contributions to the concept and design of the study, the analysis and interpretation of data from the current trial landscapes and the critical revision of the manuscript. J.G. and M.H. drafted the manuscript and were involved in revising it critically for important intellectual content. All authors gave their approval of the final prepublication version, revised the manuscript critically and participated sufficiently in the work to take public responsibility for appropriate portions of the content. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and agreed to the published version of the manuscript.

Conflict of Interest

J.E. has received honoraria from Novartis, MSD, Eisai, Pfizer and AstraZeneca. A.K. received honoria from Gilead as well as support for attending meetings from Lilly. N.A. received honoraria from Thieme, Gilead and travel support from AstraZeneca, Pfizer, Novartis. M.H. received research support from Helsinn Healthcare SA, honoraria from Lilly, honoraria for written scientific work from Thieme and travel support from Novartis, Lilly Deutschland GmbH, and AstraZeneca. P.P. received honoraria from Novartis and AstraZeneca. All other authors declare no conflicts of interest.

Acknowledgement

We would also like to extend our gratitude to the patients who took part in the trials leading to this review and to the scientists of the pivotal trials.

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Publication History

Received: 24 March 2025

Accepted after revision: 24 May 2025

Article published online:
30 June 2025