In this fifth episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, of the Division of Gynecologic Oncology, Allegheny Health Network, and assistant professor of OBGYN at Drexel University, and Christopher B. Morse, MD, gynecologic oncologist, Allegheny Health Network, share key takeaways from their discussion on how to best individualize care for patients with ovarian cancer.

: In summary, we have covered a lot of ground. 

 is clearly very important. Homologous recombination, in general, is very important in the treatment of [patients with] ovary cancer. We have a large number of patients who will benefit, at least in terms of progression-free survival, with 

We have already shown that it is helpful in the recurrence space, and as we showed you today, it is also helpful in the frontline space. The question is, what do we do moving forward? Is that trying the PARP again in a sub-selected population? Is that adding in other drugs that may recapitulate a PARP sensitivity, such as ATRI inhibitors or WEE1 inhibitors? I think we all eagerly await the answers to these questions.

I would like to thank Dr Morris very much for sharing his expertise with us today. I feel like we have covered all the important aspects of frontline treatment in [ovarian cancer with regard to] PARP [inhibitors] and 

I would also like to thank everyone who watched us today and please tune in for our next episode.

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In this fifth episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, and Christopher Morse, MD, share key takeaways from their discussion on how to best individualize care for patients with ovarian cancer.

Taking Action to Individualize Ovarian Cancer Care: Key Takeaways

In this fourth episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, of the Division of Gynecologic Oncology, Allegheny Health Network, and assistant professor of OBGYN at Drexel University, and Christopher B. Morse, MD, gynecologic oncologist, Allegheny Health Network, discuss key developments made with PARP inhibitors in the ovarian cancer treatment paradigm.

: Dr Morris, can you tell me a little bit about why there is so much excitement around PARP inhibitors [in ovarian cancer]? What do [these agents] actually bring to the patient?

: A lot of what we are getting so excited about are data that have come out of several large randomized trials, all of which had been published in the 

[These trials have all] looked at the impact of adding [a] PARP inhibitor to the frontline setting. 

The [phase 3] study that came out in 2018, was called SOLO-1 [NCT01844986], and [this] looked at just patients [with the 

] mutation who were given olaparib [Lynparza] after completion of initial carboplatin/paclitaxel chemotherapy. [Results] showed a very, very striking improvement in median progression-free survival [PFS]. The most recent updated data showed a PFS of 56 months vs almost 14 months in those who had a mutation and those who did not.

Other PARP inhibitors, such as niraparib [Zejula], have also been studied in this setting. It is important to know about the [phase 3] PRIMA study [NCT02655016], which came out in 2019. This [study] looked at patients who either had a mutation and were found to be homologous recombination deficient [(HRD) or] those who were homologous recombination proficient. In this study, we saw a similar increase in the median PFS [with the PARP inhibitor, at] 21.9 months vs 10.4 months. [These findings were] not quite as striking as the SOLO-1 data, but still significant. Even in all comers, meaning all patients who are enrolled to the study, we also saw an improvement in the median PFS [with the PARP inhibitor] that was [found to be] significant.

[Another] exciting thing has come out and helps us [sequence] therapy in the frontline setting. What if you have a patient who, for whatever reason, you have them on bevacizumab [Avastin] in the frontline setting, and then you find out that they have a mutation? [Should we] be adding a PARP [to the mix] for those patients? [The phase 3] PAOLA-1 [study (NCT02477644)] showed that the patients, especially those who are HRD, or mutation carriers that are on bevacizumab maintenance with olaparib maintenance, have a similar fairly impressive improvement in their PFS of 37 months vs 17 months. 

For us, as gynecologic oncologists, all these data are really, really exciting. [They are] pushing the envelope further for our patients, improving their PFS. [PARP inhibitors are] generally an [approach] that is well tolerated. It really is an exciting time in gynecologic oncology.

: You are 100% right. We eagerly await the overall survival data at this time. Some of the points that you touched on are really important. [I will note] that SOLO-1 [included patients with] 

 only. As Dr Morris mentioned, the PRIMA trial had [patients with] both HRD and [

] in this, so not exactly the same population. That is part of the reason why their PFS is a little bit lower. I think the other thing that is really interesting about this is in POALA-1, there was not a PARP-only arm; it was bevacizumab vs bevacizumab plus olaparib. What is very interesting is even when you have a known active agent, and you add a PARP inhibitor on top of it, you still see some additional benefit.

