Tewari Reviews Maintenance Treatments for Patients With Advanced Ovarian Cancer

Krishnansu S. Tewari, MD

Philip J. DiSaia, MD, Chair of Gynecologic Oncology

Director of Continuing Medical Education

Professor and Chief, Division of Gynecologic Oncology

UCI School of Medicine

Irvine, CA

Targeted Oncology^TM: Which trials have relevant data for a patient such as this?

TEWARI: Mainly SOLO-1 [NCT01844986], PRIMA [NCT02655016], and PAOLA-1 [NCT02477644]. The GOG-0218 study [NCT00262847] was probably our first phase 3 randomized trial in using targeted therapy in ovarian cancer.¹

This study…introduced bevacizumab [Avastin] to the world of ovarian cancer, and it was our first indication for bevacizumab in ovarian cancer or in gynecologic cancer.

Although we didn’t get that indication until a few years later, and the first time we got that indication was in the recurrent setting. The approval of bevacizumab in frontline therapy with chemotherapy and as a first-line maintenance therapy did not happen until 2018, even though GOG-0218 was presented in 2010 and published in the New England Journal of Medicine in 2011.²

[Although] Europe adopted bevacizumab with chemotherapy for primary treatment in a high-risk subpopulation, it look a long time for investigators and the FDA to get on board with it in the United States. But it’s important because now that we have this option available, in the PAOLA-1 study that looked at bevacizumab with or without olaparib [Lynparza], bevacizumab was able to serve as a control arm because it was ultimately approved.^2,3

The other 2 trials, SOLO-1 and PRIMA, studied 2 PARP inhibitors, olaparib and niraparib [Zejula].^3-5 And then in PAOLA-1, olaparib was in one of the experimental arms with bevacizumab.⁴ What was remarkable about these studies is they all met their primary end point, which was PFS [progression-free survival].^3-5 They all significantly delayed the occurrence of progression or death in these patient populations that they were studied in.

In PAOLA-1, these were patients who had a germline or somatic BRCA mutation. PRIMA was more of a real-world, all-comers population, as was [SOLO-1].^4,5 Importantly, in PAOLA-1 and PRIMA, they did sub-analyses in the populations [with] HRD, and even those [with] BRCA mutations. Advanced stage disease was studied in all 3 trials.

What were the designs of these trials?

The patients in PRIMA had primary surgery, whereas neoadjuvant chemotherapy followed by cytoreduction was permissible in PAOLA-1 and SOLO-1.^3-5 The treatment duration was 25 months of therapy in SOLO-1, until progression with PRIMA, and [for PAOLA-1 it was] 15 months for bevacizumab and 24 months for olaparib. SOLO-1 received FDA regulatory approval for using olaparib for patients with germline or somatic BRCA mutations first, and then SOLO-1 [results were] presented by Kathleen Moore, MD, at ESMO [European Society for Medical Oncology Congress] in 2018. PRIMA and PAOLA-1 [results] were presented at ESMO in 2019, and by June 2020, right in the midst of the [COVID-19] pandemic, we got the approval for niraparib as a maintenance therapy for all-comers and bevacizumab plus olaparib as a maintenance therapy for patients with HRD-positive tumors.^6-8

So although the indications are kind of overlapped, it is olaparib for germline somatic BRCA mutations, niraparib for everybody, and bevacizumab plus olaparib for patients who are HRD positive, which also includes [patients with BRCA mutations].^6-8

I like to conceptualize these trials by SOLO-1 bringing olaparib to patients with BRCA-mutated tumors, PAOLA-1 with bevacizumab, and olaparib for patients who have HRD but not BRCA-mutated [tumors], although you can use the combination for BRCA-mutated [tumors].^3,4 The way I conceptualize [it] is bevacizumab plus olaparib for HRD-positive BRCA wild-type tumors, and PRIMA for HR-proficient patients, even though the label says it can be used as maintenance therapy for everyone.⁹

How was the efficacy for these trials presented?

In SOLO-1, when it was originally presented, we did not have the median PFS. It was at least 21 months, and when Dr Moore presented this, it was just listed as not reached.³ But if you looked at the control arm, which was 13.8 months, you could calculate at the time of the presentation that 41 months had elapsed and patients were not progressing. When she did the update, we found that the median PFS was 56 months and now think about that, that’s almost 5 years PFS for patients with a BRCA-mutated tumor, whether it arises as a result of a germline mutation or a somatic mutation in the tumor itself. Extraordinary.

