AVAHO

This transcript has been edited for clarity.

New guidelines have lowered the age to begin screening for colon cancer to 45 years old. Although this change is positive, we’re still seeing advanced cancer in younger patients who haven’t been screened in time. 

Once diagnosed, these patients undergo surgery and chemotherapy and often return to us asking, “What can I do now to help myself?” 

Two recent studies highlight interventions that are simple, affordable, and actionable today: exercise and aspirin. Let’s take a closer look at the results.

 

Exercise’s Risk Reduction Potential

The idea that exercise reduces cancer recurrence and mortality is supported by observational data. The mechanistic effects behind this have been ascribed to metabolic growth factors, inflammatory changes, immune function changes, and perhaps even positive impact on sleep. 

A study just published in The New England Journal of Medicine examined structured exercise after adjuvant chemotherapy for colon cancer. The phase 3 randomized CHALLENGE trial, mostly conducted at Canadian and Australian centers, recruited patients with resected stage II or III colon cancer (9.8% and 90.2%, respectively) who had completed adjuvant chemotherapy. Patients with recurrences within a year of diagnosis were excluded, as they were more likely to have highly aggressive, biologically active disease. 

Patients were randomized to receive healthcare education materials alone or in conjunction with a structured exercise program over a 3-year follow-up period. 

The exercise intervention, delivered in person or virtually, focused on increasing recreational aerobic activity over baseline by at least 10 metabolic equivalent task (MET). An increment of 10 MET hours per week is not too vigorous. It is essentially the equivalent of adding about 45-60 minutes of brisk walking or 25-30 minutes of jogging 3-4 times a week.

Patients were asked to increase MET over the first 6 months and then maintain or further increase the amount over the next 2.5 years. They were permitted to structure their own exercise program by choosing the type, frequency, intensity, and duration of aerobic exercise. 

The primary endpoint was disease-free survival, with secondary endpoints assessing overall survival, patient-reported outcomes, and other outcomes. Although designed to detect differences at 3 years, follow-up was also performed out to 5 and 8 years.

At a median follow-up of 7.9 years, exercise reduced the relative risk of disease recurrence, new primary cancer, or death by 28% (P = .02). This benefit persisted — and even strengthened — over time, with disease-free survival increasing by 6.4 and 7.1 percentage points at 5 and 8 years, respectively. 

Musculoskeletal adverse events were slightly higher in the exercise group compared with the health education group (18.5% vs 11.5%, respectively), but only 10% were directly attributed to the exercise. 

There are considerations when interpreting these results. First, there was an attrition over time for compliance and training. It would be interesting to see whether that impacted the results. Second, it’s unclear whether patient pedigree or a genomic pathway may predispose to a benefit here for the exercise group. 

But overall, this phase 3 trial provides class 1 evidence supporting exercise as a low-cost, high-impact intervention to reduce cancer recurrence.

 

Adjuvant Aspirin in Colon Cancer Subset

That’s a perfect segue into another recent study looking at the effects of adjuvant aspirin on the prevention of recurrence.

The ALASCCA trial— conducted across centers in Sweden, Denmark, Finland, and Norway — assessed patients with stage I-III rectal cancer or stage II-III colon cancer. It focused on a subset of patients with an oncogenic abnormality called PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha). 

PIK3CA occurs in approximately a third of colon cancers and is associated with significant chemotherapy resistance and a higher rate of disease progression. 

Of the included patients, 1103 (37%) had alterations in the PIK3CA pathway. Researchers randomized patients to receive either 160 mg of aspirin or placebo daily for 3 years, starting within 3 months of surgery. 

Among patients with PIK3CA mutations, aspirin dramatically reduced the risk for time to recurrence by nearly 50% at 3 years (P = .044). Adverse events associated with aspirin were minimal, including one case each of gastrointestinal bleeding, hematoma, and allergic reaction. 

There is no evidence that higher aspirin doses provide greater prevention of colorectal cancer recurrence. The 160-mg use in the current study is fairly normal, roughly equivalent to two low-dose (81-mg) aspirin tablets. 

Now, it’s worth noting that the use of aspirin for the primary prevention of cardiovascular disease was initially recommended by the US Preventive Services Task Force in 2016. This recommendation was then recanted in 2022, when the same group reported limited net benefit to this approach. 

 

Two Proactive Actions

These studies highlight 2 interventions — exercise and aspirin — that are low cost, accessible, and appeal to patients eager to help prevent their cancer from recurring. 

Exercise is broadly beneficial and can be recommended immediately. 

For aspirin, patients should work with their oncologist to determine their PIK3CA mutation status, as this subgroup appears to benefit the most. 

These findings offer patients meaningful, proactive interventions they can apply to support their recovery and reduce the risk of recurrence. Hopefully these new findings will help guide your clinical conversations.

Johnson is a regular contributor to Medscape. He is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease. He disclosed that he is an adviser for ISOThrive. 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

New guidelines have lowered the age to begin screening for colon cancer to 45 years old. Although this change is positive, we’re still seeing advanced cancer in younger patients who haven’t been screened in time. 

Once diagnosed, these patients undergo surgery and chemotherapy and often return to us asking, “What can I do now to help myself?” 

Two recent studies highlight interventions that are simple, affordable, and actionable today: exercise and aspirin. Let’s take a closer look at the results.

 

Exercise’s Risk Reduction Potential

The idea that exercise reduces cancer recurrence and mortality is supported by observational data. The mechanistic effects behind this have been ascribed to metabolic growth factors, inflammatory changes, immune function changes, and perhaps even positive impact on sleep. 

A study just published in The New England Journal of Medicine examined structured exercise after adjuvant chemotherapy for colon cancer. The phase 3 randomized CHALLENGE trial, mostly conducted at Canadian and Australian centers, recruited patients with resected stage II or III colon cancer (9.8% and 90.2%, respectively) who had completed adjuvant chemotherapy. Patients with recurrences within a year of diagnosis were excluded, as they were more likely to have highly aggressive, biologically active disease. 

Patients were randomized to receive healthcare education materials alone or in conjunction with a structured exercise program over a 3-year follow-up period. 

The exercise intervention, delivered in person or virtually, focused on increasing recreational aerobic activity over baseline by at least 10 metabolic equivalent task (MET). An increment of 10 MET hours per week is not too vigorous. It is essentially the equivalent of adding about 45-60 minutes of brisk walking or 25-30 minutes of jogging 3-4 times a week.

Patients were asked to increase MET over the first 6 months and then maintain or further increase the amount over the next 2.5 years. They were permitted to structure their own exercise program by choosing the type, frequency, intensity, and duration of aerobic exercise. 

The primary endpoint was disease-free survival, with secondary endpoints assessing overall survival, patient-reported outcomes, and other outcomes. Although designed to detect differences at 3 years, follow-up was also performed out to 5 and 8 years.

At a median follow-up of 7.9 years, exercise reduced the relative risk of disease recurrence, new primary cancer, or death by 28% (P = .02). This benefit persisted — and even strengthened — over time, with disease-free survival increasing by 6.4 and 7.1 percentage points at 5 and 8 years, respectively. 

Musculoskeletal adverse events were slightly higher in the exercise group compared with the health education group (18.5% vs 11.5%, respectively), but only 10% were directly attributed to the exercise. 

There are considerations when interpreting these results. First, there was an attrition over time for compliance and training. It would be interesting to see whether that impacted the results. Second, it’s unclear whether patient pedigree or a genomic pathway may predispose to a benefit here for the exercise group. 

But overall, this phase 3 trial provides class 1 evidence supporting exercise as a low-cost, high-impact intervention to reduce cancer recurrence.

 

Adjuvant Aspirin in Colon Cancer Subset

That’s a perfect segue into another recent study looking at the effects of adjuvant aspirin on the prevention of recurrence.

The ALASCCA trial— conducted across centers in Sweden, Denmark, Finland, and Norway — assessed patients with stage I-III rectal cancer or stage II-III colon cancer. It focused on a subset of patients with an oncogenic abnormality called PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha). 

PIK3CA occurs in approximately a third of colon cancers and is associated with significant chemotherapy resistance and a higher rate of disease progression. 

Of the included patients, 1103 (37%) had alterations in the PIK3CA pathway. Researchers randomized patients to receive either 160 mg of aspirin or placebo daily for 3 years, starting within 3 months of surgery. 

Among patients with PIK3CA mutations, aspirin dramatically reduced the risk for time to recurrence by nearly 50% at 3 years (P = .044). Adverse events associated with aspirin were minimal, including one case each of gastrointestinal bleeding, hematoma, and allergic reaction. 

There is no evidence that higher aspirin doses provide greater prevention of colorectal cancer recurrence. The 160-mg use in the current study is fairly normal, roughly equivalent to two low-dose (81-mg) aspirin tablets. 

Now, it’s worth noting that the use of aspirin for the primary prevention of cardiovascular disease was initially recommended by the US Preventive Services Task Force in 2016. This recommendation was then recanted in 2022, when the same group reported limited net benefit to this approach. 

 

Two Proactive Actions

These studies highlight 2 interventions — exercise and aspirin — that are low cost, accessible, and appeal to patients eager to help prevent their cancer from recurring. 

Exercise is broadly beneficial and can be recommended immediately. 

For aspirin, patients should work with their oncologist to determine their PIK3CA mutation status, as this subgroup appears to benefit the most. 

These findings offer patients meaningful, proactive interventions they can apply to support their recovery and reduce the risk of recurrence. Hopefully these new findings will help guide your clinical conversations.

Johnson is a regular contributor to Medscape. He is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease. He disclosed that he is an adviser for ISOThrive. 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

New guidelines have lowered the age to begin screening for colon cancer to 45 years old. Although this change is positive, we’re still seeing advanced cancer in younger patients who haven’t been screened in time. 

Once diagnosed, these patients undergo surgery and chemotherapy and often return to us asking, “What can I do now to help myself?” 

Two recent studies highlight interventions that are simple, affordable, and actionable today: exercise and aspirin. Let’s take a closer look at the results.

 

Exercise’s Risk Reduction Potential

The idea that exercise reduces cancer recurrence and mortality is supported by observational data. The mechanistic effects behind this have been ascribed to metabolic growth factors, inflammatory changes, immune function changes, and perhaps even positive impact on sleep. 

A study just published in The New England Journal of Medicine examined structured exercise after adjuvant chemotherapy for colon cancer. The phase 3 randomized CHALLENGE trial, mostly conducted at Canadian and Australian centers, recruited patients with resected stage II or III colon cancer (9.8% and 90.2%, respectively) who had completed adjuvant chemotherapy. Patients with recurrences within a year of diagnosis were excluded, as they were more likely to have highly aggressive, biologically active disease. 

Patients were randomized to receive healthcare education materials alone or in conjunction with a structured exercise program over a 3-year follow-up period. 

The exercise intervention, delivered in person or virtually, focused on increasing recreational aerobic activity over baseline by at least 10 metabolic equivalent task (MET). An increment of 10 MET hours per week is not too vigorous. It is essentially the equivalent of adding about 45-60 minutes of brisk walking or 25-30 minutes of jogging 3-4 times a week.

