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CME / ABIM MOC

Ovarian Cancer Consult: Adapting to PARP Inhibitors

  • Authors: Bradley J. Monk, MD, FACS, FACOG; Shannon N. Westin, MD, MPH; Floor Backes, MD
  • CME / ABIM MOC Released: 1/20/2023
  • Valid for credit through: 1/20/2024
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  • Credits Available

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    ABIM Diplomates - maximum of 0.50 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for oncologists, obstetrician/gynecologists, surgeons, and pathologists. 

The goal of this activity is to improve knowledge and skills of the ovarian cancer (OC) multidisciplinary team with regard to the management of patients with OC receiving PARP inhibitors.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Clinical trial data associated with PARP inhibitor therapy for patients with OC
  • Have greater competence related to
    • Mitigating treatment‐related adverse events for patients with OC receiving PARP inhibitors
    • Tailoring treatment decisions for patients with OC


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Faculty

  • Bradley J. Monk, MD, FACS, FACOG

    Professor
    Division of Gynecologic Oncology
    University of Arizona College of Medicine
    Director, Principal Investigator, Community Research Development
    HonorHealth Research Institute
    Phoenix, Arizona

    Disclosures

    Bradley J. Monk, MD, FACS, FACOG, has the following relevant financial relationships:
    Consultant or advisor for: Acrivon Therapeutics; Adaptimmune Therapeutics; Agenus; Akeso Bio; Amgen; Aravive; AstraZeneca; Bayer; Clovis Oncology; Eisai; Elevar Therapeutics; EMD Merck; Genmab/Seagen; Gradalis; Hengrui; ImmunoGen; Iovance Biotherapeutics; Karyopharm; Laekna Therapeutics; MacroGenics; Merck; Mersana Therapeutics; Myriad Genetics; Novocure; OncoC4; Panavance Therapeutics; Pfizer; Pieris Pharmaceuticals; Puma Biotechnology; Regeneron; Roche/Genentech; Sorrento Therapeutics; TESARO/GlaxoSmithKline; US Oncology Research; VBL Therapeutics; Verastem Oncology; Zentalis Pharmaceuticals
    Speaker or member of speakers bureau for: AstraZeneca; Clovis Oncology; Eisai; Merck; Myriad Genetics; Roche/Genentech; TESARO/GlaxoSmithKline
    Other: Investigator: Gradalis Inc.; US Oncology Research; Honorarium: Novartis

  • Floor Backes, MD

    Professor, Gynecologic Oncology
    The Ohio State University
    and James Cancer Hospital
    Columbus, Ohio

    Disclosures

    Floor Backes, MD, has the following relevant financial relationships:
    Consultant or advisor for: Agenus; AstraZeneca; Eisai; Genentech; GlaxoSmithKline; Merck
    Research funding from: Clovis Oncology; Eisai; ImmunoGen; Merck

  • Shannon N. Westin, MD, MPH

    Professor
    Medical Director, Gynecologic Oncology Center
    Director, Early Drug Development and Phase 1
    Department of Gynecologic Oncology and Reproductive Medicine
    University of Texas
    MD Anderson Cancer Center
    Houston, Texas

    Disclosures

    Shannon N. Westin, MD, MPH, has no relevant financial relationships.

Editor

  • Amy Furedy, RN, OCN

    Medical Education Director, Medscape, LLC

    Disclosures

    Amy Furedy, RN, OCN, has no relevant financial relationships.

Compliance Reviewer

  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC

Ovarian Cancer Consult: Adapting to PARP Inhibitors

Authors: Bradley J. Monk, MD, FACS, FACOG; Shannon N. Westin, MD, MPH; Floor Backes, MDFaculty and Disclosures

CME / ABIM MOC Released: 1/20/2023

Valid for credit through: 1/20/2024

processing....

