The DESTINY-Endometrial01 is a global, randomized (treatment assignment for the individual patient is by chance) Phase 3 study investigating a new treatment option for patients with advanced or recurrent endometrial cancer whose tumor cells overexpress HER2 and have a pMMR status. Two new combination therapies with the drug Trastuzumab deruxtecan (T-DXd with Rilvegostomig or Pembrolizumab) are compared with the current standard therapy of chemotherapy and immunotherapy. The aim is to find out whether the new treatments can prevent disease progression for longer.

What is being investigated in this study?

Endometrial carcinomas are among the most common cancers of the uterus.

For patients with advanced or recurrent disease at initial diagnosis, standard treatment often consists of a combination of chemotherapy and immunotherapy. Nevertheless, many patients experience disease progression over time, which is why new therapeutic approaches are needed.

The study targets patients whose tumors express human epidermal growth factor receptor 2 (HER2). HER2 is a protein on the surface of tumor cells that can transmit growth signals to the cancer cell. Some endometrial carcinomas show an increased presence of HER2, which can be used as a target for directed therapies.

In addition, the tumors must have a so-called pMMR status (proficient Mismatch Repair). This means that this repair system for genetic errors is fundamentally functional. These tumors often respond less well to immunotherapies than tumors with a defective repair system (dMMR), which is why new treatment strategies are being investigated.

This study uses, among other things, Trastuzumab deruxtecan (T-DXd). This is a so-called antibody-drug conjugate (ADC). The antibody specifically recognizes HER2 on the surface of tumor cells and then introduces a cell toxin into the cancer cell to destroy it.

In this study, T-DXd is combined either with Pembrolizumab, an immunotherapy, or with Rilvegostomig. Rilvegostomig is a new immunotherapeutic agent designed to simultaneously influence various mechanisms of the immune system to strengthen the body’s defense against the tumor.

What is the aim of the study?

The primary objective of the study is to investigate whether the combination of Trastuzumab deruxtecan with Rilvegostomig or Pembrolizumab can prevent disease progression for longer than the current standard treatment of chemotherapy and Pembrolizumab.

Furthermore, the study will investigate whether the new treatment strategies affect overall survival and how well the therapies are tolerated. Quality of life and patient-reported symptoms during treatment will also be examined.

What is the study procedure?

Patients participating in the study will be randomly assigned to one of three treatment arms:

Arm 1:
Trastuzumab deruxtecan + Rilvegostomig as an infusion every three weeks.

Arm 2:
Trastuzumab deruxtecan + Pembrolizumab as an infusion every three weeks.

Arm 3:
Current standard therapy consisting of chemotherapy with Carboplatin and Paclitaxel + Pembrolizumab for 6 treatment cycles. Subsequently, Pembrolizumab will be continued as maintenance therapy for up to 14 cycles.

Treatment will be continued in all study arms until disease progression, unacceptable side effects occur, or other reasons for discontinuing therapy arise.

Throughout the study, regular examinations will take place to monitor the effect of the treatment, possible side effects, and the general health status of the patients.

Are there risks?

You will be informed about possible risks or side effects associated with participation by your doctor during an informational consultation.

Eligibility criteria:

Women aged 18 years and older can participate in this study with:

• confirmed diagnosis of epithelial endometrial carcinoma. All histological types are permissible, with the exception of sarcomas (carcinosarcomas are permissible).
• advanced endometrial carcinoma (Stage III/IV) at initial diagnosis or first recurrence of endometrial carcinoma
• centrally confirmed positive HER2 status (IHC 3+ or 2+)
• confirmed pMMR status (functional MMR repair mechanism)
• No prior systemic therapy for the disease is allowed, with the exception of: adjuvant/neoadjuvant chemotherapy or chemoradiotherapy (for recurrences, recurrence or progression of the disease must have occurred ≥ 6 months after the last chemotherapy dose), treatment with Trastuzumab in the adjuvant/neoadjuvant setting and previous radiation therapy are permitted
• Previous treatment with ADCs or immune checkpoint inhibitors, including (but not limited to) anti-PD-1/PD-L1/PD-L2 and anti-CTLA-4 antibodies, as well as therapeutic cancer vaccines, is not permitted.

In addition, there are other criteria that must be met for participation in the study. Further information can be obtained from your treating physicians.