Patients were asked to increase MET over the first 6 months and then maintain or further increase the amount over the next 2.5 years. They were permitted to structure their own exercise program by choosing the type, frequency, intensity, and duration of aerobic exercise. 

The primary endpoint was disease-free survival, with secondary endpoints assessing overall survival, patient-reported outcomes, and other outcomes. Although designed to detect differences at 3 years, follow-up was also performed out to 5 and 8 years.

At a median follow-up of 7.9 years, exercise reduced the relative risk of disease recurrence, new primary cancer, or death by 28% (P = .02). This benefit persisted — and even strengthened — over time, with disease-free survival increasing by 6.4 and 7.1 percentage points at 5 and 8 years, respectively. 

Musculoskeletal adverse events were slightly higher in the exercise group compared with the health education group (18.5% vs 11.5%, respectively), but only 10% were directly attributed to the exercise. 

There are considerations when interpreting these results. First, there was an attrition over time for compliance and training. It would be interesting to see whether that impacted the results. Second, it’s unclear whether patient pedigree or a genomic pathway may predispose to a benefit here for the exercise group. 

But overall, this phase 3 trial provides class 1 evidence supporting exercise as a low-cost, high-impact intervention to reduce cancer recurrence.

 

Adjuvant Aspirin in Colon Cancer Subset

That’s a perfect segue into another recent study looking at the effects of adjuvant aspirin on the prevention of recurrence.

The ALASCCA trial— conducted across centers in Sweden, Denmark, Finland, and Norway — assessed patients with stage I-III rectal cancer or stage II-III colon cancer. It focused on a subset of patients with an oncogenic abnormality called PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha). 

PIK3CA occurs in approximately a third of colon cancers and is associated with significant chemotherapy resistance and a higher rate of disease progression. 

Of the included patients, 1103 (37%) had alterations in the PIK3CA pathway. Researchers randomized patients to receive either 160 mg of aspirin or placebo daily for 3 years, starting within 3 months of surgery. 

Among patients with PIK3CA mutations, aspirin dramatically reduced the risk for time to recurrence by nearly 50% at 3 years (P = .044). Adverse events associated with aspirin were minimal, including one case each of gastrointestinal bleeding, hematoma, and allergic reaction. 

There is no evidence that higher aspirin doses provide greater prevention of colorectal cancer recurrence. The 160-mg use in the current study is fairly normal, roughly equivalent to two low-dose (81-mg) aspirin tablets. 

Now, it’s worth noting that the use of aspirin for the primary prevention of cardiovascular disease was initially recommended by the US Preventive Services Task Force in 2016. This recommendation was then recanted in 2022, when the same group reported limited net benefit to this approach. 

 

Two Proactive Actions

These studies highlight 2 interventions — exercise and aspirin — that are low cost, accessible, and appeal to patients eager to help prevent their cancer from recurring. 

Exercise is broadly beneficial and can be recommended immediately. 

For aspirin, patients should work with their oncologist to determine their PIK3CA mutation status, as this subgroup appears to benefit the most. 

These findings offer patients meaningful, proactive interventions they can apply to support their recovery and reduce the risk of recurrence. Hopefully these new findings will help guide your clinical conversations.

Johnson is a regular contributor to Medscape. He is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease. He disclosed that he is an adviser for ISOThrive. 

A version of this article appeared on Medscape.com.

Endometrial cancer is a common type of gynecologic cancer, and its incidence is rising steadily in the United States and globally. Most cases are endometrioid adenocarcinomas, arising from the inner lining of the uterus — the endometrium. While many patients are diagnosed early because of noticeable symptoms like abnormal bleeding, trends in both incidence and mortality are concerning, especially given the persistent racial and socioeconomic disparities in outcomes.

In addition to being the most common uterine malignancy, endometrial cancer is at the forefront of precision oncology in gynecology. The traditional classification systems based on histology and hormone dependence are now being augmented by molecular subtyping that better informs prognosis and treatment. As diagnostic tools, genetic testing, and therapeutic strategies advance, the management of endometrial cancer is becoming increasingly personalized. 

Here are five things to know about endometrial cancer:

1. Endometrial cancer is one of the few cancers with increasing mortality.

Endometrial cancer accounts for the majority of uterine cancers in the United States with an overall lifetime risk for women of about 1 in 40. Since the mid-2000s, incidence rates have risen steadily, by > 1% per year, reflecting both lifestyle and environmental factors. Importantly, the disease tends to be diagnosed at an early stage due to the presence of warning signs like postmenopausal bleeding, which contributes to relatively favorable survival outcomes when caught early.

However, mortality trends continue to evolve. From 1999 to 2013, death rates from endometrial cancer in the US declined slightly, but since 2013, they have increased sharply — by > 8% annually — according to recent data. This upward trend in mortality disproportionately affects non-Hispanic Black women, who experience the highest mortality rate (4.7 per 100,000) among all racial and ethnic groups. This disparity is likely caused by a complex interplay of factors, including delays in diagnosis, more aggressive tumor biology, and inequities in access to care. Addressing these disparities remains a key priority in improving outcomes.

 

2. Risk factors go beyond hormones and age.

Risk factors for endometrial cancer include prolonged exposure to unopposed estrogen, which can result from estrogen-only hormone replacement therapy, higher BMI, and early menarche or late menopause. Nulliparity (having never been pregnant) and older age also increase risk, as does tamoxifen use — a medication commonly prescribed for breast cancer prevention. These factors cumulatively increase endometrial proliferation and the potential for atypical cellular changes. Endometrial hyperplasia, a known precursor to cancer, is often linked to these hormonal imbalances and may require surveillance or treatment.

Beyond estrogen’s influence, a growing body of research is uncovering additional risk contributors. Women with polycystic ovary syndrome (PCOS), metabolic syndrome, or diabetes face elevated risk of developing endometrial cancer. Genetic syndromes, particularly Lynch and Cowden syndromes, are associated with significantly increased lifetime risks of endometrial cancer. Environmental exposures, such as the use of hair relaxers, are being investigated as emerging risk factors. Additionally, race remains a risk marker, with Black women not only experiencing higher mortality but also more aggressive subtypes of the disease. These complex, overlapping risks highlight the importance of individualized risk assessment and early intervention strategies.

 

3. Postmenopausal bleeding is the hallmark symptom — but not the only one.

In endometrial cancer, the majority of cases are diagnosed at an early stage, largely because of the hallmark symptom of postmenopausal bleeding. In addition to bleeding, patients may present with vaginal discharge, pyometra, and even pain and abdominal distension in advanced disease. Any bleeding in a postmenopausal woman should prompt evaluation, as it may signal endometrial hyperplasia or carcinoma. In premenopausal women, irregular or heavy menstrual bleeding may raise suspicion, particularly when accompanied by risk factors such as PCOS.

The diagnostic workup for suspected endometrial cancer in women, particularly those presenting with postmenopausal bleeding, begins with a focused clinical assessment and frequently includes transvaginal ultrasound (TVUS) to evaluate the endometrium. While TVUS can aid in identifying structural abnormalities or suggest malignancy, endometrial sampling is warranted in all postmenopausal women with abnormal bleeding, regardless of endometrial thickness. Office-based biopsy is the preferred initial approach due to its convenience and diagnostic yield; however, if the sample is nondiagnostic or technically difficult to obtain, hysteroscopy with directed biopsy or dilation and curettage should be pursued.

 

4. Classification systems are evolving to include molecular subtypes.

Historically, endometrial cancers were classified using the World Health Organization system based on histology and by hormone dependence: Type 1 (estrogen-dependent, typically endometrioid and low grade) and Type 2 (non-estrogen dependent, often serous and high grade). Type 1 cancers tend to have a better prognosis and slower progression, while Type 2 cancers are more aggressive and require intensive treatment. While helpful, this binary classification does not fully capture the biological diversity or treatment responsiveness of the disease.

The field is now moving toward molecular classification, which offers a more nuanced understanding. The four main molecular subtypes include: polymerase epsilon (POLE)-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and no specific molecular profile (NSMP). These groups differ in prognosis and therapeutic implications. POLE-mutant tumors with extremely high mutational burdens generally have excellent outcomes and may not require aggressive adjuvant therapy. In contrast, p53-abnormal tumors are associated with chromosomal instability, TP53 mutations, and poor outcomes, necessitating more aggressive multimodal treatment. MMR-deficient tumors are particularly responsive to immunotherapy. These molecular distinctions are changing how clinicians approach risk stratification and management in patients with endometrial cancer.

 

5. Treatment is increasingly personalized — and immunotherapy is expanding.

The cornerstone of treatment for early-stage endometrial cancer is surgical: total hysterectomy with bilateral salpingo-oophorectomy, often with sentinel node mapping or lymphadenectomy. Adjuvant therapy depends on factors such as stage, grade, histology, and molecular subtype. Fertility-sparing management with progestin therapy is an option for highly selected patients with early-stage, low-grade tumors. Clinical guidelines recommend that fertility desires be addressed prior to initiating treatment, as standard surgical management typically results in loss of reproductive capacity.

For advanced or recurrent disease, treatment becomes more complex and increasingly individualized. Chemotherapy, often with carboplatin and paclitaxel, is standard for stage III/IV and recurrent disease. Molecular findings now guide additional therapy: For instance, MMR-deficient tumors may respond to checkpoint inhibitors. As targeted agents and combination regimens continue to emerge, treatment of endometrial is increasingly focused on precision medicine.

Markman is professor of medical oncology and therapeutics research and President of Medicine & Science at City of Hope in Atlanta and Chicago. He has disclosed relevant financial relationships with AstraZeneca, GSK and Myriad.

A version of this article first appeared on Medscape.com.

Endometrial cancer is a common type of gynecologic cancer, and its incidence is rising steadily in the United States and globally. Most cases are endometrioid adenocarcinomas, arising from the inner lining of the uterus — the endometrium. While many patients are diagnosed early because of noticeable symptoms like abnormal bleeding, trends in both incidence and mortality are concerning, especially given the persistent racial and socioeconomic disparities in outcomes.

In addition to being the most common uterine malignancy, endometrial cancer is at the forefront of precision oncology in gynecology. The traditional classification systems based on histology and hormone dependence are now being augmented by molecular subtyping that better informs prognosis and treatment. As diagnostic tools, genetic testing, and therapeutic strategies advance, the management of endometrial cancer is becoming increasingly personalized. 

Here are five things to know about endometrial cancer:

1. Endometrial cancer is one of the few cancers with increasing mortality.

Endometrial cancer accounts for the majority of uterine cancers in the United States with an overall lifetime risk for women of about 1 in 40. Since the mid-2000s, incidence rates have risen steadily, by > 1% per year, reflecting both lifestyle and environmental factors. Importantly, the disease tends to be diagnosed at an early stage due to the presence of warning signs like postmenopausal bleeding, which contributes to relatively favorable survival outcomes when caught early.

