Quick Facts:
- A combination of durvalumab (Imfinzi), olaparib (Lynparza), chemotherapy, and bevacizumab (Avistin) can delay the disease progression in patients with advanced epithelial ovarian cancers without BRCA mutations.
- Most ovarian cancer patients do not have a BRCA mutation, and there have not been very many effective treatment options for them.
- On average, patients experience progression-free survival improvements of more than 10 months with the new treatment compared to standard treatments.
- The DUO-O trial results are extremely encouraging, offering a significant advancement in the treatment of ovarian cancer without BRCA mutations, who have not had very many options.
- Still, further research is needed to determine if it leads to improved overall survival.
Now, exciting data shows that a multi-pronged approach of immunotherapy, a PARP inhibitor, traditional chemotherapy and targeted therapy could help stop the progression of the disease in certain patients that have not had very many options.
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The data, from the DUO-O trial, is being presented at the 2023 American Society for Clinical Oncology's (ASCO) Annual Meeting.
"Progress has been not quick enough for advanced ovarian cancers… 80% of women diagnosed with ovarian cancer are diagnosed at an advanced stage,” Dr. Merry Markham, Chief, and Professor of Medicine in the Division of Hematology/Oncology at the University of Florida, said in a press discussion.
“These women, when they are sitting in front of [their physicians], they know what they are facing," she added.
The new treatment combination leads to a progression-free survival benefit (PFS), which is the time patients live without any worsening of their disease after their diagnosis and treatment. On average, patients experienced PFS improvements of more than 10 months with the new treatment.
It is important to distinguish between PFS and overall survival (OS). The latter is a measure of how long patients live after their diagnosis. PFS benefit does not always confer improved OS. Thus, it would be interesting to see whether the treatment leads to an OS benefit when future results of this study are reported.
“While progression-free survival (PFS) may not necessarily mean overall survival, but we hope that it does… even PFS is very important to our patients,” Dr. Markham added.
“For women who want to be able to not be on chemotherapy [when their cancer returns] shortly after her initial diagnosis or in the next 3-5 years, this represents meaningful progress."
Ovarian Cancer, The “Cancer That Whispers”
Women have two ovaries that are located within their pelvis on each side of the uterus. Their function is to produce eggs and to manufacture female hormones, including progesterone and estrogen.
When ovaries release an egg, usually once during a menstrual cycle, it travels to the uterus through cylindrical structures called the fallopian tubes, which have a funnel-shaped opening. The ovaries are surrounded by the inner linings of the pelvis, called the peritoneum.
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Ovarian cancer is a cancer that starts in the ovaries, or the associated areas, such as the fallopian tubes and the peritoneum. The American Cancer Society estimates that around 19,710 women will be diagnosed with ovarian cancer in 2023. This translates into 1 in 78 chances of developing cancer for the average woman.
During this same year, it will result in 13,270 deaths, making it the fifth deadliest cancer among women.
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Most Ovarian Cancers Are Caught Late
Around two-thirds of all ovarian cancer cases go undiagnosed until they have progressed to advanced stages and are less likely to be curable. 50-70% of the patients diagnosed with the disease die within 5 years.
The disease is known as the “cancer that whispers” because the early stages of it may produce no symptoms or only vague symptoms that are often misdiagnosed.
These symptoms can include pain in the abdomen, nausea, bloating, feeling full after eating small amounts of food, tiredness, and a change in bowel habits, among other things. These symptoms can also occur in many other conditions, most of which are benign.
Additionally, there is no specific screening test for ovarian cancer.
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It is not uncommon for these cancers to go undiagnosed well into the later stages, such as stage 3 or 4. Unfortunately, the later the stage, the more challenging its treatment.
Even if the cancer is caught and treated at early stages, the chance of it returning in the future is almost 80%.
These numbers underscore the pressing need for effective treatments for advanced-stage ovarian cancer. Dr. Susan Galbraith, Executive Vice President, of Oncology Research & Development at AstraZeneca, encapsulated this need in the press release: "While there has been significant progress for patients with advanced ovarian cancer, an unmet need still remains."
Dr. Carol Aghajanian, Chief of the Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center, and a principal investigator on the study, echoed this sentiment in a press briefing: "[An] unmet need remains, especially in some non-BRCA mutated patients."
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Majority Of The Ovarian Cancers Lack BRCA Mutations
Around 15-20% of ovarian cancers carry genetic mutations within their BRCA1 or BRCA2 genes. That means that most of ovarian cancers, however, do not contain BRCA mutations.
The BRCA genes produce proteins that are involved in repairing DNA damage and preventing unchecked growth. When these genes have mutations, cancer has a higher chance of developing.
These mutations can often be targeted with highly specific drugs, which can potentially improve the outcomes for advanced diseases.
Treatments for ovarian cancers without BRCA mutations, on the other hand, can be more limited and suboptimal. This is especially true for advanced disease. Depending on how advanced the disease is, only 30-77% of the patients are alive five years after their diagnosis.
A New Treatment Combination Shows Promise in New Study
The new study, called the DUO-O Phase III clinical trial, explored the benefit of a new treatment combination for patients with advanced ovarian cancers.
The researchers used various combinations of the immunotherapy drug durvalumab with chemotherapy medications (carboplatin/paclitaxel), olaparib, and bevacizumab to treat the patients.
The study recruited more than 1200 patients with advanced high-grade epithelial ovarian cancers without BRCA mutations. Epithelial means that the cancer started in the cell layer covering the ovaries, the most common form of ovarian cancer.
"[These were] patients who had not previously received systemic therapy [chemotherapy] and were PARP-inhibitor and immunotherapy naïve," said Dr. Aghajanian.