Further information on the study and centers where participation is possible can be found on the study homepage: https://www.astrazenecaclinicaltrials.com/study/D781DC00001/

This study is conducted by:

The PYNNACLE study is a phase 1/2 clinical trial investigating a new medication called Rezatapopt. The study is aimed at patients with various advanced or metastatic cancers (e.g., ovarian, breast, lung, or endometrial cancer) whose tumor has a specific genetic alteration called the TP53-Y220C mutation. The objective is to determine how safe and effective Rezatapopt is and which dose is most suitable.

Participation:

Further information about the study and centers where participation is possible can be found on the study homepage: https://www.pynnaclestudy.com/

The SARA study is a Europe-wide survey study on the quality of life of patients with endometrial cancer. The aim is to record acute and long-term side effects of treatment, as well as their impact on the daily lives and well-being of patients.

What is being investigated in the survey?

Endometrial cancer is one of the most common cancers among women in industrialized countries – ranking fourth after breast, colorectal, and lung cancer. In most cases, the disease is detected early, which increases the chances of recovery. Despite good survival rates, treatment can cause side effects that can impair the quality of life in the long term. These can be physical (e.g., nerve damage such as polyneuropathy or hair loss), psychological, or social. The SARA study aims to better understand how these burdens are experienced and what long-term consequences they have for patients. The survey considers many aspects of life with endometrial cancer: comorbidities, general health status, polypharmacy (taking multiple medications), side effects, psychological well-being, daily life, relationships, employment, and level of information about treatment options.

What is the aim of the survey?

The main goal of the study is to record the frequency of certain side effects – particularly nerve damage (polyneuropathy) and hair loss – and to assess how strongly these affect the quality of life.
In addition, the following points will also be investigated:

• treatment preferences and therapy adherence (whether and how well therapies are followed)
• financial and time burdens due to the disease
• how well patients feel informed about treatment options and medical guidelines

What is the survey process?

A total of approximately 500 patients are to be surveyed for the study, including 100 patients from Germany. Participation in the SARA study is via a questionnaire that affected women can complete – regardless of the stage of their disease or what treatment they are receiving (or have received). Three groups of patients are compared:

• Group A: Women with a first-time diagnosis of endometrial cancer
• Group B: Women with a recurrence of the disease
• Group C: Women who are in the post-treatment phase

Are there any risks?

Expression 21 is a survey study and therefore has no participation risks.

Participation requirements:

The survey is voluntary and is aimed at all women affected by endometrial cancer, regardless of whether the disease has occurred for the first time or has recurred. The minimum age for participation is 18 years.

Where can I participate in the survey?

Currently, patients can participate in the study through the participating centers. Online participation will also be possible soon.

What is being investigated in this study?

The EMRISK study is an observational study in two phases in which patients are surveyed about their medical history and risk factors for nausea and vomiting and about the actual occurrence of nausea and vomiting during chemotherapy. The study investigates whether a valid model for predicting the risk of nausea and vomiting can be derived from this information.

What is the objective of the study?

This study aims to develop a model to predict a patient’s risk of nausea and vomiting during chemotherapy.

What is the study procedure?

The study will be conducted with a total of 519 patients. In the first phase, 191 patients complete a questionnaire before their first chemotherapy session that provides information about their personal risk factors for nausea and vomiting. During chemotherapy treatment, a diary is then used to document when and how severely nausea and vomiting actually occur.

Correlations between the risk factors and the occurrence of nausea and vomiting are identified in order to develop a model that calculates the personal risk for each individual patient. Before the first chemotherapy session, before the fourth cycle, and after the end of treatment, patients are surveyed about their quality of life using the QLQ-C30 questionnaire. In the second phase, this model is applied to 328 patients before their treatment to verify its predictive value.

The first study phase has already been successfully completed.

Are there any risks?

No, EMRISK is an observational study. Patients participating in the study would receive the same therapy if they were not participating in the study. Therefore, study participation does not entail any risks.

Participation Requirements:

Women aged 18 years and older can participate in this study

• who have been diagnosed with a primary gynecological cancer,
• with planned chemotherapy of at least three cycles, adjuvant and neoadjuvant (as standard therapy),
• who are willing and able to complete the questionnaires and maintain the diary,
• and who have provided written informed consent.