However, mortality trends continue to evolve. From 1999 to 2013, death rates from endometrial cancer in the US declined slightly, but since 2013, they have increased sharply — by > 8% annually — according to recent data. This upward trend in mortality disproportionately affects non-Hispanic Black women, who experience the highest mortality rate (4.7 per 100,000) among all racial and ethnic groups. This disparity is likely caused by a complex interplay of factors, including delays in diagnosis, more aggressive tumor biology, and inequities in access to care. Addressing these disparities remains a key priority in improving outcomes.

 

2. Risk factors go beyond hormones and age.

Risk factors for endometrial cancer include prolonged exposure to unopposed estrogen, which can result from estrogen-only hormone replacement therapy, higher BMI, and early menarche or late menopause. Nulliparity (having never been pregnant) and older age also increase risk, as does tamoxifen use — a medication commonly prescribed for breast cancer prevention. These factors cumulatively increase endometrial proliferation and the potential for atypical cellular changes. Endometrial hyperplasia, a known precursor to cancer, is often linked to these hormonal imbalances and may require surveillance or treatment.

Beyond estrogen’s influence, a growing body of research is uncovering additional risk contributors. Women with polycystic ovary syndrome (PCOS), metabolic syndrome, or diabetes face elevated risk of developing endometrial cancer. Genetic syndromes, particularly Lynch and Cowden syndromes, are associated with significantly increased lifetime risks of endometrial cancer. Environmental exposures, such as the use of hair relaxers, are being investigated as emerging risk factors. Additionally, race remains a risk marker, with Black women not only experiencing higher mortality but also more aggressive subtypes of the disease. These complex, overlapping risks highlight the importance of individualized risk assessment and early intervention strategies.

 

3. Postmenopausal bleeding is the hallmark symptom — but not the only one.

In endometrial cancer, the majority of cases are diagnosed at an early stage, largely because of the hallmark symptom of postmenopausal bleeding. In addition to bleeding, patients may present with vaginal discharge, pyometra, and even pain and abdominal distension in advanced disease. Any bleeding in a postmenopausal woman should prompt evaluation, as it may signal endometrial hyperplasia or carcinoma. In premenopausal women, irregular or heavy menstrual bleeding may raise suspicion, particularly when accompanied by risk factors such as PCOS.

The diagnostic workup for suspected endometrial cancer in women, particularly those presenting with postmenopausal bleeding, begins with a focused clinical assessment and frequently includes transvaginal ultrasound (TVUS) to evaluate the endometrium. While TVUS can aid in identifying structural abnormalities or suggest malignancy, endometrial sampling is warranted in all postmenopausal women with abnormal bleeding, regardless of endometrial thickness. Office-based biopsy is the preferred initial approach due to its convenience and diagnostic yield; however, if the sample is nondiagnostic or technically difficult to obtain, hysteroscopy with directed biopsy or dilation and curettage should be pursued.

 

4. Classification systems are evolving to include molecular subtypes.

Historically, endometrial cancers were classified using the World Health Organization system based on histology and by hormone dependence: Type 1 (estrogen-dependent, typically endometrioid and low grade) and Type 2 (non-estrogen dependent, often serous and high grade). Type 1 cancers tend to have a better prognosis and slower progression, while Type 2 cancers are more aggressive and require intensive treatment. While helpful, this binary classification does not fully capture the biological diversity or treatment responsiveness of the disease.

The field is now moving toward molecular classification, which offers a more nuanced understanding. The four main molecular subtypes include: polymerase epsilon (POLE)-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and no specific molecular profile (NSMP). These groups differ in prognosis and therapeutic implications. POLE-mutant tumors with extremely high mutational burdens generally have excellent outcomes and may not require aggressive adjuvant therapy. In contrast, p53-abnormal tumors are associated with chromosomal instability, TP53 mutations, and poor outcomes, necessitating more aggressive multimodal treatment. MMR-deficient tumors are particularly responsive to immunotherapy. These molecular distinctions are changing how clinicians approach risk stratification and management in patients with endometrial cancer.

 

5. Treatment is increasingly personalized — and immunotherapy is expanding.

The cornerstone of treatment for early-stage endometrial cancer is surgical: total hysterectomy with bilateral salpingo-oophorectomy, often with sentinel node mapping or lymphadenectomy. Adjuvant therapy depends on factors such as stage, grade, histology, and molecular subtype. Fertility-sparing management with progestin therapy is an option for highly selected patients with early-stage, low-grade tumors. Clinical guidelines recommend that fertility desires be addressed prior to initiating treatment, as standard surgical management typically results in loss of reproductive capacity.

For advanced or recurrent disease, treatment becomes more complex and increasingly individualized. Chemotherapy, often with carboplatin and paclitaxel, is standard for stage III/IV and recurrent disease. Molecular findings now guide additional therapy: For instance, MMR-deficient tumors may respond to checkpoint inhibitors. As targeted agents and combination regimens continue to emerge, treatment of endometrial is increasingly focused on precision medicine.

Markman is professor of medical oncology and therapeutics research and President of Medicine & Science at City of Hope in Atlanta and Chicago. He has disclosed relevant financial relationships with AstraZeneca, GSK and Myriad.

A version of this article first appeared on Medscape.com.

Endometrial cancer is a common type of gynecologic cancer, and its incidence is rising steadily in the United States and globally. Most cases are endometrioid adenocarcinomas, arising from the inner lining of the uterus — the endometrium. While many patients are diagnosed early because of noticeable symptoms like abnormal bleeding, trends in both incidence and mortality are concerning, especially given the persistent racial and socioeconomic disparities in outcomes.

In addition to being the most common uterine malignancy, endometrial cancer is at the forefront of precision oncology in gynecology. The traditional classification systems based on histology and hormone dependence are now being augmented by molecular subtyping that better informs prognosis and treatment. As diagnostic tools, genetic testing, and therapeutic strategies advance, the management of endometrial cancer is becoming increasingly personalized. 

Here are five things to know about endometrial cancer:

1. Endometrial cancer is one of the few cancers with increasing mortality.

Endometrial cancer accounts for the majority of uterine cancers in the United States with an overall lifetime risk for women of about 1 in 40. Since the mid-2000s, incidence rates have risen steadily, by > 1% per year, reflecting both lifestyle and environmental factors. Importantly, the disease tends to be diagnosed at an early stage due to the presence of warning signs like postmenopausal bleeding, which contributes to relatively favorable survival outcomes when caught early.

However, mortality trends continue to evolve. From 1999 to 2013, death rates from endometrial cancer in the US declined slightly, but since 2013, they have increased sharply — by > 8% annually — according to recent data. This upward trend in mortality disproportionately affects non-Hispanic Black women, who experience the highest mortality rate (4.7 per 100,000) among all racial and ethnic groups. This disparity is likely caused by a complex interplay of factors, including delays in diagnosis, more aggressive tumor biology, and inequities in access to care. Addressing these disparities remains a key priority in improving outcomes.

 

2. Risk factors go beyond hormones and age.

Risk factors for endometrial cancer include prolonged exposure to unopposed estrogen, which can result from estrogen-only hormone replacement therapy, higher BMI, and early menarche or late menopause. Nulliparity (having never been pregnant) and older age also increase risk, as does tamoxifen use — a medication commonly prescribed for breast cancer prevention. These factors cumulatively increase endometrial proliferation and the potential for atypical cellular changes. Endometrial hyperplasia, a known precursor to cancer, is often linked to these hormonal imbalances and may require surveillance or treatment.

Beyond estrogen’s influence, a growing body of research is uncovering additional risk contributors. Women with polycystic ovary syndrome (PCOS), metabolic syndrome, or diabetes face elevated risk of developing endometrial cancer. Genetic syndromes, particularly Lynch and Cowden syndromes, are associated with significantly increased lifetime risks of endometrial cancer. Environmental exposures, such as the use of hair relaxers, are being investigated as emerging risk factors. Additionally, race remains a risk marker, with Black women not only experiencing higher mortality but also more aggressive subtypes of the disease. These complex, overlapping risks highlight the importance of individualized risk assessment and early intervention strategies.

 

3. Postmenopausal bleeding is the hallmark symptom — but not the only one.

In endometrial cancer, the majority of cases are diagnosed at an early stage, largely because of the hallmark symptom of postmenopausal bleeding. In addition to bleeding, patients may present with vaginal discharge, pyometra, and even pain and abdominal distension in advanced disease. Any bleeding in a postmenopausal woman should prompt evaluation, as it may signal endometrial hyperplasia or carcinoma. In premenopausal women, irregular or heavy menstrual bleeding may raise suspicion, particularly when accompanied by risk factors such as PCOS.

The diagnostic workup for suspected endometrial cancer in women, particularly those presenting with postmenopausal bleeding, begins with a focused clinical assessment and frequently includes transvaginal ultrasound (TVUS) to evaluate the endometrium. While TVUS can aid in identifying structural abnormalities or suggest malignancy, endometrial sampling is warranted in all postmenopausal women with abnormal bleeding, regardless of endometrial thickness. Office-based biopsy is the preferred initial approach due to its convenience and diagnostic yield; however, if the sample is nondiagnostic or technically difficult to obtain, hysteroscopy with directed biopsy or dilation and curettage should be pursued.

 

4. Classification systems are evolving to include molecular subtypes.

Historically, endometrial cancers were classified using the World Health Organization system based on histology and by hormone dependence: Type 1 (estrogen-dependent, typically endometrioid and low grade) and Type 2 (non-estrogen dependent, often serous and high grade). Type 1 cancers tend to have a better prognosis and slower progression, while Type 2 cancers are more aggressive and require intensive treatment. While helpful, this binary classification does not fully capture the biological diversity or treatment responsiveness of the disease.

The field is now moving toward molecular classification, which offers a more nuanced understanding. The four main molecular subtypes include: polymerase epsilon (POLE)-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and no specific molecular profile (NSMP). These groups differ in prognosis and therapeutic implications. POLE-mutant tumors with extremely high mutational burdens generally have excellent outcomes and may not require aggressive adjuvant therapy. In contrast, p53-abnormal tumors are associated with chromosomal instability, TP53 mutations, and poor outcomes, necessitating more aggressive multimodal treatment. MMR-deficient tumors are particularly responsive to immunotherapy. These molecular distinctions are changing how clinicians approach risk stratification and management in patients with endometrial cancer.

 

5. Treatment is increasingly personalized — and immunotherapy is expanding.

The cornerstone of treatment for early-stage endometrial cancer is surgical: total hysterectomy with bilateral salpingo-oophorectomy, often with sentinel node mapping or lymphadenectomy. Adjuvant therapy depends on factors such as stage, grade, histology, and molecular subtype. Fertility-sparing management with progestin therapy is an option for highly selected patients with early-stage, low-grade tumors. Clinical guidelines recommend that fertility desires be addressed prior to initiating treatment, as standard surgical management typically results in loss of reproductive capacity.

For advanced or recurrent disease, treatment becomes more complex and increasingly individualized. Chemotherapy, often with carboplatin and paclitaxel, is standard for stage III/IV and recurrent disease. Molecular findings now guide additional therapy: For instance, MMR-deficient tumors may respond to checkpoint inhibitors. As targeted agents and combination regimens continue to emerge, treatment of endometrial is increasingly focused on precision medicine.