Activity Transcript

Chapter 1: Adapting to PARP Inhibitors: Frontline Treatment of Advanced Ovarian Cancer

Bradley J. Monk, MD, FACS, FACOG: Greetings. I am so excited to be with you today and I'm so grateful that you're taking time out of your busy schedules to dissect the front-line treatment of advanced ovarian cancer, a case-based approach, but predicated on evidence. This is critical here. This is not my opinion, these are consensus guidelines. I want to really walk you through this on a high level; but at the same time, provide details that hopefully you can integrate into your practice.

Imagine you show up to the office and you're asked to see a 56-year-old woman with abdominal pain with normal labs, except a very high CA-125. Has some, quite frankly, irrelevant medical history, has an aunt that died of ovarian cancer. And you get this CT scan that was ordered by the primary care physician and you can see here the really dramatic carcinomatosis here in the omentum and ascites. Look at all this disease.

And so you now begin to ask the question, well, clearly this is cancer, but what type of cancer is it? And if you're a gynecologic oncologist, obviously is it GYN or non-GYN? And even if it's GYN, what's the histologic cell type? And if it's a serous cancer, is it a high-grade serous or low-grade serous? Because these are treated differently. So you really say, "Okay, I'm going to get a biopsy to figure out because I can't develop a treatment plan until I have a biopsy." You send her for a core biopsy and we can sort of figure out what type of cancer it is on a very small biopsy. We can do immunohistochemistry. PAX8 is possibly GYN. ER PAX8 is consistent with GYN, and this WT1 basically says it's serous. And again, WT1, PAX8...just make sure it's not a mesothelioma; it almost never is.

And then you can sort of look at p53 and p16, and if those are positive, it's a high grade serous. So you figure out if it's a serous here, and then do immunohistochemistry. Now remember, p53 can either be strong, so the gene is mutated and accumulates, or null where it's not expressed at all. That's obviously mutated. The normal p53 is mottled, okay. So then you go to this first question on this algorithm and remember everybody gets germline testing, if they're not BRCA germline, then they get a tumor test, which is HRD. And so that's a given. And now you have to figure out should she get neoadjuvant chemotherapy versus primary debulking before she starts to global standard intravenous every three week carboplatin and paclitaxel. 175 milligrams per square meter paclitaxel and an AUC of five or six generally in this young otherwise healthy woman, six.

So you send her to the surgeon, if you're not a surgeon yourself. And trust me, you want no part of that, that patient is best served beyond question with a neoadjuvant chemotherapy and interval debulking. Now if you are uncertain, you should not make a big incision, put your hand in there, you shouldn't do a laparoscopy. But it's pretty obvious that this patient needs neoadjuvant chemotherapy. And now you have to make the decision should she get bevacizumab or not? There are a number of contraindications to bevacizumab, uncontrolled hypertension, kidney disease, and so on. I can tell you at least half of the patients in this country are not getting bevacizumab. We talk to the patient, look at the contraindications. I probably use a little bit more bevacizumab than most people, but ultimately it was decided to not give her bevacizumab. She had three cycles, had an interval debulking, we were able to cut the cancer out, and now we have a third decision and it's based on whether she got bevacizumab or not, and the third decision is: do I add a PARP inhibitor? Again with this algorithm that we published now two years ago. And remember she's not on bevacizumab. So if she's HRD, because remember you did it over here, you would add olaparib to the bevacizumab if she was on bevacizumab, but she's not. So it's either PRIMA, which is a niraparib randomized phase three New England Journal paper, or SOLO1, randomized phase three trial with olaparib. Picking between these two probably is not as important as people think, but you would have to make a choice. Another study that we reported is ATHENA with rucaparib. It has an action date with the FDA in June. Now if she did get bevacizumab and she's HRD, she could get PAOLA-1, which is combination, adding olaparib in the maintenance space to the bevacizumab. And if she's not HRD, then she would continue just to bevacizumab alone. It's a fairly straightforward algorithm, but you have to make all of these decisions. And stepwise, the only decision that you don't have to make is should you do molecular testing. So I've been working on this for many years. It was my privilege to be part of a maintenance paclitaxel way back here in 2003. But ultimately bevacizumab and then ultimately olaparib and niraparib, and now ultimately the combination all frontline, all FDA approved, and many of them molecularly informed. This is molecularly informed BRCA mutated, and this is molecularly informed HRD. Niraparib, all comer, but it works better in HRD. And bevacizumab works pretty well, but again, we have no biomarker. So if you have an overlapping indication like you do here, or you can give olaparib or niraparib, or even theoretically ATHENA, which is part of the ASCO guidelines published on September 23rd, you have to pick between these three medications, which are not the same. And you'll make that decision, but they all work: SOLO1, PRIMA, or the combination.