Probably the greatest clinical trial in our field was SOLO-1.³ PRIMA was an all-comers trial; it did not restrict the eligibility to just patients with BRCA mutations. But in the BRCA group, we had a doubling PFS.⁵ You wonder, “If these drugs are so similar, why are we seeing 56 months [with olaparib] vs 22 months [with niraparib]?”^3,5

First of all, [PRIMA] was not powered to study patients with BRCA mutations, so there is a smaller group of patients.⁵ Also, in the PRIMA study population, they tended to be [more ill] than the patients in SOLO-1.^3,5 [In those with] HRD-positive tumors, we have a decrease in hazard ratio or death of 0.5 and then in the HR-proficient population, it doesn’t work as well as it does in patients who are HRD positive or in patients with BRCA mutations, but still [there is] a 32% reduction in the risk of progression or death with niraparib.⁵ So this was pivotal in getting the all-comers indication for niraparib. And then in PAOLA-1 the combination of olaparib plus bevacizumab [showed] a somewhat similar trend.⁴ These drugs work best in the patients with BRCA mutations for this regimen. It still works, but not as well, in the HRD-proficient patients, and then in the HRD-negative patients we have a hazard ratio that is approaching 1.0.

Now what is important to note is the primary end point was PFS. We do not have survival data yet on any of these studies, but if you look at this with the median PFS of 56 months, it looks like there are going to be many patients who are going to enjoy a survival benefit in SOLO-1.³ It’s interesting to note, in the SOLO-2 study [NCT01874353] done in the platinum-sensitive phase, maintenance therapy with olaparib in the platinum responders who are rechallenged with platinum did show a survival benefit.¹⁰

What are the National Comprehensive Cancer Network (NCCN) recommendations?

The NCCN guidelines recommend treating stage II, III, and IV ovarian cancer with platinum-based chemotherapy followed by maintenance therapy.¹¹ If you have an advanced patient and they received bevacizumab with their chemotherapy; if they’re germline, somatic, or BRCA mutated, and they’ve had a complete response, they can go on niraparib, olaparib, or bevacizumab plus olaparib, [which are all recommended as] category 1. If they had stable or progressive disease, then they are [treated] as if they had recurrent disease. If they received bevacizumab as their primary therapy and they’re BRCA1 and they had a complete response, we would want to check their HRD status. If they are HRD positive, bevacizumab plus olaparib [is recommended]; if they’re HR proficient or status is unknown, they can get maintenance therapy with bevacizumab.

In my opinion, they can also get maintenance therapy with olaparib because it has it all-comers indication for patients who are HR proficient.¹² I’m not sure what the NCCN’s reason is for not including niraparib as an option for the HR-proficient patients if they received bevacizumab initially, maybe because the idea is to just continue bevacizumab as maintenance.¹¹ But there is an option called switch maintenance and if, for example, the patients are getting a lot of proteinuria or hypertension you can switch out the bevacizumab and substitute niraparib.

Please discuss the subgroup analyses and safety for patients treated with maintenance therapy.

[Now let’s discuss the subgroup analysis of PRIMA]. You have your patients with BRCA mutations and, again, that means they have HRD, but you don’t have to have a BRCA mutation to have evidence of genomic scarring as picked up in the [patients who are HRD positive].⁵ You can be BRCA wild type and have a mutation and maybe RAD51C, RAD51D, BRIP1, one of these other genes that code for proteins that interact with BRCA that perform double-strand DNA repair. And then in the HR-proficient patients, the drug still worked, but the median PFS rates were not as striking. In the patients with stage IV disease, the benefit was not as great, but [there was a] 21% reduction in the risk of infection or death, a very important trial.

The OS [overall survival] at 2 years for those patients on niraparib was 91% vs 85% with placebo, and this is for the HRD population [HR, 0.61; 95% CI, 0.27-1.39].⁵ For the intent-to-treat population, [those who received niraparib had a 2-year survival of 84% vs 77% in the placebo group (HR, 0.7; 95% CI, 0.44-1.11)], a 30% reduction in the hazard ratio of death for this group of patients.

[In terms of] safety, thrombocytopenia tended to be a bigger deal with niraparib, especially at the 300-mg dose.⁹ In fact, when niraparib was first approved in the recurrent setting, the dose was 300 mg and we have since learned using a radar analysis that, based on a baseline platelet count and a weight of 77 kg or less, the starting dose could safely be reduced to 200 mg with not such a dramatic effect on thrombocytopenia. In fact, when niraparib got the label for primary maintenance therapy in addition to improving it, the dose was changed to 300 mg. So other than the thrombocytopenia, which was the same at the 300-mg dose, the safety profile is the same as olaparib.