Markman is professor of medical oncology and therapeutics research and President of Medicine & Science at City of Hope in Atlanta and Chicago. He has disclosed relevant financial relationships with AstraZeneca, GSK and Myriad.

A version of this article first appeared on Medscape.com.

TOPLINE:

Bone health management for older women with breast cancer receiving aromatase inhibitors (AIs) varied substantially across 5 UK hospitals. Despite the higher risk for fractures, women aged > 80 years were less likely to receive DEXA scans or bisphosphonates, highlighting the urgent need for standardised bone monitoring and treatment in frail older patients.

METHODOLOGY:

• This secondary analysis of the multicentre Age Gap study included 529 women (age ≥ 70 years) with oestrogen receptor-positive early breast cancer who received AIs, either as primary or adjuvant treatment, at five hospitals in the UK.
• Researchers collected comprehensive data including the type of endocrine therapy, DEXA scan results, bisphosphonate usage, calcium and vitamin D supplementation, and the incidence of fractures during or after AI therapy.
• Frailty was assessed using a modified Rockwood Frailty Index, with scores being calculated across 75 variables to categorise patients as robust (< 0.08), prefrail (0.08-0.25), or frail (> 0.25).

TAKEAWAY:

• Overall, 67% of patients had baseline DEXA scans. Of these, 42% were osteopenic and 18% osteoporotic. Scans were more common in 70- to 79-year-olds than in those aged ≥ 80 years and in women undergoing surgery than in those undergoing primary endocrine therapy, with marked variation across centres (P < .001 for all).
• Among patients receiving AI therapy, 43% were prescribed bisphosphonates, especially those who had surgery (hazard ratio [HR], 1.36; P = .04) and those aged 70-79 years (HR, 1.31; P = .02); 33% had vitamin D plus calcium along with bisphosphonates.
• During follow-up, 23% of patients had fractures, with significant variation across centres (P = .02), and 38% of these patients had received prior bisphosphonates.
• Although 94% of patients were frail or prefrail, frailty did not correlate with baseline hip (P = .10) or spine (P = .89) T scores. Bisphosphonates plus AIs were prescribed in 70% of nonfrail participants vs 43% of prefrail and 47% of frail participants (P = .02).

IN PRACTICE:

“Patient’s age and general health influence bone health decision making, with older and frailer patients often receiving non-standard care. Despite national and international recommendations, there is still wide variation in bone health management, highlighting the need for further education and standardised bone health care in older women with breast cancer,” the authors wrote.

SOURCE:

This study was led by Elisavet Theodoulou, University of Sheffield, Sheffield, England. It was published online, in the Journal of Geriatric Oncology.

LIMITATIONS:

The study’s inclusion of only 5 hospital sites limited the ability to draw broader conclusions about bone health management practices across a wider range of centres. Additionally, the interpretation of the results was complicated by the introduction of adjuvant bisphosphonates during the study period, making the cohort unstable in terms of bisphosphonate usage indications.

DISCLOSURES:

The Age Gap study was supported by the National Institute for Health and Care Research Programme Grants for Applied Research. The authors declared having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Bone health management for older women with breast cancer receiving aromatase inhibitors (AIs) varied substantially across 5 UK hospitals. Despite the higher risk for fractures, women aged > 80 years were less likely to receive DEXA scans or bisphosphonates, highlighting the urgent need for standardised bone monitoring and treatment in frail older patients.

METHODOLOGY:

• This secondary analysis of the multicentre Age Gap study included 529 women (age ≥ 70 years) with oestrogen receptor-positive early breast cancer who received AIs, either as primary or adjuvant treatment, at five hospitals in the UK.
• Researchers collected comprehensive data including the type of endocrine therapy, DEXA scan results, bisphosphonate usage, calcium and vitamin D supplementation, and the incidence of fractures during or after AI therapy.
• Frailty was assessed using a modified Rockwood Frailty Index, with scores being calculated across 75 variables to categorise patients as robust (< 0.08), prefrail (0.08-0.25), or frail (> 0.25).

TAKEAWAY:

• Overall, 67% of patients had baseline DEXA scans. Of these, 42% were osteopenic and 18% osteoporotic. Scans were more common in 70- to 79-year-olds than in those aged ≥ 80 years and in women undergoing surgery than in those undergoing primary endocrine therapy, with marked variation across centres (P < .001 for all).
• Among patients receiving AI therapy, 43% were prescribed bisphosphonates, especially those who had surgery (hazard ratio [HR], 1.36; P = .04) and those aged 70-79 years (HR, 1.31; P = .02); 33% had vitamin D plus calcium along with bisphosphonates.
• During follow-up, 23% of patients had fractures, with significant variation across centres (P = .02), and 38% of these patients had received prior bisphosphonates.
• Although 94% of patients were frail or prefrail, frailty did not correlate with baseline hip (P = .10) or spine (P = .89) T scores. Bisphosphonates plus AIs were prescribed in 70% of nonfrail participants vs 43% of prefrail and 47% of frail participants (P = .02).

IN PRACTICE:

“Patient’s age and general health influence bone health decision making, with older and frailer patients often receiving non-standard care. Despite national and international recommendations, there is still wide variation in bone health management, highlighting the need for further education and standardised bone health care in older women with breast cancer,” the authors wrote.

SOURCE:

This study was led by Elisavet Theodoulou, University of Sheffield, Sheffield, England. It was published online, in the Journal of Geriatric Oncology.

LIMITATIONS:

The study’s inclusion of only 5 hospital sites limited the ability to draw broader conclusions about bone health management practices across a wider range of centres. Additionally, the interpretation of the results was complicated by the introduction of adjuvant bisphosphonates during the study period, making the cohort unstable in terms of bisphosphonate usage indications.

DISCLOSURES:

The Age Gap study was supported by the National Institute for Health and Care Research Programme Grants for Applied Research. The authors declared having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Bone health management for older women with breast cancer receiving aromatase inhibitors (AIs) varied substantially across 5 UK hospitals. Despite the higher risk for fractures, women aged > 80 years were less likely to receive DEXA scans or bisphosphonates, highlighting the urgent need for standardised bone monitoring and treatment in frail older patients.

METHODOLOGY:

• This secondary analysis of the multicentre Age Gap study included 529 women (age ≥ 70 years) with oestrogen receptor-positive early breast cancer who received AIs, either as primary or adjuvant treatment, at five hospitals in the UK.
• Researchers collected comprehensive data including the type of endocrine therapy, DEXA scan results, bisphosphonate usage, calcium and vitamin D supplementation, and the incidence of fractures during or after AI therapy.
• Frailty was assessed using a modified Rockwood Frailty Index, with scores being calculated across 75 variables to categorise patients as robust (< 0.08), prefrail (0.08-0.25), or frail (> 0.25).

TAKEAWAY:

• Overall, 67% of patients had baseline DEXA scans. Of these, 42% were osteopenic and 18% osteoporotic. Scans were more common in 70- to 79-year-olds than in those aged ≥ 80 years and in women undergoing surgery than in those undergoing primary endocrine therapy, with marked variation across centres (P < .001 for all).
• Among patients receiving AI therapy, 43% were prescribed bisphosphonates, especially those who had surgery (hazard ratio [HR], 1.36; P = .04) and those aged 70-79 years (HR, 1.31; P = .02); 33% had vitamin D plus calcium along with bisphosphonates.
• During follow-up, 23% of patients had fractures, with significant variation across centres (P = .02), and 38% of these patients had received prior bisphosphonates.
• Although 94% of patients were frail or prefrail, frailty did not correlate with baseline hip (P = .10) or spine (P = .89) T scores. Bisphosphonates plus AIs were prescribed in 70% of nonfrail participants vs 43% of prefrail and 47% of frail participants (P = .02).

IN PRACTICE:

“Patient’s age and general health influence bone health decision making, with older and frailer patients often receiving non-standard care. Despite national and international recommendations, there is still wide variation in bone health management, highlighting the need for further education and standardised bone health care in older women with breast cancer,” the authors wrote.

SOURCE:

This study was led by Elisavet Theodoulou, University of Sheffield, Sheffield, England. It was published online, in the Journal of Geriatric Oncology.

LIMITATIONS:

The study’s inclusion of only 5 hospital sites limited the ability to draw broader conclusions about bone health management practices across a wider range of centres. Additionally, the interpretation of the results was complicated by the introduction of adjuvant bisphosphonates during the study period, making the cohort unstable in terms of bisphosphonate usage indications.

DISCLOSURES:

The Age Gap study was supported by the National Institute for Health and Care Research Programme Grants for Applied Research. The authors declared having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Women with a new diagnosis of irritable bowel syndrome (IBS) have a significantly higher risk for ovarian cancer at 3 months and 6 months post-diagnosis, but this risk is no longer elevated beyond 8 months.

METHODOLOGY:

• Ovarian cancer often presents with nonspecific symptoms overlapping those of IBS. The frequency of misdiagnosis remains unknown, and not all IBS guidelines recommend screening for ovarian cancer.
• Researchers conducted a retrospective cohort study using US administrative claims data to compare ovarian cancer incidence in adult women with and without a new IBS diagnosis.
• Diagnostic codes were used to identify cases of IBS and ovarian cancer.

TAKEAWAY:

• The cohort comprised 9804 women with IBS and 79,804 women without IBS, identified between January 2017 and December 2020.
• Women with IBS had a significantly higher risk for ovarian cancer at 3 months (hazard ratio [HR], 1.71; P = .02) and 6 months (HR, 1.43; P = .02), but not beyond 8 months post-diagnosis.
• Women with both IBS and endometriosis had an even greater risk for ovarian cancer at 3 months (HR, 4.20; P = .01), 6 months (HR, 3.52; P = .01), and after 1 year (HR, 2.67; P = .04).
• Increasing age was significantly associated with higher ovarian cancer incidence only in women younger than 50 years (HR, 1.07; P < .01), regardless of IBS status.

IN PRACTICE:

“Identifying patient-specific risk factors, such as chronic pelvic pain or endometriosis, could help develop tailored risk profiles and improve the approach to personalized care in women with IBS-type symptoms,” the authors wrote.

SOURCE:

This study was led by Andrea Shin, Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles. It was published online in Alimentary Pharmacology & Therapeutics.

LIMITATIONS:

The use of diagnostic codes for identifying IBS may have led to misclassification or reflected symptoms rather than confirmed and validated diagnosis.

DISCLOSURES:

This study received support from the National Institutes of Health. Some authors reported serving as consultants, advisors, and/or receiving research support from pharmaceutical and healthcare companies; one author reported having stock options.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Women with a new diagnosis of irritable bowel syndrome (IBS) have a significantly higher risk for ovarian cancer at 3 months and 6 months post-diagnosis, but this risk is no longer elevated beyond 8 months.

METHODOLOGY:

• Ovarian cancer often presents with nonspecific symptoms overlapping those of IBS. The frequency of misdiagnosis remains unknown, and not all IBS guidelines recommend screening for ovarian cancer.
• Researchers conducted a retrospective cohort study using US administrative claims data to compare ovarian cancer incidence in adult women with and without a new IBS diagnosis.
• Diagnostic codes were used to identify cases of IBS and ovarian cancer.