Check back next Wednesday to view the next segment in this series.

In this fourth episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, and Christopher Morse, MD, discuss key developments made with PARP inhibitors in the ovarian cancer treatment paradigm.

Taking Action to Individualize Ovarian Cancer Care: Excitement Surrounding PARP Inhibition

In this second episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, of the Division of Gynecologic Oncology, Allegheny Health Network, and assistant professor of OBGYN at Drexel University, and Christopher B. Morse, MD, gynecologic oncologist, Allegheny Health Network, explain the differences between germline and somatic testing in patients with ovarian cancer.

: The other thing that we need to talk about is that not all ovary cancer is created equal. I like to tell my patients that ovary cancer is kind of like ice cream. All of it is ice cream, but you have different flavors. You have your vanilla, which is your high-grade serous disease; you have your Rocky Road, which is clear cell, or your chocolate, which is endometrioid—whatever your flavor choice may happen to be. Could you tell me a little bit about the histologies, or the flavors, of ovarian cancer, that [are associated with 

: The most common histology that we see typically associated with [these] mutations is typically high-grade serous; that is the driver. Then, to a lesser extent, [we see this with] endometrioid [disease]. Other ovarian cancer histologies, such as clear cell or mucinous, are not typically associated with these mutations. When you see patients with a high-grade serious ovary cancer, there is a fair chance that they could carry a mutation in the genes in the homologous recombination repair pathway.

: I think that is super important. High-grade serous [cancers] are the ones that you have to be worried about. From the data, approximately 50% of the patients with high-grade serous [disease] could theoretically have some sort of defect in their homologous recombination pathway. The numbers that I see most commonly quoted are a 14% chance [of having] of a germline mutation and somewhere in the neighborhood of a 6% [chance of having a] somatic [mutation]. 

 methylation has been shown in up to 10% of patients, and there are some other genes that are important. 

When you talk about somatic testing in a little bit, maybe you could hit some of the less common genes, like the RAD51 genes, for example. Could you [explain to] the people who are watching, what is the difference between germline and somatic [mutations], and why does it matter?

: When we talk with patients about doing things like tumor testing, where we actually send a portion of their tumor for testing, that is what we refer to as somatic testing. [With this, we try to] see whether there is a mutation that is within their tumor specifically. 

The other thing that we talked to them about is germline testing. When we talk about germline testing, that is where the patients go and meet with a genetic counselor. They talk about their family history of cancer, and then they get their blood tested to see whether they carry a mutation that would be in every cell of their body, something that they could pass on to offspring. It is important to have both aspects of genetic testing performed, so that it not only impacts what treatment they might [receive], but also helps with counseling of other family members; [this is] specifically [true for] germline testing.

When we do germline testing, and somatic testing for that matter, we are testing for more than just BRCA1 and BRCA2

genes because there are other genes that increase a patient's risk of ovary cancer, breast cancer, and other cancers. Other mutations, such as 

, are all mutations, that according to National Comprehensive Cancer Network guidelines, put you at increased risk of ovary cancer and consideration for risk-reducing surgery should be made. However, [for] a patient who has 1 of these mutations, the lifetime risk of developing ovary cancer, for example, is generally really less than what we see with 

; [however, that risk is] still elevated over that 1.5% that you mentioned [for] the average patient without a mutation.

: In terms of somatic testing, I would think it would be very similar to 

[in that] you would be testing for genes. Is that the way we test for homologous recombination deficiency [HRD]?

: No, so one of the things about HRD is that it is really a phenotype; it is something we are looking for when we do somatic testing. We are looking for evidence of HRD, and typically, we are looking for things like genomic scarring, which shows us that the ability for the tumor to repair things like double-stranded DNA break has been lost. There are several different platforms that are employed for testing for the genomic scarring, which is a sign of HRD.

: One of the difficulties is knowing which company to use. All of them use loss of heterozygosity, otherwise known as LOH; however, some of them add additional [factors]. I also know that some companies are expanding what they give. 