So you have to make this decision. And again, it's predicated on whether or not you're using bevacizumab. Now people use bevacizumab more in these higher risk groups, stage four, stage three, residual disease. But look at the benefit of the combination olaparib and bevacizumab in the lower risk patient. So this is a very impressive. A big difference based on the risk, the lower risk, and also the lower risk BRCA mutated. Now if you're getting olaparib alone, do you really need the bevacizumab? Probably not if she's BRCA mutated, as this patient is. All have a consistent benefit in BRCA mutated, in HRD, and in PRIMA, niraparib, HRD test negative.

I'm happy to say that at ESMO, the overall survival was updated for this patient, if you were to use olaparib. And you can see that really the benefit for overall survival now is after five years. And you can see this difference in just over 20 months with a very dramatic hazard ratio of 0.55. So to not give a PARP inhibitor if the patient has a BRCA mutation like ours, quite frankly is reckless, unless the patient has a contraindication. Oh, and there are no contraindications to olaparib. Now if you want to give both medications, that's fine. This also was updated for overall survival at ESMO, and the hazard ratio is not quite as good. It's a little higher 0.62, and it's a 17-month difference rather than a 20-month difference. But still evidence-based survival benefit. PRIMA was also updated. This is niraparib alone in all comers. In here you see the investigator-assessed HRD and the investigator-assessed all comers. Remember that our New England Journal paper was BICR, so not only does this have a longer follow-up, but it also shows what the investigator thought rather than the blinded independent review.

I'd be remiss to not discuss safety of these three trials. Treatment emergent adverse events are common. You can even have some dose interruptions, but the discontinuation rates are universally low. And this is at 20% of either medication, that's why it's higher. So if you have an adverse event, you obviously can try concomitant medication such as an antiemetic, but if it's let's say nausea or fatigue, stop, and she'll feel better. And then you dose reduce and if you get to the lowest dose, then you discontinue. So that's what was done here. You would have to choose olaparib or niraparib. Based on her weight, you would have a lower dose of niraparib and she should do well, and she should have a survival benefit versus the alternative, which would be placebo.

Thank you. Greetings from Scottsdale, Arizona. I wish we were together, but I thank you for your attention and so long for now.

Chapter 2: Treatment of Platinum-Sensitive Ovarian Cancer

Shannon N. Westin, MD, MPH: Hello, my name is Shannon Westin and I'm a professor and medical director of gynecologic oncology and reproductive medicine at the University of Texas MD Anderson Cancer Center, and it's my pleasure to discuss with you today the treatment of platinum-sensitive ovarian cancer.

Let's start with a case. This patient was 62, stage IIIC, high-grade serous ovarian cancer. She had testing done, which revealed she was germline BRCA wild-type, somatic BRCA1-mutant, and has a history of undergoing an optimal tumor reductive surgery and being treated with 6 cycles of intravenous paclitaxel and carboplatin. For reasons that we won't get into today, she did not receive a maintenance strategy during her upfront treatment.

Now you're seeing her for the first time. She presents as a new patient approximately 1 year after the completion of this primary therapy. She's having some crampy abdominal pain and early satiety. She's 80 kilos, her platelets are 323,000, and her cancer antigen (CA)-125 is elevated to 574. She does have an excellent performance status and no residual toxicities leftover from her primary therapy. You appropriately get some imaging, and you can see that she has metastasis to her liver and carcinomatosis, as well ascites. You have her undergo a biopsy, which reveals the recurrence of her high-grade serous tumor.