These patients initially received surgeries, which removed the bulk of their tumors. They were then divided into three treatment arms.
Patients in the first arm received a placebo, chemotherapy, and bevacizumab followed by maintenance bevacizumab and placebos. Placebos, sometimes called "sugar pills," are pills that look like a drug but have no medical effect.
In the second arm, patients were treated with durvalumab, chemotherapy, and bevacizumab followed by durvalumab, bevacizumab, and a placebo.
In the third and final arm, patients were given durvalumab, chemotherapy, and bevacizumab followed by maintenance durvalumab, bevacizumab, and olaparib.
The Results Speak For Themselves
The investigators sought to compare progression-free survival (PFS), which is the time patients live without any worsening of their disease after treatment. Patients in the third arm had a PFS of 37.3 months, compared to 24.4 months for patients in the second arm, and 23.0 months in the first arm.
In the third arm, patients’ cancer was kept at bay, on average, for more than 10 months longer than those who received more conventional treatments. Such a significant improvement is an exceedingly uncommon occurrence in the world of ovarian cancer treatment.
This supports that the third regimen (durvalumab, chemotherapy, and bevacizumab followed by maintenance durvalumab, bevacizumab, and olaparib) is a significantly more effective treatment for advanced ovarian cancers without BRCA mutations.
"These results are an important milestone in our ongoing journey to address unmet need in ovarian cancer. The DUO-O trial demonstrates the potential of combining PARP inhibition with immunotherapy,” Galbraith said in a press release.
How Does Durvalumab Work?
Durvalumab is a type of immunotherapy called human monoclonal antibody. It is a small molecule that binds to certain proteins on the surface of cancer cells. These include PD-1, PD-L1, and CD80 proteins that help cancer cells evade destruction by a patient's native immune system.
More specifically, PD-1 and CD80 are proteins expressed on several immune cells. These proteins can interact with PD-L1, a conjugate protein expressed by tumor cells, essentially rendering tumors invisible to and safe from the immune system.
Had this interaction been prevented, the errant tumors cell could have been eliminated by the immune system. Durvalumab accomplishes just that, by binding to PD-L1 and preventing it from interacting with PD-1 and CD80 proteins.
Durvalumab's versatile mechanism of action makes it useful in many cancers, including ovarian cancer.
How Does Bevacizumab Work?
Bevacizumab attacks a protein called the vascular endothelial growth factor (VEGF). This protein is one of the main proteins that help the tumor grow a network of blood vessels to sustain its growth.
By blocking VEGF, bevacizumab prevents the formation of blood vessels in the tumor. This process starves the cancer cells and prevents them from growing and spreading.
How Does Olaparib Work?
Olaparib belongs to a class of medication called poly (ADP-ribose) polymerase (PARP) inhibitors. These medications work by preventing cancer cells from repairing their damaged DNA, which eventually leads to their death.
How Does Chemotherapy Work?
Chemotherapy disrupts tumor cell division.
To grow and multiply, tumor cells divide and propagate very rapidly. Each time they divide, they replicate their DNA and give one copy to each "daughter" cell.
Chemotherapy disrupts this process of DNA replication, which subsequently kills the dividing tumor cells.
Side Effects Of The Treatment Combination
The side effects of the treatment include side effects from the individual drugs included in the treatment. When taking durvalumab, bevacizumab, and olaparib, patients can commonly experience:
- Fever
- Chills
- Cough
- Nausea
- Vomiting
- Feeling cold
- Depressed mood
- Chest pain or tightness
- Bloating
- Stomach pain
- Constipation
- Stiff neck or back
- Bleeding gums
- Easy bruising
- Body aches and pains
- Black, tarry stools
- Blood in the urine
- Weight loss
The side effects of chemotherapy are related to its effects on normal body tissues. The specific side effects that patients may experience depend on the drug they are given. Some of the more common side effects may include:
- Nausea and vomiting
- Loss of appetite
- Mouth sores and ulcers
- Constipation and/or diarrhea
- Decrease in blood cell counts
- Numbness and tingling
Other, more serious side effects can also occur.
In the DUO-O trial, the most reported side effects were nausea and a decrease in blood cell counts.
It is important to note that when compared to other standard treatments for advanced ovarian cancer, the side effects from the above drugs are comparable and tolerable.
A Major Leap In The Right Direction For Ovarian Cancer Without BRCA Mutations
Most cases of ovarian cancer are diagnosed at advanced stages. This usually means that the cancers are significantly less curable and require more toxic treatments than if they had been caught at an earlier stage.
While 15-20% of ovarian cancers carry BRCA mutations, which can be targeted with specific drugs, most cases do not. This can limit the treatment options available to women with cancers without BRCA mutations.
But now, "data from the DUO-O trial provide encouraging evidence for [olaparib] and [durvalumab] combination in patients without tumor BRCA mutations and reinforce our continued commitment to finding new treatment approaches for these patients," noted Dr. Galbraith.
PFS benefit is often used as a surrogate for an OS benefit. However, a PFS benefit does not always translate into improved survival. Thus, it remains to be seen whether the PFS benefit seen with the new treatment combination leads to extended patient lifespans as well.
Questions to Ask Your Doctor
If you have been diagnosed with advanced ovarian cancer, here are some questions you may consider asking your doctor to help understand your situation:
- What is the stage of my ovarian cancer?
- Do I have a BRCA mutation? How can I be tested?
- What treatment options are available to me based on these factors?
- Would I benefit from a PARP inhibitor?
- Are there ways to manage the side effects of the treatment I receive?
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