Dr. John Chan, a division director in GYN Oncology, at California Pacific Medical Center in San Francisco, talks about PARP Inhibitors for ovarian cancer.
Interview conducted by Ivanhoe Broadcast News in September 2022.
What are PARP inhibitors and how do they work in the body?
CHAN: PARP inhibitors are a new drug that we are using in patients with advanced ovarian cancer. Let’s start with PARPs. PARPs are essentially an enzyme that can go along the DNA of the cancer cell and repair defects or breaks in the DNA. Cancer biologists have now developed an inhibitor against these enzymes, so it locks these enzymes so that the DNA of the cancer cells stay broken and eventually go into apoptosis or cell death. PARP inhibitors are a targeted therapy. PARP inhibitors are a novel – PARP inhibitors are a targeted agent that’s used in advanced ovarian cancer in the maintenance and treatment
Can you tell us about the treatments that are a part of the research we’re discussing today?
CHAN: In this current study, we performed a retrospective cohort analysis evaluating patients with advanced ovarian cancer after they’ve completed chemotherapy. Some patients went on active surveillance, and another group received PARP inhibitor maintenance. And we wanted to see if these PARP inhibitors could impact their progression-free survival compared to the active surveyed patients.
Can you describe the patient population that was a part of the study?
CHAN: In this cohort of over 700 patients, the median age of these patients were about 63 years old. Most of these patients had Stage III advanced stage ovarian cancer, and about a third had Stage IV disease.
How did you and your colleagues gather the data? How many women were in the study and how long did it take?
CHAN: In this study of over 700 women with advanced stage ovarian cancer, we collected the data from electronic health records using the Flatiron database. In this study, we started the study looking at 2017 and up to the middle or June of 2021.
What were the findings and the implications of the findings?
CHAN: Yeah. We found that the maintenance PARP inhibitor after chemotherapy significantly improved the progression-free survival of all women with advanced ovarian cancer. And that included patients with BRCA mutations and in the non-BRCA mutated homologous recombination deficient and homologous recombination proficient patients. This drug was able to improve their progression-free survival.
Can you explain what you mean by active surveillance?
CHAN: Typically, patients, when they’re diagnosed with ovarian cancer, after surgery and chemotherapy, most of these patients undergo active surveillance. Meaning that they get lab tests, CT scans and physical exams as needed in order to follow these patients to see if their cancer recurs. Given that these patients have advanced stage disease, nearly 70 percent of these patients ultimately will develop recurrence within two or three years from their last treatment. The ability to give these women some sort of a maintenance strategy so that we can prolong their progression-free survival, delay their recurrence, and potentially improve their overall survival is very impactful.
Why is it so important for clinicians and patients to be aware of new therapies for women with ovarian cancer, especially for women diagnosed in the advanced stage?
CHAN: It’s important for women to understand these treatment options that are available today. The reason why is because even with the technology that we have today, we still don’t know how to find these cancers early. Most patients with ovarian cancer are found in Stage III or Stage IV disease. In those patients, despite good surgery, adequate chemotherapy, 70, 80% of the time these cancers still recur. The ability to give these patients a maintenance strategy so that we can prolong their progression-free survival and potentially impact overall survival is very important to them.
Is there anything else I didn’t ask you, that you think it’s important for people to know? What makes this unique and distinguishes it from some of the other research on advanced ovarian cancer?
CHAN: Yeah. I think the previous studies, including randomized clinical trials, have shown the benefit on the use of maintenance PARP inhibitors. However, we don’t know how this type of research in a more sterile clinical trial setting may ultimately translate into the real-world setting. The ability to take real world data that can validate what we’ve found in clinical trials is very important. The reason why real-world data, particularly using electronic health care records, is very important, is for two reasons. No. 1, it allows a more holistic and a more comprehensive approach to evaluate these women diagnosed with advanced ovarian cancer in the community setting that is in real life. The second most important thing is that many a times we feel that patients who are enrolled in clinical trials may be healthier, may be younger and more homogeneous in terms of access to care. The ability to look at real-world data where you’re not able to select your patients as you can in a clinical trial setting, it allows us to better understand the impact of these drugs on the patients in our community so that it’s applicable to our patient care.
What were the findings and the implications of the findings?
CHAN: Yeah. We found that the maintenance PARP inhibitor after chemotherapy significantly improved the progression-free survival of all women with advanced ovarian cancer. And that included patients with BRCA mutations and in the non-BRCA mutated homologous recombination deficient and homologous recombination proficient patients. This drug was able to improve their progression-free survival.
Could you talk a little about maintenance therapy, what it is, and why those facing the disease should learn more about it?
CHAN: Maintenance therapy in advanced ovarian cancer is important. The reason why is because 70 percent of patients with advanced ovarian cancer will ultimately recur. Most of the patients with advanced ovarian cancer, even after a good surgery and systemic chemotherapy, the cancer will relapse. For these patients, the ability to get some form of a maintenance strategy so that we can extend that progression-free survival and potentially lead to better overall outcomes are very important.