This study is supported by:

The TroFuse-033 study is an international, randomized (the treatment assignment for the individual patient is determined by chance) phase 3 study investigating a new combination therapy in patients with advanced or recurrent endometrial cancer whose tumor exhibits a functioning so-called mismatch repair mechanism (pMMR). The study examines whether a combination of Sacituzumab Tirumotecan (sac-TMT) and Pembrolizumab as maintenance therapy is more effective than maintenance therapy with Pembrolizumab alone.

What is being investigated in this study?

Endometrial cancer is one of the most common cancers of the uterus. When the disease is advanced or returns after surgery, treatment options are often limited.

Endometrial cancer can exhibit different biological characteristics. An important factor is whether certain repair mechanisms in the tumor cells are functional or not. One of these repair mechanisms is called mismatch repair (MMR).
When this repair mechanism does not function, it is referred to as dMMR (deficient mismatch repair). Such tumors often have many genetic alterations and frequently respond particularly well to immunotherapies such as Pembrolizumab.
If the repair system functions normally, it is referred to as pMMR (proficient mismatch repair). Patients with pMMR tumors often respond only to a limited extent to immunotherapies.

This study therefore examines a new therapeutic approach: Sacituzumab Tirumotecan (sac-TMT), an antibody-drug conjugate that can target cancer cells specifically, is combined with Pembrolizumab, an immunotherapy. The goal is to enhance the effect of Pembrolizumab and delay disease progression for a longer period.

What is the goal of the study?

The primary goal of the TroFuse-033 study is to examine whether patients with the combination of sac-TMT and Pembrolizumab live longer without disease progression than patients who receive only Pembrolizumab. Additionally, the study aims to investigate whether overall survival is extended and how well the therapy is tolerated.

What is the course of the study?

At the beginning, all participants receive a so-called induction treatment. This consists of the immunotherapy Pembrolizumab combined with the chemotherapy agents Carboplatin and Paclitaxel. The induction treatment is administered every 3 weeks for a total of 6 months.
If the disease does not progress further during this phase, patients transition to the maintenance phase. There they are randomly assigned to one of two groups:

Group 1:
Pembrolizumab every 6 weeks + Sacituzumab Tirumotecan every 2 weeks for up to 18 months

Group 2:
Pembrolizumab every 6 weeks for up to 18 months

If the disease progresses again despite these treatments, the treatment is discontinued and patients are treated outside the study.

Are there risks?

You will be informed about possible risks or side effects associated with participation during an informed consent discussion with your physician.

Participation requirements:

Women aged 18 years and older can participate in this study with:

• confirmed diagnosis of newly diagnosed, advanced (stage III or IV) or recurrent endometrial cancer
• confirmed pMMR status (functioning MM repair mechanism)
• no prior systemic therapy for the disease in the advanced stage, except: chemotherapy in early cancer stage, radiation ± chemotherapy (completed at least 2 weeks before the start of study treatment), hormone therapy (completed at least 1 week before the start of study treatment)

In addition, there are other criteria that must be met for participation in the study. Further information is available from your treating physicians.

This study is supported by:

The DUOLife study is a non-interventional observational study. This means that patients receive an already planned or initiated and approved therapy – no therapies or other interventions are prescribed or adjusted by the study. This study aims solely to collect data on real-world experience from routine treatment in Germany (real-world data): How effective and tolerable is first-line therapy with carboplatin, paclitaxel, and durvalumab, followed by maintenance therapy with durvalumab – alone or in combination with olaparib – in patients with advanced or recurrent endometrial cancer (also known as uterine cancer)?

What is being investigated in this study?

Advanced (FIGO III or IV) or recurrent endometrial cancer is increasingly treated with chemotherapy in combination with immunotherapy. This study investigates how well such a therapy works in routine clinical practice. Large clinical trials have already confirmed the benefit of these therapies in hundreds of patients. Now, the effect is to be investigated outside of large clinical trials in normal routine treatment in Germany. This makes it possible to examine the effect of the therapy even in patients who did not participate in or could not participate in the clinical trials.