TAKEAWAY:

• The cohort comprised 9804 women with IBS and 79,804 women without IBS, identified between January 2017 and December 2020.
• Women with IBS had a significantly higher risk for ovarian cancer at 3 months (hazard ratio [HR], 1.71; P = .02) and 6 months (HR, 1.43; P = .02), but not beyond 8 months post-diagnosis.
• Women with both IBS and endometriosis had an even greater risk for ovarian cancer at 3 months (HR, 4.20; P = .01), 6 months (HR, 3.52; P = .01), and after 1 year (HR, 2.67; P = .04).
• Increasing age was significantly associated with higher ovarian cancer incidence only in women younger than 50 years (HR, 1.07; P < .01), regardless of IBS status.

IN PRACTICE:

“Identifying patient-specific risk factors, such as chronic pelvic pain or endometriosis, could help develop tailored risk profiles and improve the approach to personalized care in women with IBS-type symptoms,” the authors wrote.

SOURCE:

This study was led by Andrea Shin, Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles. It was published online in Alimentary Pharmacology & Therapeutics.

LIMITATIONS:

The use of diagnostic codes for identifying IBS may have led to misclassification or reflected symptoms rather than confirmed and validated diagnosis.

DISCLOSURES:

This study received support from the National Institutes of Health. Some authors reported serving as consultants, advisors, and/or receiving research support from pharmaceutical and healthcare companies; one author reported having stock options.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Women with a new diagnosis of irritable bowel syndrome (IBS) have a significantly higher risk for ovarian cancer at 3 months and 6 months post-diagnosis, but this risk is no longer elevated beyond 8 months.

METHODOLOGY:

• Ovarian cancer often presents with nonspecific symptoms overlapping those of IBS. The frequency of misdiagnosis remains unknown, and not all IBS guidelines recommend screening for ovarian cancer.
• Researchers conducted a retrospective cohort study using US administrative claims data to compare ovarian cancer incidence in adult women with and without a new IBS diagnosis.
• Diagnostic codes were used to identify cases of IBS and ovarian cancer.

TAKEAWAY:

• The cohort comprised 9804 women with IBS and 79,804 women without IBS, identified between January 2017 and December 2020.
• Women with IBS had a significantly higher risk for ovarian cancer at 3 months (hazard ratio [HR], 1.71; P = .02) and 6 months (HR, 1.43; P = .02), but not beyond 8 months post-diagnosis.
• Women with both IBS and endometriosis had an even greater risk for ovarian cancer at 3 months (HR, 4.20; P = .01), 6 months (HR, 3.52; P = .01), and after 1 year (HR, 2.67; P = .04).
• Increasing age was significantly associated with higher ovarian cancer incidence only in women younger than 50 years (HR, 1.07; P < .01), regardless of IBS status.

IN PRACTICE:

“Identifying patient-specific risk factors, such as chronic pelvic pain or endometriosis, could help develop tailored risk profiles and improve the approach to personalized care in women with IBS-type symptoms,” the authors wrote.

SOURCE:

This study was led by Andrea Shin, Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles. It was published online in Alimentary Pharmacology & Therapeutics.

LIMITATIONS:

The use of diagnostic codes for identifying IBS may have led to misclassification or reflected symptoms rather than confirmed and validated diagnosis.

DISCLOSURES:

This study received support from the National Institutes of Health. Some authors reported serving as consultants, advisors, and/or receiving research support from pharmaceutical and healthcare companies; one author reported having stock options.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

A bid by GlaxoSmithKline (GSK) to bring its multiple myeloma drug belantamab mafodotin (Blenrep) back to the market hit a stumbling block during an FDA panel meeting held on July 17.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 5-3 against belantamab in combination with bortezomib and dexamethasone and 7-1 against belantamab in combination with pomalidamide and dexamethasone on the specific questions of whether the benefits of each treatment regimen at the proposed doses outweigh the risks for patients with relapsed or refractory disease after at least one prior line of therapy.

ODAC members voting no cited concerns about the lack of exploration of optimal dosing, as well as high rates of ocular toxicity and a lack of diversity among trial participants.

“This was a challenging decision because the efficacy data were strong, but the toxicity data were also very strong,” said Neil Vasan, MD, PhD, of New York University Langone Health in New York City.

Regarding optimal dosing, Vasan, who voted no on both questions, cited “a missed opportunity over the course of many years during the development of this drug to explore these different dosages,” but he also noted that “the building blocks are here to explore this question in the future.”

Belantamab, an antibody-drug conjugate targeting B-cell maturation antigen, was granted accelerated approval as a late-line therapy for relapsed or refractory multiple myeloma in August 2020 based on findings from the DREAMM-2 trial. However, GSK voluntarily withdrew the drug from the US market in 2023 after the confirmatory DREAMM-3 trial did not meet its primary endpoint of improved progression-free survival (PFS).

The company continued to explore belantamab in combination with other agents and in earlier lines of therapy. Based on findings from the DREAMM-7 and DREAMM-8 trials, which both showed improved PFS vs standard-of-care triplet therapies, the company submitted a new Biologics License Application in November 2024 seeking approval of the belantamab-based regimens.

Findings from DREAMM-7 and DREAMM-8 were reported at the 2025 American Society of Clinical Oncology conference in Chicago in June.

Both studies met their primary PFS endpoints, but the FDA expressed concerns about adverse events, dosing, and the relevance of the data for US patients and therefore sought input from ODAC members on the proposed dosages of 2.5 mg/kg every 3 weeks for the belantamab plus bortezomib and dexamethasone combination and 2.5 mg/kg in cycle 1, followed by 1.0 mg/kg every 4 weeks for the belantamab plus pomalidamide and dexamethasone combination.

Although GSK and several patients with multiple myeloma touted life-saving benefits of belantamab and argued that ocular toxicity associated with treatment is manageable and transient, most — but not all — ODAC members were unconvinced, at least as to the immediate questions regarding the benefit-risk profile.

“This is probably one of the most difficult votes I’ve done as a member of this committee,” said Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minnesota, who voted yes on belantamab plus bortezomib and dexamethasone.

Nowakowski noted mistakes made from a regulatory perspective, including a lack of appropriate US patient representation in the trials and attention to dose optimization, but ultimately said that, as a practicing hematologist, he couldn’t ignore the drug’s clear activity, including a possible overall survival benefit, and the potential for mitigating toxicity with careful follow-up and dose reductions.

John DeFlice, MD, of Cedars-Sinai Samuel Oschin Cancer Center in Los Angeles — a multiple myeloma survivor and patient representative on the committee — voted yes on both questions, noting that, based on the testimony of patients and the clinical experience of the investigators, belantamab is “an amazing drug for an incurable disease.”

“I think [these] are the wrong issues to be evaluated,” DeFlice said of the specific questions posed by the FDA at the hearing.

The FDA considers the recommendations of its advisory panels in making final approval decisions but is not bound by them.

A version of this article first appeared on Medscape.com.

A bid by GlaxoSmithKline (GSK) to bring its multiple myeloma drug belantamab mafodotin (Blenrep) back to the market hit a stumbling block during an FDA panel meeting held on July 17.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 5-3 against belantamab in combination with bortezomib and dexamethasone and 7-1 against belantamab in combination with pomalidamide and dexamethasone on the specific questions of whether the benefits of each treatment regimen at the proposed doses outweigh the risks for patients with relapsed or refractory disease after at least one prior line of therapy.

ODAC members voting no cited concerns about the lack of exploration of optimal dosing, as well as high rates of ocular toxicity and a lack of diversity among trial participants.

“This was a challenging decision because the efficacy data were strong, but the toxicity data were also very strong,” said Neil Vasan, MD, PhD, of New York University Langone Health in New York City.

Regarding optimal dosing, Vasan, who voted no on both questions, cited “a missed opportunity over the course of many years during the development of this drug to explore these different dosages,” but he also noted that “the building blocks are here to explore this question in the future.”

Belantamab, an antibody-drug conjugate targeting B-cell maturation antigen, was granted accelerated approval as a late-line therapy for relapsed or refractory multiple myeloma in August 2020 based on findings from the DREAMM-2 trial. However, GSK voluntarily withdrew the drug from the US market in 2023 after the confirmatory DREAMM-3 trial did not meet its primary endpoint of improved progression-free survival (PFS).

The company continued to explore belantamab in combination with other agents and in earlier lines of therapy. Based on findings from the DREAMM-7 and DREAMM-8 trials, which both showed improved PFS vs standard-of-care triplet therapies, the company submitted a new Biologics License Application in November 2024 seeking approval of the belantamab-based regimens.

Findings from DREAMM-7 and DREAMM-8 were reported at the 2025 American Society of Clinical Oncology conference in Chicago in June.

Both studies met their primary PFS endpoints, but the FDA expressed concerns about adverse events, dosing, and the relevance of the data for US patients and therefore sought input from ODAC members on the proposed dosages of 2.5 mg/kg every 3 weeks for the belantamab plus bortezomib and dexamethasone combination and 2.5 mg/kg in cycle 1, followed by 1.0 mg/kg every 4 weeks for the belantamab plus pomalidamide and dexamethasone combination.

Although GSK and several patients with multiple myeloma touted life-saving benefits of belantamab and argued that ocular toxicity associated with treatment is manageable and transient, most — but not all — ODAC members were unconvinced, at least as to the immediate questions regarding the benefit-risk profile.

“This is probably one of the most difficult votes I’ve done as a member of this committee,” said Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minnesota, who voted yes on belantamab plus bortezomib and dexamethasone.

Nowakowski noted mistakes made from a regulatory perspective, including a lack of appropriate US patient representation in the trials and attention to dose optimization, but ultimately said that, as a practicing hematologist, he couldn’t ignore the drug’s clear activity, including a possible overall survival benefit, and the potential for mitigating toxicity with careful follow-up and dose reductions.

John DeFlice, MD, of Cedars-Sinai Samuel Oschin Cancer Center in Los Angeles — a multiple myeloma survivor and patient representative on the committee — voted yes on both questions, noting that, based on the testimony of patients and the clinical experience of the investigators, belantamab is “an amazing drug for an incurable disease.”

“I think [these] are the wrong issues to be evaluated,” DeFlice said of the specific questions posed by the FDA at the hearing.

The FDA considers the recommendations of its advisory panels in making final approval decisions but is not bound by them.

A version of this article first appeared on Medscape.com.

A bid by GlaxoSmithKline (GSK) to bring its multiple myeloma drug belantamab mafodotin (Blenrep) back to the market hit a stumbling block during an FDA panel meeting held on July 17.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 5-3 against belantamab in combination with bortezomib and dexamethasone and 7-1 against belantamab in combination with pomalidamide and dexamethasone on the specific questions of whether the benefits of each treatment regimen at the proposed doses outweigh the risks for patients with relapsed or refractory disease after at least one prior line of therapy.

ODAC members voting no cited concerns about the lack of exploration of optimal dosing, as well as high rates of ocular toxicity and a lack of diversity among trial participants.