In this setting, we see a patient that has diffuse disease, including ascites, so there's some key questions when we have this patient in front of us. Should we do surgery? Is there any additional testing we need? And, of course, we always want to consider if there are residual adverse events (AEs).

First, let's tackle the surgery question. You can consider secondary cytoreductive surgery in the appropriate patient with platinum-sensitive recurrence. But what we found when we look at the randomized trials that have explored this, it does seem that the most important thing is having a good way to select these patients. One such way is the AGO score. Now, our patient meets some of these scores: platinum sensitivity, good performance status, and no residual disease on her primary surgery. However, she does have ascites, which makes this not an ideal patient for secondary cytoreductive surgery.

So then, what will we consider for chemotherapy? Really, the world is your oyster here. The bottom line is the National Comprehensive Cancer Network (NCCN) guidelines will tell us platinum-based chemotherapy of some kind, and this site's audience will know that our options are weekly paclitaxel, paclitaxel every 3 weeks, docetaxel, pegylated liposomal doxorubicin, or gemcitabine, and this, of course, can be given with or without bevacizumab maintenance. What will we consider for our patient? Well, in fact, as she was going undergoing her diagnostic workup, she did get admitted for a partial small bowel obstruction. It resolved with conservative management, but that made us a little bit more hesitant to explore bevacizumab for her. So, for her second-line therapy, she received 6 cycles of pegylated liposomal doxorubicin with carboplatin and no bevacizumab, and she had no evidence of disease at the completion of treatment.

Then comes our question, what about a maintenance strategy? What options might we have for her? Now, when we're incorporating maintenance therapy, and this is the same as the factors that we consider when we're thinking about this front-line. What's our indication? What drugs do we have available to us? What's the patient's BRCA status? Has she had homologous recombination deficiency (HRD) testing? Residual toxicities and AEs from her prior therapy? What she had as prior therapy, and specifically there is did she have bevacizumab or not? Is the schedule important to her? And what is the cost? All of these questions and all of these factors are going to build into what we decide to do with the patient in front of us.

I think this savvy audience will know we have 3 major trials of poly-(ADP ribose) polymerase (PARP) inhibitor maintenance in the second line: SOLO-2, NOVA, and ARIEL3. In addition, the Study 19 is also quite informative for the use of olaparib. All 3 of these agents are FDA-approved, although we've had some changing landscapes lately that I'm going to cover in the next few minutes.

First, let's talk about Study 19. This was olaparib as maintenance for women with platinum-sensitive relapsed ovarian cancer. This was an all-comers population, but they did do a planned subset analysis teasing out based on biomarker. You can see in the overall population there was a statistically significant improvement and reduction in the risk of death and progression for women who received olaparib. That difference did seem to be driven based on the presence of a BRCA mutation. Now, it's important to note the progression-free survival (PFS) difference was statistically significant. The overall survival (OS), they didn't put enough alpha towards that, so although we saw a clinically significant difference, it wasn't statistically significant. But this did contribute to the FDA approval of olaparib for patients with relapsed ovarian cancer.

This was further supported by the SOLO-2 study. Now, SOLO-2 was in a more select group of patients, still platinum-sensitive relapsed ovarian cancer, but also requirement for a BRCA mutation. These patients had at least 2 prior lines of platinum therapy and had benefit to their most recent platinum, and then were randomized 2:1 to olaparib vs placebo. The primary endpoint was PFS and we did see a clear benefit in this patient population, with a 70% reduction in the risk of progression. This did yield an overall FDA approval for all comers in August 2017. With regards to OS, we did see a clinically significant difference, 12.9 months, between olaparib and placebo, despite almost 40% of the patients on the placebo arm receiving a PARP inhibitor (PARPi) in a later line of therapy. This did not meet statistical significance, although when they teased out some of the overall analysis, the full analysis set based on an adjusted case report form (CRF), as well as in a group that looked at myriad testing, they did see an improvement in OS.