As such, it is very important for physicians to understand what exactly they are getting when they order something so that they can treat their patients best. [They need] to determine whether [their patients are] homologous recombination deficient or if they are homologous recombination proficient.

In this third episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, and Christopher Morse, MD, explain the differences between germline and somatic testing in patients with ovarian cancer.

Taking Action to Individualize Ovarian Cancer Care: Somatic Vs Germline Testing

In this second episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, of the Division of Gynecologic Oncology, Allegheny Health Network, and assistant professor of OBGYN at Drexel University, and Christopher B. Morse, MD, gynecologic oncologist, Allegheny Health Network, discuss how to counsel patients with ovarian cancer whose tumors harbor 

: Now, the other thing that some people talk about is [something] called synthetic lethality. You have a situation where you had 

, then you created another situation where you took out your backup, and all of a sudden, you do not have all your repair mechanisms, [and] the cell dies—hence, synthetic lethality. That is a pretty good synopsis of how that works in general, and Dr Morris is an expert in this.

Dr Morris, I would love to talk to you a little bit more about what this means in general for your patients. How do you counsel those patients [with 

 mutations] when they come into your office?

: That is an excellent question. As a gynecologic oncologist, not only [do we] treat patients who have [these] cancers, but we also see a lot of patients who get tested—either through cascade testing where another family member was diagnosed with a mutation and then they get tested, or just based on their family history—and are found to have a 

We see them when they are younger, and we will discuss with them what their lifetime risk of [diseases] like breast and ovarian cancer is. [We also discuss whether] there is anything that we can do to prevent their chance of ever developing one of these cancers.

If it is okay with you, I am going to share a slide that I made to outline some of the conversations that we have with these patients.

: I think that's wonderful. I'm a visual learner, so I appreciate you bringing something up.

: When we talk about patients who are at increased risk for breast and ovarian cancers, we focus a lot on 

 mutations; that is because they are the most prevalent mutations in [these diseases]. The lifetime risk of breast cancer is quite high, and this is over the entire lifetime of a patient. The risk of developing breast cancer is somewhere in [the range] of 60% to 70% for both 

The risk of ovarian cancer is elevated, as well; it is roughly about 40% for 

Really, the recommendations for patients who know that they have one of these mutations is to consider what is called a risk-reducing surgery, or a prophylactic surgery, to remove both the ovaries and the fallopian tubes at a certain age. This age does have some range to it. A lot of these  conversations and decisions you are making with patients; [you are] making sure that they have completed their childbearing and that they are ready to proceed with this surgery.

because these cancers tend to happen a little earlier than 

-associated cancers, we recommend risk-reducing removal of the ovaries and fallopian tubes roughly at the age range of 35 years to 40 years. For 

, it is [recommended that this happens] slightly later [on in their lives], around 40 years to 45 years, just because these patients tend to develop ovarian cancer at a later age compared with 

Current recommendations are for removal of the ovaries and fallopian tubes. As we know, a lot of these cancers start and originate in the fallopian tubes and not the ovaries. The role of hysterectomy is less clear, but most of the recommendations from the National Comprehensive Cancer Network [support the] consideration of removal of the ovaries and fallopian tubes.

Interestingly, we also know that for patients who do develop an ovary cancer or a fallopian tube cancer, when mutation carriers are compared with those who do not have a mutation, they also tend to have a better prognosis. For 

, the 5-year overall survival [rate] is roughly 44% vs 36%, [respectively]; for 

, it is even a little bit higher, at 52% vs 36%, [respectively]. The reason for that is thought to be that it is improvement in terms of response to the typical chemotherapy agents that we use, like carboplatin and paclitaxel. However, now that we have the introduction of PARP inhibitors, that is also pushing the envelope further for these patients.

: There are two things that [you mentioned that] I thought were really important. Number one, I think that the lifetime risk in the average woman walking down the street, just to put it in perspective for people who are not gynecologic oncologists, is around 1.5% to 2%; these are extremely increased risks. 

The other thing that Dr Morris said that is really important is [understanding] this prognosis difference. It is really interesting that in the cancer that you are less likely to get, the ovary cancer, has a better survival. I do not understand exactly why that is; I do not think there are data on that. However, I think it is really important [to note]. I mention this to my patients all the time. I feel kind of weird when I am talking to them; I kind of hope that they have a 

 mutation, but I kind of hope they do not; I feel very torn about it, because that is what gave them this cancer. However, I am kind of hoping that they have the 

mutation because I know that they are going do better. It is this weird dichotomy that I find myself in. I do not know if you feel the same way.