In terms of adverse events with olaparib, there is acute myeloid leukemia—that is a risk of [approximately] 1% to 2%, very small; maybe mild diarrhea, anemia, fatigue, ischemia, dyspepsia.¹² Those are some of the main things, and this is a common thing with all of the PARP inhibitors.

In PAOLA-1, again, this was chemotherapy with bevacizumab followed by bevacizumab with or without olaparib.⁴ Similar to what they did with the PRIMA study with niraparib, they looked at different populations. The HRD-positive population included those with BRCA mutations. The reduction in the hazard ratio in progression or death was 67% for the patients who are HRD positive who did not have BRCA mutations…and even in the HRD-negative/ unknown group, [the median PFS was 16.9 months for olaparib plus bevacizumab] and 16 months for the placebo plus bevacizumab group, not much of a difference [HR, 0.92; 95% CI, 0.72-1.17].

So this is why when the FDA approved this combination regimen, they restricted it to these 2 groups.⁸ They did not get an all-comers indication like niraparib did.⁷ For adverse events, again the combination was well tolerated. Bevacizumab has an adverse event profile. Black box warnings are wound healing, bleeding, fistula, and gastrointestinal perforation, but the combination was relatively well tolerated, so this was a viable maintenance strategy for patients who are HRD positive.^4,13

What is the role of germline and somatic testing in these patients?

All women [who receive a diagnosis of epithelial ovarian cancer should be offered germline genetic testing for BRCA1/2 and other susceptibility genes].¹⁴ It’s surprising; it should be routine now, but there are large pockets of patients around this country who, according to a Journal of Clinical Oncology paper published in 2019, are still not getting referred for genetic testing for BRCA.¹⁵ All women with ovarian cancer should be tested, and I think that we need to advocate for that.

I saw a patient today who is in the middle of chemotherapy. I gave her neoadjuvant chemotherapy, took her to surgery. She’s back on chemotherapy now and doing well, and she got her genetic testing back and she has a somatic BRCA mutation; I told her she hit the jackpot. That’s like winning the lottery because, since it’s not germline, we don’t have to worry about breast cancer and we don’t have to worry about her children. But at the same time, since she has the somatic BRCA, she can benefit from olaparib as a maintenance strategy where now, at 5 years for follow-up, the median PFS is 56 months.³ The reality is, of the patients with BRCA mutations, only maybe a quarter of them are going to be based on having a somatic mutation. Of the entire population of women with ovarian cancer, 15% have a germline [mutation] and approximately 6% will have a somatic [mutation], so it’s really uncommon.

_REFERENCES

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_{2. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483. doi:10.1056/NEJMoa1104390}

_{3. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858}

_{4. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361}

_{5. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962}

_{6. FDA approved olaparib (LYNPARZA, AstraZeneca Pharmaceuticals LP) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. FDA. Updated December 26, 2018. Accessed February 24, 2022. https://bit.ly/3tLJdoo}

_{7. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. News release. FDA. April 29, 2020. Accessed February 24, 2022. https://bit.ly/3HSadaR}

_{8. FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. News release. FDA. Updated May 11, 2020. Accessed February 24, 2022. https://bit.ly/3MOYf5B}

_{9. Zejula. Prescribing information. GlaxoSmithKline; 2021. Accessed February 24, 2022. https://bit.ly/3vZAaTD}

_{10. Poveda A, Floquet A, Ledermann JA, et al; SOLO2/ENGOT-Ov21 Investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Oncol. 2021;22(5):620-631. doi:10.1016/S1470-2045(21)00073-5}

_{11. NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 1.2022. Accessed February 24, 2022. https://bit.ly/3CtSeGm}

_{12. Lynparza. Prescribing information. AstraZeneca Pharmaceuticals LP; 2021. Accessed February 24, 2022. https://bit.ly/3KsX6hS}

_{13. Avastin. Prescribing information. Genentech, Inc; 2021. Accessed February 24, 2022. https://bit.ly/3CtMuMU}

_{14. Konstantinopoulos PA, Norquist B, Lacchetti C, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38(11):1222-1245. doi:10.1200/JCO.19.02960}

_{15. Kurian AW, Ward KC, Howlader N, et al. Genetic testing and results in a population-based cohort of breast cancer patients and ovarian cancer patients. J Clin Oncol. 2019;37(15):1305-1315. doi:10.1200/JCO.18.01854}