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
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
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
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
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.