As a researcher and a physician working in this disease, how long have you worked in this disease area – years? What was it like for you to see the types of results that you were seeing in the research? How did it make you feel? Were people in your area really excited about it? What was it like? And what does it mean for you as a physician treating this disease to now have this potential tool in your toolbox?
CHAN: As a gynecologist, I’ve been taking care of women with advanced ovarian cancer for the last 20, 25 years. For a while, in the initial eight to 10 years, all we had were systemic chemotherapies. After a systemic chemotherapy, when you re-treat these patients with another systemic chemotherapy, the progression-free survival is shorter and shorter. For about eight years, we had no new drugs. When this class of drugs called PARP inhibitors came into our treatment paradigm, it really revolutionized the way we care for ovarian cancer patients. We’re seeing impacts in our advanced ovarian cancer patients that we’ve never seen before. The reason why is because these drugs can extend that progression-free survival more than any other compounds that we’ve experienced in our careers.
Can you talk about the signs and symptoms of ovarian cancer and who the disease impacts?
CHAN: Yes. Ovarian cancer has formally been known as a silent disease. The reason why is because we don’t really have a good screening test. We can’t find this cancer early. And the patients do have symptoms. But the problem is that these symptoms are very nonspecific. Bloating, feeling full early after eating, increasing in abdominal girth, pelvic discomfort, or pain, some gastrointestinal or genitourinary symptoms. All these symptoms are so nonspecific. Nothing really points directly at an ovarian cancer diagnosis. That’s what makes this cancer so challenging to diagnose, detect and, most importantly, that’s why we don’t know how to find these cancers in its early stage. Most of the patients are found with advanced Stage III and Stage IV disease.
Can you talk about the risk factors for ovarian cancer, including any genetic characteristics and family history?
CHAN: Yes. We’ve known that patients who have a family history of ovarian cancer do have a slight increased risk of ovarian cancer themselves. But in addition, we’re able to find that patients with a BRCA mutation do have a significant lifetime risk of developing ovarian cancer and developing ovarian cancer at a much younger age. Those who have this genetic mutation, through screening, we can do prophylactic surgeries on them so that we can remove their ovaries and their fallopian tubes early to prevent the development of cancer, and do better screening tests such as different mammograms and MRIs to improve early detection of breast cancer because they have a risk for breast cancer too.
How can genetic testing be helpful for those diagnosed with ovarian cancer?
CHAN: Testing for genetics is recommended by all guidelines in the oncology field. The reason why is because in the patients who have been diagnosed with ovarian cancer, a significant proportion of them actually don’t have a family history. Even though they have the BRCA mutation, they don’t have a family history to point to that. Testing all patients with ovarian cancer for BRCA mutation is very important for two or three reasons. Number one is by identifying this genetic mutation, you’re able to do better screening for their breast health. You’ll be able to inform their mom, sisters, or their daughters regarding their risk of developing cancer so they can do prophylactic measures to decrease their risk of cancer. Lastly, by identifying those patients who have BRCA mutation, you have access to a new class of drug called PARP inhibitors. In these patients who have this genetic mutation, these PARP inhibitors work super good on them.
Can you explain what they are and how the introduction of PARP inhibitors and what that meant to you as a clinician and how that’s changed practice?
CHAN: PARP inhibitors are a class of drugs that work towards blocking the DNA repair mechanism. If the cancer cells’ DNA can’t repair themselves because the PARP inhibitors are used, the cancer cells undergo cell death. The ability to introduce these PARP inhibitors in the upfront recurrent and in their treatment setting for patients with advanced ovarian cancer and other cancers, you’re able to significantly improve the progression-free survival of these women and offer them a new class of drugs that can get them better outcomes than standard chemotherapy alone.
When we think about maintenance therapy and think about it from the patient perspective, why do you think it’s so important that patients even understand what maintenance therapy is? And what do they need to know about it?
CHAN: I think maintenance therapy is important for these patients because many of these patients know that advanced ovarian cancer is a very challenging disease. Meaning that by the time you find them, many of these patients have Stage III or Stage IV cancers with 70 to 80 percent of them will ultimately relapse. After four months of treatment with surgery and chemotherapy, many of these patients feel concerned or nervous about just doing nothing, just doing active surveillance. To give these patients this option of a maintenance strategy so that we can extend their progression-free survival and improve their outcomes, it gives them a new sense of hope so that they can continue to keep the pressure on the cancer to prevent it from relapsing.
Can you talk a little bit about the poster you’re presenting here at ASCO? What were the findings and the implications of this finding?
CHAN: In this poster that we’re presenting at ASCO, we took the electronic health care records of over 700 women with advanced ovarian cancer. Some of these patients, majority in fact, only received active surveillance. They didn’t get any more treatment after they finished surgery and chemotherapy, and a subgroup of these patients were able to get access to PARP inhibitors. Since this study spanned from 2017 to 2021, the patients in the more recent years were the ones who actually got access to the PARP inhibitor after FDA approval. We follow these women out and we found that those who received active surveillance in the community setting, using the EHR our records to follow this cohort of these patients in a retrospective fashion, we showed that there was a significant improvement in progression-free survival in those who received maintenance therapy with PARP inhibitors.