Durvalumab is an immune checkpoint inhibitor. The drug helps the body’s immune system better recognize and fight cancer cells. Many tumor cells are protected from attack by immune cells by a specific protein (PD-L1) on their surface. Durvalumab blocks this protective mechanism, allowing the immune system to attack the cancer cells. The combination of chemotherapy and immunotherapy can mutually reinforce each other: chemotherapy can damage tumor cells, making them more “visible” to the immune system – and durvalumab then helps the immune system fight them more effectively.

After chemotherapy, durvalumab is continued as maintenance therapy to keep any remaining cancer cells under long-term control and prevent recurrence.

Endometrial cancer can have different biological characteristics. An important factor is whether certain repair mechanisms in the tumor cells are functional or not. One of these repair mechanisms is called mismatch repair (MMR).
If this repair mechanism does not work, it is referred to as dMMR (deficient mismatch repair). Such tumors often have many genetic changes and frequently respond particularly well to immunotherapies like durvalumab.
If the repair system functions normally, it is referred to as pMMR (proficient mismatch repair). These tumors are generally less sensitive to immunotherapies, so additional drugs such as olaparib are used to enhance the effect.

Olaparib is a PARP inhibitor, a drug that prevents cancer cells from repairing damage to their DNA. The addition of olaparib to durvalumab maintenance therapy in pMMR tumors can help better control tumor growth by making cancer cells more susceptible to an immune response. This therapeutic benefit has already been demonstrated in the past, for example, by the DUO-E study.
The goal is to achieve the most effective and long-term control of the disease, even in patients with pMMR tumors, through the combined maintenance therapy of durvalumab + olaparib.

What is the aim of the study?

The DUOLife study focuses on the question of how long it takes until the next therapy is needed – a measure called rwTTNT (real-world Time to Next Treatment). In addition, it also assesses, among other things, how long the disease remains under control (rwPFS = real-world progression-free survival), what side effects occurred, and how patients are doing in their daily lives (quality of life, symptoms).

What is the study procedure?

A total of approximately 150 patients are expected to participate in Germany. All will receive a therapy that is already used in clinical routine – so it is not a clinical study with experimental treatment.

For every patient with endometrial cancer, the tumor’s dMMR or pMMR status is determined at diagnosis. Depending on their diagnosis, patients can be enrolled in one of these two groups:

• dMMR cohort: Patients receive chemotherapy in combination with durvalumab. This is followed by maintenance therapy with durvalumab.
• pMMR cohort: Patients also receive the combination of chemotherapy and durvalumab, followed by maintenance therapy with durvalumab plus olaparib.

For the study, no additional examinations or visits to the study center beyond routine care are required. In addition to routine examinations, you will only be asked to complete questionnaires for the evaluation of quality of life.

Are there risks?

This is a purely observational study, meaning patients receive their planned or already initiated cancer therapy. They do not receive any additional medications or other treatments (excluding medications for comorbidities or medications for potential side effects of routine treatment). The risks and side effects are therefore the same as if the treatment were to take place outside of this observational study.

Eligibility criteria:

Women aged 18 years and older can participate in this study if they have:

• Advanced (FIGO stage III or IV) or recurrent endometrial cancer
• Known MMR status (genetic characteristic of the tumor, determined at diagnosis: dMMR or pMMR)
• Planned or already initiated first-line therapy with a combination of chemotherapy (carboplatin + paclitaxel, abbreviated CP) and durvalumab
• Willingness to regularly complete quality of life questionnaires (known as PROs – patient-reported outcomes)

However, there are also other criteria that must be met for participation in the study. Further information can be obtained from your treating physicians.

This study is supported by:

What is being investigated in this study?

The XPORT-EC-042 is a randomized (random assignment to treatment arms), placebo-controlled, double-blind (physicians and participants do not know who was assigned to which arm) Phase 3 study with Selinexor as maintenance therapy following systemic therapy in patients with advanced or recurrent endometrial cancer, without p53 mutation in tumor tissue.

The current standard therapy for the first-line treatment of advanced or recurrent endometrial cancer is the intravenous administration of carboplatin and paclitaxel (chemotherapy). Although more than half of patients respond to treatment, unfortunately, almost all patients experience a recurrence (return of the disease) within a short period. Therefore, a maintenance therapy is currently being sought that further supports the initial tumor response to chemotherapy and delays the recurrence and/or progression of the disease by eliminating residual cancer cells. Previous studies (SIGN and SIENDO) have already found initial evidence that Selinexor improves disease control in patients with endometrial cancer. The XPORT study aims to build on this and further investigate the efficacy of Selinexor as maintenance therapy in patients with endometrial carcinoma without p53 mutation.