: Certainly, when you have a patient who already carries a diagnosis of ovary cancer, and you find out that they have either a germline or somatic mutation in 

, it helps you because it opens up the therapeutics that will really help to extend their survival.

In this second episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, and Christopher Morse, MD, discuss how to counsel patients with ovarian cancer whose tumors harbor BRCA mutations.

Taking Action to Individualize Ovarian Cancer Care: Counseling Those with BRCA Mutations

In this first episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, of the Division of Gynecologic Oncology, Allegheny Health Network, and assistant professor of OBGYN at Drexel University, and Christopher B. Morse, MD, gynecologic oncologist, Allegheny Health Network, discuss how 

 mutational status affects treatment decisions for patients with ovarian cancer.

: We are focusing today on gynecologic malignancies, particularly in ovarian cancer. The goal of this video blog and its subsequent episodes are to review important [updates] in cancer treatment and how Allegheny Health Network is able to treat cancer. I'm joined today by Dr Christopher Morse. He's one of the gynecologic oncologists at Allegheny Health Network.

Chris, I have been thinking about this a lot, and I feel like ovarian cancer treatment has totally changed. Can you talk to me about how you think about 

 and how that affects your treatment of your [patients with] ovarian cancer?

: Yes, and I agree with you. The landscape and the treatment paradigms that we use for treating ovarian cancer in the past decade have really changed dramatically. A lot of what has led to that change is the testing of patients who carry a mutation, such as 

, which not only puts them at increased risk for developing ovarian or breast cancers, but also leads to defects in the way that their DNA is repaired through something called homologous recombination deficiency (HRD), which we will review shortly.

What is really interesting about these defects is that we can target [them] with new therapeutics called PARP inhibitors, which have really revolutionized the way that we think about treating patients—not only after their initial surgery and chemotherapy with maintenance therapy...but also possibly during later lines of treatment, as well. As such, I think [this has] really shifted the paradigm of how we treat ovarian cancer, and it has greatly improved the quality of life for our patients, as well as progression-free survival.

: I could not agree with you more, and I really loved what you said about the repair mechanisms. I am just going to show my inner nerd right now. I think that the most important thing is to really understand how your drugs work. As you alluded to, I am going take the attempt to show everybody what we are talking about. 

Overall, HRD is a repair of double-stranded DNA, right? So, let's make both of the helixes here. What happens when you have cancer is that occasionally you will have a break; you will have a bit of DNA off, which, obviously, you know. Then, you have homologous recombination, like you mentioned. Because homologous recombination is a high-fidelity repair mechanism, you will get your DNA—and let me just highlight that bit that got repaired—and you have a very high-fidelity repair, which is wonderful. What is important, though, as you alluded to, is 

 is absolutely critical to homologous recombination. If you knock out 

, you lose your homologous recombination, as you mentioned before. Now, if you lose that, what people will default to is generally single-stranded DNA repair. The most common one that people talk about is base excision repair. Please excuse my terrible doctor handwriting. 

Of course, Dr Morse knows all of this already, but what happens is people will default to this base excision repair. Now, you have a situation with 

 carriers who already have the HRD loss. If you take out the base excision repair, [suddenly], you have a problem. That is exactly what PARP inhibitors do; they take out that base excision repair and then you cannot repair your DNA, [which] leads to cell death or fancy word would be apoptosis.

In this first episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, and Christopher Morse, MD, discuss how BRCA mutational status affects treatment decisions for patients with ovarian cancer.

Christopher Morse, MD

Articles

Taking Action to Individualize Ovarian Cancer Care: Key Takeaways

Taking Action to Individualize Ovarian Cancer Care: Excitement Surrounding PARP Inhibition

Taking Action to Individualize Ovarian Cancer Care: Somatic Vs Germline Testing

Taking Action to Individualize Ovarian Cancer Care: Counseling Those with BRCA Mutations

Taking Action to Individualize Ovarian Cancer Care: Effect of BRCA on Treatment