Can you talk a little about the fact that this is real world evidence and how does it distinguish this data from past randomized clinical trial research that’s been done?
CHAN: Yes. I think it’s important to evaluate how these drugs behave. How do they impact the patients in a community and also on a population level? Clinical trials are important because they allow us to have a standardized treatment with a control group that is well matched. However, there are some deficiencies in these clinical trials too, meaning that many times they’re noted to have younger patients, patients with better performance status, maybe the patients that are more compliant and easier to treat and they don’t necessarily represent the cohort that’s in our community, the patients that we see on a daily basis. The ability to take population data, electronic health care record data, where you have a group of patients that’s not selected as you do in a sterile clinical trial involvement or clinical trial enrollment, this allows us to better understand the implications of these drugs on a population level where it’s in the community, where there’s a more holistic and more comprehensive group of patients. Then the second thing that’s really important is that this group of patients that we get from electronic health care records, they may consist of a more heterogeneous group of patients where subgroups of patients may not have been well represented in the clinical trial, this EHR data will allow us to accomplish that.
Based on these findings, how might we approach treatment in practice?
CHAN: Based on the findings that we see in this poster; it validated the findings that we saw in the randomized clinical trial. That in the community setting, in the real-world population patients, we’re able to show that the adoption of this PARP inhibitor over time and the use of these PARP inhibitors can significantly improve the progression-free survival of these patients, similar to what was found in the randomized clinical trials.
What is the significance of these findings for women with advanced ovarian cancer?
CHAN: The significance of these findings in the real-world setting is important because many patients feel that the randomized clinical trials may not be patients like them. They may be younger. They may be a different racial group. They may not fully represent patients that are in the community. The ability to tell the patients that even in a real-world data and a real-world population level, we’re able to see the impact of these drugs and similar efficacy as it is in the randomized clinical trials, it’s very reassuring for these patients. It allows these patients to feel like they can adopt these types of treatments without the sterile environment of the clinical trial because they can also get this benefit.
Can you talk about, like, what is the side effect profile of this treatment? And what’s the benefit to continuing maintenance therapy versus surveil?
CHAN: Good point. Yes. I think it’s very important to consider side effects and adverse events associated with these treatments. Many of these patients have suffered from side effects from systemic chemotherapy. To engage these patients with another treatment that can potentially have a new set of side effects is very challenging. What we do tell these patients and reassure them with is the fact that these drugs are tolerable. In the clinical trial setting, ninety percent of the patients can complete this treatment without discontinuation. Although the side effects are real, such as gastrointestinal side effects, bone marrow suppression, fatigue, most of these side effects are in the initial first two or three months. After the patients adjust to these drugs, ninety percent of these patients will be able to complete the treatment recommendations of two or three years of these PARP inhibitors.
Why don’t you think there’s broader use of PARPs given the findings that you’ve seen in your research?
CHAN: I think there hasn’t been a significant adoption of these PARPs yet. I know that these trial data need to be disseminated into the community and it takes time. In this clinical study that we did starting from 2017 up to June of 2021, we’re already seeing a significant increase from 10 to even fifty percent in these patients with advanced stage ovarian cancer. I think that with better education and dissemination of knowledge, such as the one that we have here in ASCO, showing that in the real-world setting, these patients are getting this benefit. The ability to continue to disseminate this knowledge and information, we hope that more and more patients will have the ability get access to these drugs that are effective in treating ovarian cancer.
Why is BRCA bracket testing important, and can you talk about HRV-type 2?
CHAN: You don’t necessarily have to have BRT positive for BRCA to receive a PARP.
What is genetic testing and how can it be helpful for those diagnosed with ovarian cancer?
CHAN: I look at genetic testing as there’s two parts. One is genome line testing, meaning testing every cell in your body, whether you have this BRCA mutation. And that can be done through saliva or through blood. The other part of testing is testing the patient’s tumor specimen. That is looking at tumors that may express homologous recombination deficiency. When you have HRD positive tumors or HR proficient tumors – actually, let me take that back. When you have HRD positive tumors or HRD negative tumors, those can have significantly different implications in terms of their outcomes with their ovarian cancer and their treatment efficacy associated with PARP inhibitors. In this current study, we show that all women, whether they have BRCA mutation, HRD positive or HRD negative tumors, all these patients get benefit associated with the use of PARP maintenance therapy. However, the patients who do have BRCA mutation or HRD positive tumors, they do have a more efficacy associated with the use of these maintenance PARPs.
Is there anything else you wanted to add?
CHAN: Yeah. I think I’d like to conclude with two important points. Number one is that in this clinical study where we did real-world patients, we were able to replicate what we saw in the randomized clinical trials, that these PARP inhibitors can significantly improve the progression-free survival with ovarian cancer and advanced stage ovarian cancer. The second thing that is really important is to give these patients this sense of encouragement and a sense of hope that there are these drugs out there now that you can do to improve their progression-free survival and their outcomes. These drugs are tolerable, and physicians are disseminating this knowledge. We are seeing that adoption over the years of this study that we did. We hope that in the future we’ll continue to educate physicians and the patients about the benefit of these PARP inhibitors so that all women with advanced ovarian cancer can get the benefit.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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