“This was a challenging decision because the efficacy data were strong, but the toxicity data were also very strong,” said Neil Vasan, MD, PhD, of New York University Langone Health in New York City.

Regarding optimal dosing, Vasan, who voted no on both questions, cited “a missed opportunity over the course of many years during the development of this drug to explore these different dosages,” but he also noted that “the building blocks are here to explore this question in the future.”

Belantamab, an antibody-drug conjugate targeting B-cell maturation antigen, was granted accelerated approval as a late-line therapy for relapsed or refractory multiple myeloma in August 2020 based on findings from the DREAMM-2 trial. However, GSK voluntarily withdrew the drug from the US market in 2023 after the confirmatory DREAMM-3 trial did not meet its primary endpoint of improved progression-free survival (PFS).

The company continued to explore belantamab in combination with other agents and in earlier lines of therapy. Based on findings from the DREAMM-7 and DREAMM-8 trials, which both showed improved PFS vs standard-of-care triplet therapies, the company submitted a new Biologics License Application in November 2024 seeking approval of the belantamab-based regimens.

Findings from DREAMM-7 and DREAMM-8 were reported at the 2025 American Society of Clinical Oncology conference in Chicago in June.

Both studies met their primary PFS endpoints, but the FDA expressed concerns about adverse events, dosing, and the relevance of the data for US patients and therefore sought input from ODAC members on the proposed dosages of 2.5 mg/kg every 3 weeks for the belantamab plus bortezomib and dexamethasone combination and 2.5 mg/kg in cycle 1, followed by 1.0 mg/kg every 4 weeks for the belantamab plus pomalidamide and dexamethasone combination.

Although GSK and several patients with multiple myeloma touted life-saving benefits of belantamab and argued that ocular toxicity associated with treatment is manageable and transient, most — but not all — ODAC members were unconvinced, at least as to the immediate questions regarding the benefit-risk profile.

“This is probably one of the most difficult votes I’ve done as a member of this committee,” said Grzegorz S. Nowakowski, MD, of the Mayo Clinic, Rochester, Minnesota, who voted yes on belantamab plus bortezomib and dexamethasone.

Nowakowski noted mistakes made from a regulatory perspective, including a lack of appropriate US patient representation in the trials and attention to dose optimization, but ultimately said that, as a practicing hematologist, he couldn’t ignore the drug’s clear activity, including a possible overall survival benefit, and the potential for mitigating toxicity with careful follow-up and dose reductions.

John DeFlice, MD, of Cedars-Sinai Samuel Oschin Cancer Center in Los Angeles — a multiple myeloma survivor and patient representative on the committee — voted yes on both questions, noting that, based on the testimony of patients and the clinical experience of the investigators, belantamab is “an amazing drug for an incurable disease.”

“I think [these] are the wrong issues to be evaluated,” DeFlice said of the specific questions posed by the FDA at the hearing.

The FDA considers the recommendations of its advisory panels in making final approval decisions but is not bound by them.

A version of this article first appeared on Medscape.com.

Treatment of metastatic renal cell carcinoma (RCC) is complex and requires careful analysis of risk and treatment options, an oncologist said at the July Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, regarding treating veterans with kidney cancer.

“We’ve come a long way in treating this disease, but individualizing therapy remains critical, especially in complex populations like our veterans,” said Matthew B. Rettig, MD, chief of Hematology-Oncology at the Veterans Affairs Greater Los Angeles Healthcare System and professor of Medicine and Urology at UCLA.

Rettig emphasized 2 critical early questions clinicians should consider when encountering metastatic RCC. First: Can the patient be treated with localized interventions such as metastasectomy, radiation therapy, or nephrectomy? These can be curative, Rettig said.

And second: Does the patient currently need systemic therapy? “[There are] a small subset of patients,” Rettig said, “who go into a durable, complete remission, dare I say ‘cure,’ with immunotherapeutic-based approaches.”

Rettig highlighted the International Metastatic Renal Cell Carcinoma Database Consortium criteria as a guide for clinicians as they determine the best strategy for treatment. The Database Consortium estimates survival in various lines of therapy by incorporating 6 prognostic factors: anemia, hypercalcemia, neutrophilia, thrombocytosis, performance status, and time from diagnosis to treatment. 

These criteria classify patients into favorable, intermediate, or poor risk categories that can guide first-line systemic therapy. The criteria also provide estimates of median survival. 

Rettig noted a “huge percentage” of veterans mirror the intermediate-risk demographics of clinical trial cohorts but often present with greater comorbidity burdens: “That plays into whether we treat and how we treat,” he said.

Rettig highlighted kidney cancer guidelines from the National Comprehensive Cancer Network and noted that several trials examined first-line use of combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors. 

There’s a general theme in the findings, he said: “You have OS (overall survival) and PFS (progression-free survival) benefit in the intermediate/poor risk group, but only PFS benefit in the patients who have favorable-risk disease. And you see higher objective response rates with the combinations.

“If you have a patient who's highly symptomatic or has an organ system threatened by a metastasis, you'd want to use a combination that elicits a higher objective response rate,” Rettig added.

A TKI is going to be the most appropriate second-line therapy for patients who received a prior checkpoint inhibitor, Rettig said.

“Don't change to another checkpoint inhibitor,” he said. “We have enough phase 3 data that indicates checkpoint inhibitors are no longer really adding to benefit once they’ve had a checkpoint inhibitor.”

Rettig said to even consider checkpoint inhibitors for patients who are checkpoint inhibitor-naïve, especially given the potential for durable remissions. As for third-line therapy, he said, “we have both belzutifan and tivozanib, which have been shown to improve PFS. More studies are ongoing.”

There are many adverse events linked to TKIs, Rettig said, including cardiovascular problems, thrombosis, hypertension, heart failure, torsades de pointes, QT prolongation, and gastrointestinal toxicity. TKIs tend to be the major drivers of adverse events in combination therapy.

Rettig emphasized the shorter half-life of the TKI axitinib, which he said allows for easier management of toxicities: “That’s why it’s preferred in the VA RCC clinical pathway.”

Rettig discloses relationships with Ambrx, Amgen, AVEO, Bayer, INmune Bio, Johnson & Johnson Health Care Systems, Lantheus, Merck, Myovant, Novartis, ORIC, and Progenics.

Treatment of metastatic renal cell carcinoma (RCC) is complex and requires careful analysis of risk and treatment options, an oncologist said at the July Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, regarding treating veterans with kidney cancer.

“We’ve come a long way in treating this disease, but individualizing therapy remains critical, especially in complex populations like our veterans,” said Matthew B. Rettig, MD, chief of Hematology-Oncology at the Veterans Affairs Greater Los Angeles Healthcare System and professor of Medicine and Urology at UCLA.

Rettig emphasized 2 critical early questions clinicians should consider when encountering metastatic RCC. First: Can the patient be treated with localized interventions such as metastasectomy, radiation therapy, or nephrectomy? These can be curative, Rettig said.

And second: Does the patient currently need systemic therapy? “[There are] a small subset of patients,” Rettig said, “who go into a durable, complete remission, dare I say ‘cure,’ with immunotherapeutic-based approaches.”

Rettig highlighted the International Metastatic Renal Cell Carcinoma Database Consortium criteria as a guide for clinicians as they determine the best strategy for treatment. The Database Consortium estimates survival in various lines of therapy by incorporating 6 prognostic factors: anemia, hypercalcemia, neutrophilia, thrombocytosis, performance status, and time from diagnosis to treatment. 

These criteria classify patients into favorable, intermediate, or poor risk categories that can guide first-line systemic therapy. The criteria also provide estimates of median survival. 

Rettig noted a “huge percentage” of veterans mirror the intermediate-risk demographics of clinical trial cohorts but often present with greater comorbidity burdens: “That plays into whether we treat and how we treat,” he said.

Rettig highlighted kidney cancer guidelines from the National Comprehensive Cancer Network and noted that several trials examined first-line use of combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors. 

There’s a general theme in the findings, he said: “You have OS (overall survival) and PFS (progression-free survival) benefit in the intermediate/poor risk group, but only PFS benefit in the patients who have favorable-risk disease. And you see higher objective response rates with the combinations.

“If you have a patient who's highly symptomatic or has an organ system threatened by a metastasis, you'd want to use a combination that elicits a higher objective response rate,” Rettig added.

A TKI is going to be the most appropriate second-line therapy for patients who received a prior checkpoint inhibitor, Rettig said.

“Don't change to another checkpoint inhibitor,” he said. “We have enough phase 3 data that indicates checkpoint inhibitors are no longer really adding to benefit once they’ve had a checkpoint inhibitor.”

Rettig said to even consider checkpoint inhibitors for patients who are checkpoint inhibitor-naïve, especially given the potential for durable remissions. As for third-line therapy, he said, “we have both belzutifan and tivozanib, which have been shown to improve PFS. More studies are ongoing.”

There are many adverse events linked to TKIs, Rettig said, including cardiovascular problems, thrombosis, hypertension, heart failure, torsades de pointes, QT prolongation, and gastrointestinal toxicity. TKIs tend to be the major drivers of adverse events in combination therapy.

Rettig emphasized the shorter half-life of the TKI axitinib, which he said allows for easier management of toxicities: “That’s why it’s preferred in the VA RCC clinical pathway.”

Rettig discloses relationships with Ambrx, Amgen, AVEO, Bayer, INmune Bio, Johnson & Johnson Health Care Systems, Lantheus, Merck, Myovant, Novartis, ORIC, and Progenics.

Treatment of metastatic renal cell carcinoma (RCC) is complex and requires careful analysis of risk and treatment options, an oncologist said at the July Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, regarding treating veterans with kidney cancer.

“We’ve come a long way in treating this disease, but individualizing therapy remains critical, especially in complex populations like our veterans,” said Matthew B. Rettig, MD, chief of Hematology-Oncology at the Veterans Affairs Greater Los Angeles Healthcare System and professor of Medicine and Urology at UCLA.

Rettig emphasized 2 critical early questions clinicians should consider when encountering metastatic RCC. First: Can the patient be treated with localized interventions such as metastasectomy, radiation therapy, or nephrectomy? These can be curative, Rettig said.

And second: Does the patient currently need systemic therapy? “[There are] a small subset of patients,” Rettig said, “who go into a durable, complete remission, dare I say ‘cure,’ with immunotherapeutic-based approaches.”

Rettig highlighted the International Metastatic Renal Cell Carcinoma Database Consortium criteria as a guide for clinicians as they determine the best strategy for treatment. The Database Consortium estimates survival in various lines of therapy by incorporating 6 prognostic factors: anemia, hypercalcemia, neutrophilia, thrombocytosis, performance status, and time from diagnosis to treatment. 

These criteria classify patients into favorable, intermediate, or poor risk categories that can guide first-line systemic therapy. The criteria also provide estimates of median survival. 

Rettig noted a “huge percentage” of veterans mirror the intermediate-risk demographics of clinical trial cohorts but often present with greater comorbidity burdens: “That plays into whether we treat and how we treat,” he said.

Rettig highlighted kidney cancer guidelines from the National Comprehensive Cancer Network and noted that several trials examined first-line use of combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors. 