Now, what about NOVA? NOVA was looking at niraparib for patients with platinum-sensitive relapsed ovarian cancer, similar population response to therapy, and they were randomized to niraparib vs placebo. This was actually 2 different studies. One study looking at this in a germline BRCA-mutated group and one in a BRCA wild-type, and it did meet both of its PFS endpoints in both the mutated group as well as the wild-type group. And that did lead to an all-comers maintenance indication by the FDA in March 2017.

However, when we started to tease out in planned subgroup analysis, it did seem that this benefit was driven mostly by those patients that had homologous recombination deficiency (HRD)-positive testing. You can see here the somatic mutants and the wild-types with HRD-positive did the best, but there still was some benefit in those that tested negative. So again, this had an all-comers indication. However, when there was an analysis of OS -- which, importantly, was not meant to be an analytic endpoint -- there was a concern that there was an OS detriment for the patients without a BRCA mutation who were treated with niraparib. And so, although this was not an analytic endpoint, the decision was made to pull niraparib from the non-BRCA-mutant population. So, we can only prescribe niraparib in a patient population that has a BRCA mutation. Interestingly, if you adjust for subsequent PARPi therapy, the hazard ratio actually indicates an overall trend towards survival, but it's hard to keep massaging these data anymore, so this is likely the only place we'll be able to use niraparib, is in that BRCA-mutant group.

Now, moving on to rucaparib, that was ARIEL3. This is for patients with platinum-sensitive relapsed ovarian cancer, all-comers, rucaparib vs placebo, and the benefit really was seen across all the groups again, BRCA-mutant, HRD-positive, as well as the intention-to-treat. That did yield an FDA approval for rucaparib in this population. An ultimate assessment of final OS indicated that, again, there was the best benefit for those patients in the BRCA-mutant population. However, for the population that had HRD or the all-comers population, it didn't seem as clear.

Now, again, it's very important to note that almost half of the patients that were randomized to placebo did receive subsequent PARPi therapy, which could have impacted their subsequent survival. When we teased out further the patient population with BRCA wild-type, there was less benefit for those patients treated with a PARPi despite having the potential population that would benefit.

That led to American Society of Clinical Oncology (ASCO) to update their PARPi guidelines. You can see that there's clear data to support the use of PARPis as front-line, consideration for patients in the platinum-sensitive maintenance, especially if they've not had PARP before. So, for olaparib and rucaparib, right now, we do have an all-comers population, although this may change through the FDA. But for niraparib, it's clear that for platinum-sensitive recurrence, we only give it for BRCA-mutant.

I just wanted to quickly touch on the toxicities that were observed in the second line. Really, we see PARP specific toxicities across all-comers. So, anemia, thrombocytopenia, neutropenia, all quite common with perhaps a little bit more thrombocytopenia in niraparib. We see gastrointestinal toxicities like nausea, vomiting, and constipation. And then fatigue, of course, can be an issue. The bottom line is, you want to monitor very closely while you're starting therapy, considering weekly nurse visits and assessment of symptoms, work up any causes of toxicities that might be there, and use dose reductions and delays liberally.

Let's bring it right back to our last patient. She had her complete response to carboplatin-based therapy and she qualifies, based on her BRCA mutation for olaparib, niraparib, or rucaparib. Thank you all so much.

Chapter 3: Adapting PARP Inhibitors to Treatment of Recurrent Ovarian Cancer​

Floor Backes, MD: Hi. I'm Floor Backes, professor in the Division of Gynecologic Oncology at The Ohio State University and James Cancer Hospital in Columbus, Ohio. Today I'll be talking to you about "Adapting PARP Inhibitors to Treatment of Recurrent Ovarian Cancer."

We'll start with a case. This is a 66-year-old with stage IIIC high-grade serous ovarian cancer who had a complete primary cytoreductive surgery followed by 8 cycles of carboplatin, paclitaxel, bevacizumab, and bevacizumab maintenance, and this was in 2018.

Two years later, she developed some vaginal pelvic recurrence with pelvic lymphadenopathy. And then went on to receive gemcitabine, carboplatin, and bevacizumab for 5 cycles. But unfortunately, she has an anaphylactic reaction with cycle 6 of carboplatin and declines any further platinum therapy and wants a complete break from treatment.