The SIGN study was a Phase 2 study evaluating the safety and efficacy of Selinexor in patients with advanced gynecological malignancies. The results demonstrate the efficacy of the drug in patients with heavily pretreated gynecological cancers. The SIENDO study is a study with Selinexor as maintenance therapy compared to placebo after combination chemotherapy in patients with advanced or recurrent endometrial cancer. An analysis of the SIENDO data showed that patients with endometrial cancer without p53 mutation have a significant improvement with Selinexor maintenance therapy compared to placebo. Selinexor was also safe and reasonably well tolerated in the SIENDO study.

Selinexor is a selective inhibitor, meaning it specifically inhibits a certain protein (Exportin-1). This protein is responsible for transporting certain proteins, growth regulators, and tumor-specific mRNAs out of the cell nucleus. If Exportin-1 is inhibited, these proteins accumulate in the cell nucleus and can cause cell death, thereby inhibiting tumor growth.

What is the aim of the study?

The main objective of the study is to evaluate the efficacy of Selinexor as maintenance therapy compared to placebo. For this purpose, overall survival and progression-free survival (i.e., from the start of treatment within the study until further progression of the disease) are compared between the two treatment arms. In addition, the safety and tolerability of Selinexor, as well as the quality of life during treatment, are evaluated.

What is the study procedure?

Patients are randomly assigned to one of the two treatment arms in a 1:1 ratio:

Arm A: Selinexor

Arm B: Placebo

In both treatment arms, drug treatment continues until disease progression.

Are there any risks?

You will be informed about possible risks or side effects associated with participation during an informational discussion.

Eligibility requirements:

Women aged 18 and over can participate in this study if they meet the following criteria:

• with newly confirmed diagnosis of advanced (Stage IV) or recurrent endometrial cancer
• tumor shows no p53 mutation
• at least 12 weeks of platinum-based chemotherapy as prior treatment

In addition, there are other criteria that must be met for participation in the study. Further information can be obtained from your treating physicians.

What is being investigated in this study?

This study investigates whether removal of the lymph nodes in the pelvis and alongside the abdominal aorta improves overall survival in women with uterine cancer at high risk of recurrence.

What is the aim of the study?

The study aims to clarify whether the previously standard removal of the lymph nodes in the pelvis and along the abdominal aorta in women with uterine cancer at high risk of recurrence improves the chances of cure (overall survival). If this is the case, this operation should continue to be recommended; if not, it should be omitted in the future.

What is the study procedure?

The study is being conducted nationwide in Germany at around 55 centers, and a total of 640 patients are to be included. This is a clinical study in which patients undergo surgery and are then followed up for 5 years.

It is a prospective, randomized, two-arm, multicenter, open-label study.

Eligible patients are randomly assigned to either receive the previously standard lymph node removal or to forgo it. For all patients, given the high risk of recurrence, vaginal radiotherapy (brachytherapy) and chemotherapy (carboplatin/paclitaxel) are recommended as adjuvant treatment after surgery.

Are there any risks?

You will be informed about possible risks and/or side effects associated with participation as part of an informed-consent discussion.

Eligibility requirements:

Women aged 18–75 years can participate in this study if the following criteria are met:

Excerpt from the inclusion criteria:

• Histologically confirmed endometrial cancer, clinical stage I or II, high risk of recurrence
  No previous surgery for endometrial cancer
• or surgery after hysterectomy (surgical removal of the uterus) within 8 weeks if no LNE has yet been performed
• No enlarged lymph nodes
  ECOG performance status 0–1

Excerpt from the exclusion criteria:

• Recurrence of endometrial cancer
• Sarcomas
• FIGO stage III or IV
• Previous chemo-, radio-, or endocrine therapy for endometrial cancer

In addition, there are further criteria that must be met to participate in the study. Interested patients should speak with a study physician at a study center, who can assess whether you are eligible for this study.

This study investigates whether removal of the lymph nodes in the pelvis and alongside the abdominal aorta improves overall survival in women with uterine cancer at high risk of recurrence.