There’s a general theme in the findings, he said: “You have OS (overall survival) and PFS (progression-free survival) benefit in the intermediate/poor risk group, but only PFS benefit in the patients who have favorable-risk disease. And you see higher objective response rates with the combinations.

“If you have a patient who's highly symptomatic or has an organ system threatened by a metastasis, you'd want to use a combination that elicits a higher objective response rate,” Rettig added.

A TKI is going to be the most appropriate second-line therapy for patients who received a prior checkpoint inhibitor, Rettig said.

“Don't change to another checkpoint inhibitor,” he said. “We have enough phase 3 data that indicates checkpoint inhibitors are no longer really adding to benefit once they’ve had a checkpoint inhibitor.”

Rettig said to even consider checkpoint inhibitors for patients who are checkpoint inhibitor-naïve, especially given the potential for durable remissions. As for third-line therapy, he said, “we have both belzutifan and tivozanib, which have been shown to improve PFS. More studies are ongoing.”

There are many adverse events linked to TKIs, Rettig said, including cardiovascular problems, thrombosis, hypertension, heart failure, torsades de pointes, QT prolongation, and gastrointestinal toxicity. TKIs tend to be the major drivers of adverse events in combination therapy.

Rettig emphasized the shorter half-life of the TKI axitinib, which he said allows for easier management of toxicities: “That’s why it’s preferred in the VA RCC clinical pathway.”

Rettig discloses relationships with Ambrx, Amgen, AVEO, Bayer, INmune Bio, Johnson & Johnson Health Care Systems, Lantheus, Merck, Myovant, Novartis, ORIC, and Progenics.

The Psychopharmacologic Drugs Advisory Committee of the FDA is set to meet on July 18 to consider a supplemental new drug application for brexpiprazole (Rexulti, Otsuka Pharmaceutical Co., Ltd.), in combination with sertraline, for the treatment of adults with posttraumatic stress disorder (PTSD).

If approved, it would be the first new treatment for PTSD in more than 20 years.

“It is my hope that the FDA does approve this treatment for two related reasons — the data look positive and compelling, and there’s a tremendous unmet need in PTSD,” Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada, told this news organization.

 

What’s in the Treatment Toolbox Now?

PTSD is a “common, severe, and nonremitting condition,” McIntyre noted. According to the National Center for PTSD, the condition affects roughly 13 million adults in the US in any given year. This represents about 5% of the adult population.

PTSD can develop following exposure to traumatic events such as combat, assault, disasters, or severe accidents. Core symptoms of PTSD include intrusive memories and flashbacks, avoidance behaviors, negative alterations in mood and cognition, and hyperarousal.

Currently, the selective serotonin reuptake inhibitors (SSRI), sertraline and paroxetine, are the only FDA-approved medications for PTSD, and while these medications can be effective, many patients fail to achieve remission or discontinue treatment due to adverse effects or lack of response.

Other medications used off-label to treat PTSD — including prazosin, mirtazapine, atypical antipsychotics, and mood stabilizers — have shown variable efficacy. 

There has not been a new FDA-approved drug for PTSD in over two decades, underscoring the need for better therapeutic options, particularly for patients who do not fully respond to SSRI alone.

 

Why Brexpiprazole Plus Sertraline?

Brexpiprazole is an atypical antipsychotic currently approved as adjunctive treatment of major depressive disorder (MDD) in adults; treatment of schizophrenia in adults and adolescents aged 13 years or older; and treatment of agitation associated with Alzheimer’s dementia.

The combination of brexpiprazole and sertraline could address the limitations of SSRI alone by working synergistically to treat PTSD.

Sertraline increases serotonin levels in the brain to improve mood and reduce anxiety. Brexpiprazole has a complex mechanism of action involving multiple neurotransmitter systems, including but not limited to serotonin and dopamine.

Together, they may target different aspects of PTSD, potentially leading to a more comprehensive reduction in symptoms.

 

What Do the Phase 3 Data Show?

In a pivotal, double-blind, randomized controlled, phase 3 trial, brexpiprazole plus sertraline provided significantly greater relief of PTSD symptoms than sertraline plus placebo.

The results were published late last year in JAMA Psychiatry and reported by this news organization at that time.

The trial enrolled 416 adults (mean age, 37 years; 75% women) aged 18-65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of PTSD and symptoms for at least 6 months prior to screening.

At baseline, participants had a mean Clinician Administered PTSD Scale (CAPS-5) for DSM-5 total score of 38.4, indicating moderate to high severity PTSD. The average time from the index traumatic event was 4 years, and three fourths had no prior exposure to PTSD prescription medications.

Participants underwent a 1-week placebo run-in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

At week 10, brexpiprazole plus sertraline demonstrated statistically significant greater improvement in the CAPS-5 total score (primary outcome) than sertraline plus placebo (mean change, -19.2 points vs -13.6 points; P < .001).

Brexpiprazole plus sertraline also led to statistically significant greater improvement on all key secondary and other efficacy endpoints, both clinician-reported and patient-reported, including measures of anxiety, depression, intrusive symptoms, hyperarousal, and overall functioning.

Combining an atypical antipsychotic with an antidepressant for PTSD “builds on what we’ve been doing in depression,” Elspeth Ritchie, MD, chair of Psychiatry, MedStar Washington Hospital Center, Washington, DC, noted in an interview with this news organization.

“We have found that a combination of a low-dose antipsychotic and an antidepressant is helpful for depression, so it makes sense that it will be helpful for PTSD. However, this has been mostly based on clinical decisions, without a heavy research background. Good science is always helpful to support those clinical decisions,” Ritchie told this news organization.

 

What About Safety?

In the phase 3 trial, brexpiprazole plus sertraline had a safety profile consistent with that of brexpiprazole in approved indications. The rate of discontinuation due to adverse events was low (3.9% for brexpiprazole plus sertraline vs 10.2% for sertraline plus placebo), indicating that most participants tolerated the brexpiprazole and sertraline combination treatment, the study team said.

In both treatment groups, the only treatment-emergent adverse event (TEAE) with incidence greater than 10% was nausea, a known adverse effect of sertraline treatment.

Weight gain was greater in participants receiving the combination. At the last visit, a weight gain of 7% or greater from week 1 was experienced by 8% of participants taking brexpiprazole with the sertraline group and 5% of those taking the sertraline plus placebo. Previous analyses in schizophrenia and MDD show that brexpiprazole is associated with moderate weight gain (+3 to 4 kg over 1 year).

The incidence of sedating TEAEs (a concern with some antipsychotics) was generally low, although fatigue (7% vs 4%) and somnolence (5% vs 3%) were more common with brexpiprazole plus sertraline than with sertraline alone.

There were no clinically meaningful between-group differences in changes in laboratory test parameters, vital signs, or ECG and participant-reported TEAEs related to suicidality.

 

Potential Concerns

As with any new drug application, several questions and issues are likely to be raised by the advisory committee. They could include whether the clinical benefit is substantial enough to warrant approval and how the observed effect sizes compare to existing approved therapies and evidence-based psychotherapies.

McIntyre told this news organization what’s particularly noteworthy is that the magnitude of the improvement in PTSD symptoms with brexpiprazole plus sertraline is greater than with sertraline alone. “That’s a very important statement. And this high level of efficacy was consistent on the secondary outcome measures, and the overall tolerability and safety seemed very acceptable,” he said.

What’s equally important, said McIntyre, is that most people with PTSD have depression and anxiety, and the brexpiprazole plus sertraline combination was more helpful than sertraline alone on the measures of anxiety and depression. “This is really important, especially in light of the fact that this medication [brexpiprazole] is already approved for adults living with major depressive disorder and inadequate response to antidepressants,” McIntyre said.

McIntyre added he suspects some questions the committee may have could relate to the extent to which it’s the case that brexpiprazole is effective in PTSD regardless of the antidepressant that is prescribed with it.

“There also will be the inevitable questions about the absence of long-term data which I think will need to be addressed given how chronic and relapse prone this condition is,” McIntyre said.

The committee may ask how trauma and PTSD will be screened in primary care and how outcomes related to this therapy will be evaluated in everyday clinical practice, McIntyre said.

Overall, McIntyre said brexpiprazole plus sertraline in PTSD is a “very positive” development for the field.

“PTSD is a terrible condition. It’s so darn common, and we just don’t have enough treatments for it. The data look good for my perspective. My fingers are crossed for the patients with PTSD and their families,” said McIntyre.

Ritchie reported having no relevant disclosures. McIntyre received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

The Psychopharmacologic Drugs Advisory Committee of the FDA is set to meet on July 18 to consider a supplemental new drug application for brexpiprazole (Rexulti, Otsuka Pharmaceutical Co., Ltd.), in combination with sertraline, for the treatment of adults with posttraumatic stress disorder (PTSD).

If approved, it would be the first new treatment for PTSD in more than 20 years.

“It is my hope that the FDA does approve this treatment for two related reasons — the data look positive and compelling, and there’s a tremendous unmet need in PTSD,” Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada, told this news organization.

 

What’s in the Treatment Toolbox Now?

PTSD is a “common, severe, and nonremitting condition,” McIntyre noted. According to the National Center for PTSD, the condition affects roughly 13 million adults in the US in any given year. This represents about 5% of the adult population.

PTSD can develop following exposure to traumatic events such as combat, assault, disasters, or severe accidents. Core symptoms of PTSD include intrusive memories and flashbacks, avoidance behaviors, negative alterations in mood and cognition, and hyperarousal.

Currently, the selective serotonin reuptake inhibitors (SSRI), sertraline and paroxetine, are the only FDA-approved medications for PTSD, and while these medications can be effective, many patients fail to achieve remission or discontinue treatment due to adverse effects or lack of response.

Other medications used off-label to treat PTSD — including prazosin, mirtazapine, atypical antipsychotics, and mood stabilizers — have shown variable efficacy. 

There has not been a new FDA-approved drug for PTSD in over two decades, underscoring the need for better therapeutic options, particularly for patients who do not fully respond to SSRI alone.

 

Why Brexpiprazole Plus Sertraline?

Brexpiprazole is an atypical antipsychotic currently approved as adjunctive treatment of major depressive disorder (MDD) in adults; treatment of schizophrenia in adults and adolescents aged 13 years or older; and treatment of agitation associated with Alzheimer’s dementia.

The combination of brexpiprazole and sertraline could address the limitations of SSRI alone by working synergistically to treat PTSD.

Sertraline increases serotonin levels in the brain to improve mood and reduce anxiety. Brexpiprazole has a complex mechanism of action involving multiple neurotransmitter systems, including but not limited to serotonin and dopamine.

Together, they may target different aspects of PTSD, potentially leading to a more comprehensive reduction in symptoms.

 

What Do the Phase 3 Data Show?

In a pivotal, double-blind, randomized controlled, phase 3 trial, brexpiprazole plus sertraline provided significantly greater relief of PTSD symptoms than sertraline plus placebo.

The results were published late last year in JAMA Psychiatry and reported by this news organization at that time.

The trial enrolled 416 adults (mean age, 37 years; 75% women) aged 18-65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of PTSD and symptoms for at least 6 months prior to screening.