Ten months later, she has a rising cancer antigen (CA)-125. It increases from 16 up to 164. And computed tomography (CT) of abdomen and pelvis shows small volume carcinomatosis and small volume ascites.

At our original diagnosis, she of course has germline testing and that was negative. She also had tumor testing, which showed a variety of somatic mutations in BRCA1/2, CHEK2, RAD51D, NBN, and PALB2.

So, what are our options now? She has platinum sensitive recurrence with a severe platinum allergy. Not a candidate for future platinum. But she does have recurring disease. So, her options include a platinum desensitization, non-platinum based therapy, or targeted therapy, such as with poly-(ADP ribose) polymerase (PARP) inhibitors.

The most recent American Society of Clinical Oncology (ASCO) guideline rapid communication update now shows PARP inhibitor (PARPi) maintenance is still a consideration here but PARPi treatment is not recommended. And let's dive a little bit deeper in why they came to these conclusions.

PARPi monotherapy had original approval and indications for olaparib, rucaparib, niraparib. Olaparib was approved for the suspected deleterious germline BRCA-mutated patients who were treated with more than 3 prior lines of chemotherapy. Rucaparib for BRCA mutated epithelial ovarian cancer after 2 prior chemotherapies. And then niraparib was platinum sensitive, homologous recombination deficiency (HRD) positive, and treated with 3 or more chemotherapy regimens.

You see the withdrawal dates. So, this started with rucaparib in June after the ARIEL4 overall survival (OS) results were presented. Olaparib in August of this year based on the SOLO3 OS results. And niraparib was voluntarily withdrawn in September. This caused a lot of confusion. So, let's go further into these different studies that led to these withdrawals.

SOLO3. The study design was as follows. This is a study of platinum-sensitive relapsed high grade serous or endometrioid ovarian cancer, germline BRCA mutated, with 2 or more prior lines of platinum-based therapy. These patients were randomized to olaparib or non-platinum based single-agent chemotherapy and the primary endpoint was objective response. The full-set analysis showed that the progression-free survival (PFS) was improved with olaparib over chemotherapy: 13 months with olaparib and chemotherapy, 9.2 months. We see the OS curve, which showed a similar OS of 34 and 32 months, not a statistically significant difference here. Of note, also, of the patients who received chemotherapy, 61% of those in the chemotherapy arm went on to receive a subsequent PARPi therapy.

Then there was the post-hoc subgroup analysis and an updated analysis presented to the International Gynecologic Cancer Society (IGCS) in October of this year. So, they separated these in 2 subgroups. The patients with 2 prior lines of chemotherapy and 3 prior lines. And we're looking here at the 2 prior lines. So we see that the median PFS and OS are favored for olaparib over chemotherapy with a statistically significant difference in PFS and a non-significant difference in OS.

If we look at the patients who received 3 or more prior lines of chemotherapy, there is no difference in PFS and numerically there is an improved OS with chemotherapy. But again, this is not statistically significant.

ARIEL4 was a study of rucaparib vs either weekly paclitaxel for patients who were platinum-resistant or partially platinum-sensitive compared with platinum-based chemotherapy for those who were fully platinum-sensitive. And again, a similar population was enrolled as in SOLO3. Patients who had at least 2 prior chemotherapy regimens, had either a deleterious germline or somatic BRCA mutation, no prior PARP exposure, and relapsed high grade serous ovarian cancer or endometrioids. Importantly, also, crossover to rucaparib was allowed in the chemotherapy group.

When we look at the primary endpoint, which is investigator assessed PFS in the intent-to-treat (ITT) population, we see an improvement of PFS of 7.4 months over 5.7 months with chemotherapy. If we look at duration of response as well, we see an improvement again with rucaparib treatments.

However, if we look at the updated results that were presented at European Society of Medical Oncology (ESMO) in 2022, we see that in the ITT population, chemotherapy has better OS numerically of 25 months vs 19 months with rucaparib. But again, this is not statistically significant.