At baseline, participants had a mean Clinician Administered PTSD Scale (CAPS-5) for DSM-5 total score of 38.4, indicating moderate to high severity PTSD. The average time from the index traumatic event was 4 years, and three fourths had no prior exposure to PTSD prescription medications.

Participants underwent a 1-week placebo run-in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

At week 10, brexpiprazole plus sertraline demonstrated statistically significant greater improvement in the CAPS-5 total score (primary outcome) than sertraline plus placebo (mean change, -19.2 points vs -13.6 points; P < .001).

Brexpiprazole plus sertraline also led to statistically significant greater improvement on all key secondary and other efficacy endpoints, both clinician-reported and patient-reported, including measures of anxiety, depression, intrusive symptoms, hyperarousal, and overall functioning.

Combining an atypical antipsychotic with an antidepressant for PTSD “builds on what we’ve been doing in depression,” Elspeth Ritchie, MD, chair of Psychiatry, MedStar Washington Hospital Center, Washington, DC, noted in an interview with this news organization.

“We have found that a combination of a low-dose antipsychotic and an antidepressant is helpful for depression, so it makes sense that it will be helpful for PTSD. However, this has been mostly based on clinical decisions, without a heavy research background. Good science is always helpful to support those clinical decisions,” Ritchie told this news organization.

 

What About Safety?

In the phase 3 trial, brexpiprazole plus sertraline had a safety profile consistent with that of brexpiprazole in approved indications. The rate of discontinuation due to adverse events was low (3.9% for brexpiprazole plus sertraline vs 10.2% for sertraline plus placebo), indicating that most participants tolerated the brexpiprazole and sertraline combination treatment, the study team said.

In both treatment groups, the only treatment-emergent adverse event (TEAE) with incidence greater than 10% was nausea, a known adverse effect of sertraline treatment.

Weight gain was greater in participants receiving the combination. At the last visit, a weight gain of 7% or greater from week 1 was experienced by 8% of participants taking brexpiprazole with the sertraline group and 5% of those taking the sertraline plus placebo. Previous analyses in schizophrenia and MDD show that brexpiprazole is associated with moderate weight gain (+3 to 4 kg over 1 year).

The incidence of sedating TEAEs (a concern with some antipsychotics) was generally low, although fatigue (7% vs 4%) and somnolence (5% vs 3%) were more common with brexpiprazole plus sertraline than with sertraline alone.

There were no clinically meaningful between-group differences in changes in laboratory test parameters, vital signs, or ECG and participant-reported TEAEs related to suicidality.

 

Potential Concerns

As with any new drug application, several questions and issues are likely to be raised by the advisory committee. They could include whether the clinical benefit is substantial enough to warrant approval and how the observed effect sizes compare to existing approved therapies and evidence-based psychotherapies.

McIntyre told this news organization what’s particularly noteworthy is that the magnitude of the improvement in PTSD symptoms with brexpiprazole plus sertraline is greater than with sertraline alone. “That’s a very important statement. And this high level of efficacy was consistent on the secondary outcome measures, and the overall tolerability and safety seemed very acceptable,” he said.

What’s equally important, said McIntyre, is that most people with PTSD have depression and anxiety, and the brexpiprazole plus sertraline combination was more helpful than sertraline alone on the measures of anxiety and depression. “This is really important, especially in light of the fact that this medication [brexpiprazole] is already approved for adults living with major depressive disorder and inadequate response to antidepressants,” McIntyre said.

McIntyre added he suspects some questions the committee may have could relate to the extent to which it’s the case that brexpiprazole is effective in PTSD regardless of the antidepressant that is prescribed with it.

“There also will be the inevitable questions about the absence of long-term data which I think will need to be addressed given how chronic and relapse prone this condition is,” McIntyre said.

The committee may ask how trauma and PTSD will be screened in primary care and how outcomes related to this therapy will be evaluated in everyday clinical practice, McIntyre said.

Overall, McIntyre said brexpiprazole plus sertraline in PTSD is a “very positive” development for the field.

“PTSD is a terrible condition. It’s so darn common, and we just don’t have enough treatments for it. The data look good for my perspective. My fingers are crossed for the patients with PTSD and their families,” said McIntyre.

Ritchie reported having no relevant disclosures. McIntyre received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

The Psychopharmacologic Drugs Advisory Committee of the FDA is set to meet on July 18 to consider a supplemental new drug application for brexpiprazole (Rexulti, Otsuka Pharmaceutical Co., Ltd.), in combination with sertraline, for the treatment of adults with posttraumatic stress disorder (PTSD).

If approved, it would be the first new treatment for PTSD in more than 20 years.

“It is my hope that the FDA does approve this treatment for two related reasons — the data look positive and compelling, and there’s a tremendous unmet need in PTSD,” Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada, told this news organization.

 

What’s in the Treatment Toolbox Now?

PTSD is a “common, severe, and nonremitting condition,” McIntyre noted. According to the National Center for PTSD, the condition affects roughly 13 million adults in the US in any given year. This represents about 5% of the adult population.

PTSD can develop following exposure to traumatic events such as combat, assault, disasters, or severe accidents. Core symptoms of PTSD include intrusive memories and flashbacks, avoidance behaviors, negative alterations in mood and cognition, and hyperarousal.

Currently, the selective serotonin reuptake inhibitors (SSRI), sertraline and paroxetine, are the only FDA-approved medications for PTSD, and while these medications can be effective, many patients fail to achieve remission or discontinue treatment due to adverse effects or lack of response.

Other medications used off-label to treat PTSD — including prazosin, mirtazapine, atypical antipsychotics, and mood stabilizers — have shown variable efficacy. 

There has not been a new FDA-approved drug for PTSD in over two decades, underscoring the need for better therapeutic options, particularly for patients who do not fully respond to SSRI alone.

 

Why Brexpiprazole Plus Sertraline?

Brexpiprazole is an atypical antipsychotic currently approved as adjunctive treatment of major depressive disorder (MDD) in adults; treatment of schizophrenia in adults and adolescents aged 13 years or older; and treatment of agitation associated with Alzheimer’s dementia.

The combination of brexpiprazole and sertraline could address the limitations of SSRI alone by working synergistically to treat PTSD.

Sertraline increases serotonin levels in the brain to improve mood and reduce anxiety. Brexpiprazole has a complex mechanism of action involving multiple neurotransmitter systems, including but not limited to serotonin and dopamine.

Together, they may target different aspects of PTSD, potentially leading to a more comprehensive reduction in symptoms.

 

What Do the Phase 3 Data Show?

In a pivotal, double-blind, randomized controlled, phase 3 trial, brexpiprazole plus sertraline provided significantly greater relief of PTSD symptoms than sertraline plus placebo.

The results were published late last year in JAMA Psychiatry and reported by this news organization at that time.

The trial enrolled 416 adults (mean age, 37 years; 75% women) aged 18-65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of PTSD and symptoms for at least 6 months prior to screening.

At baseline, participants had a mean Clinician Administered PTSD Scale (CAPS-5) for DSM-5 total score of 38.4, indicating moderate to high severity PTSD. The average time from the index traumatic event was 4 years, and three fourths had no prior exposure to PTSD prescription medications.

Participants underwent a 1-week placebo run-in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

At week 10, brexpiprazole plus sertraline demonstrated statistically significant greater improvement in the CAPS-5 total score (primary outcome) than sertraline plus placebo (mean change, -19.2 points vs -13.6 points; P < .001).

Brexpiprazole plus sertraline also led to statistically significant greater improvement on all key secondary and other efficacy endpoints, both clinician-reported and patient-reported, including measures of anxiety, depression, intrusive symptoms, hyperarousal, and overall functioning.

Combining an atypical antipsychotic with an antidepressant for PTSD “builds on what we’ve been doing in depression,” Elspeth Ritchie, MD, chair of Psychiatry, MedStar Washington Hospital Center, Washington, DC, noted in an interview with this news organization.

“We have found that a combination of a low-dose antipsychotic and an antidepressant is helpful for depression, so it makes sense that it will be helpful for PTSD. However, this has been mostly based on clinical decisions, without a heavy research background. Good science is always helpful to support those clinical decisions,” Ritchie told this news organization.

 

What About Safety?

In the phase 3 trial, brexpiprazole plus sertraline had a safety profile consistent with that of brexpiprazole in approved indications. The rate of discontinuation due to adverse events was low (3.9% for brexpiprazole plus sertraline vs 10.2% for sertraline plus placebo), indicating that most participants tolerated the brexpiprazole and sertraline combination treatment, the study team said.

In both treatment groups, the only treatment-emergent adverse event (TEAE) with incidence greater than 10% was nausea, a known adverse effect of sertraline treatment.

Weight gain was greater in participants receiving the combination. At the last visit, a weight gain of 7% or greater from week 1 was experienced by 8% of participants taking brexpiprazole with the sertraline group and 5% of those taking the sertraline plus placebo. Previous analyses in schizophrenia and MDD show that brexpiprazole is associated with moderate weight gain (+3 to 4 kg over 1 year).

The incidence of sedating TEAEs (a concern with some antipsychotics) was generally low, although fatigue (7% vs 4%) and somnolence (5% vs 3%) were more common with brexpiprazole plus sertraline than with sertraline alone.

There were no clinically meaningful between-group differences in changes in laboratory test parameters, vital signs, or ECG and participant-reported TEAEs related to suicidality.

 

Potential Concerns

As with any new drug application, several questions and issues are likely to be raised by the advisory committee. They could include whether the clinical benefit is substantial enough to warrant approval and how the observed effect sizes compare to existing approved therapies and evidence-based psychotherapies.

McIntyre told this news organization what’s particularly noteworthy is that the magnitude of the improvement in PTSD symptoms with brexpiprazole plus sertraline is greater than with sertraline alone. “That’s a very important statement. And this high level of efficacy was consistent on the secondary outcome measures, and the overall tolerability and safety seemed very acceptable,” he said.

What’s equally important, said McIntyre, is that most people with PTSD have depression and anxiety, and the brexpiprazole plus sertraline combination was more helpful than sertraline alone on the measures of anxiety and depression. “This is really important, especially in light of the fact that this medication [brexpiprazole] is already approved for adults living with major depressive disorder and inadequate response to antidepressants,” McIntyre said.

McIntyre added he suspects some questions the committee may have could relate to the extent to which it’s the case that brexpiprazole is effective in PTSD regardless of the antidepressant that is prescribed with it.

“There also will be the inevitable questions about the absence of long-term data which I think will need to be addressed given how chronic and relapse prone this condition is,” McIntyre said.

The committee may ask how trauma and PTSD will be screened in primary care and how outcomes related to this therapy will be evaluated in everyday clinical practice, McIntyre said.

Overall, McIntyre said brexpiprazole plus sertraline in PTSD is a “very positive” development for the field.

“PTSD is a terrible condition. It’s so darn common, and we just don’t have enough treatments for it. The data look good for my perspective. My fingers are crossed for the patients with PTSD and their families,” said McIntyre.

Ritchie reported having no relevant disclosures. McIntyre received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.