In the platinum resistant sub-group, the chemotherapy patients who received chemotherapy had better OS than those who received rucaparib, whereas those that were partially platinum-sensitive or fully platinum-sensitive had either a similar numerical OS or numerically slight improvement with chemotherapy but again, not statistically significant. As a reminder, our patient would've fit in the partially platinum sensitive category with a similar OS in either arm.

So, the PFS benefit of rucaparib did not translate into an OS benefit. And OS was favored for chemotherapy vs rucaparib in the ITT population. But this was also confounded by a high rate of crossover from chemotherapy to rucaparib. 90% of patients received rucaparib after randomization with crossover, whereas in the rucaparib arm, 42% of the patients did not receive any subsequent anti-cancer treatments. So, the difference in OS in the ITT population was driven mainly by the platinum resistant subgroup.

We cannot forget about the QUADRA study, which was a single arm study with a primary endpoint of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) in HRD positive patients who have received 3 or 4 lines of previous chemotherapy, platinum sensitive, and PARPi naive. They received treatment with niraparib 300 mg daily on a 28-day cycle and they saw an objective response rate of 27%.

Let's look a little bit further here. So, we've seen now these withdrawals of PARPis but what are some predictors of response? We talked about platinum sensitivity. From ARIEL2, which was rucaparib treatment, they also noted that the BRCA mutation, RAD51C/D mutations, high-level BRCA1 promoter methylation, and platinum sensitivity were the best predictors of response to PARPis in this setting.

From ARIEL3, similar results were obtained and this was rucaparib maintenance. Again, complete response to less platinum, longer platinum-free intervals, and then similar molecular markers and genome-wide loss of heterozygosity (LOH) as predictors of response. In QUADRA, HRD score positive and platinum sensitivity were again highlighted as predictors of response.

What are some risks associated with it though? Well, this possible detriment to OS we discussed, with the certain caveats that we also discussed. And then side effects that we have to counsel our patients about. I do want to spend a little time talking about these secondary cancers with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and all these PARPis have some increased risk of AML and MDS. We have to remember though that there are potential confounders. Patients who are platinum sensitive received treatment more and longer, have more exposure to platinum and possibly also to PARPis. There is also some data suggesting that TP53 clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of AML and MDS.

So, who is still a potential candidate for a PARPi? Those patients who are BRCA mutated with no PARPi exposure, patients with HRD tumors without prior PARPi exposure, such as LOH high, HRD positive, have an homologous recombination repair (HRR) gene mutation, or have high BRCA1 promoter methylation. Certainly, you want to pick a patient who is platinum sensitive, maybe even small volume disease. But these options should remain also for those patients who have a platinum intolerance or allergy and cannot tolerate any further platinum or patients who just flat out decline any chemotherapy or IV.

So, considerations for PARPi treatment. Obviously there has to be a physician-patient discussion about the risk, benefits, and alternatives and a shared decision-making process. If you use it, it's better to use it in earlier lines because we've seen that there are better responses if you use it earlier on. When it's used prior to developing platinum resistance or PARP resistance, less prior platinum exposure and a lower risk of AML or MDS when used in earlier lines.

Should we also be limiting the duration of PARPi use? It is hard to give a good answer to that question at this time but certainly is something that should be considered. And then in the future, for other pre-treatment considerations, should we be testing for BRCA reversion mutations and testing for TP53 CHIP mutations? These will be areas of research and maybe new developments, how we pick our patients that could still potentially be a candidate for PARPis.

Let's go back to the case. Our patient had recurrent ovarian cancer that was platinum sensitive with a platinum allergy and a somatic BRCA mutation. We reviewed her treatment options with platinum desensitization, a non-platinum agent, or targeted therapy, and she chose to proceed with a PARPi. And our 3 options are listed with olaparib 300 mg twice daily, rucaparib 600 mg twice daily, or niraparib 300 mg daily. We had an extensive patient-physician discussion and reviewed the risks and benefits in great detail.

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