Barbara Buttin, MD, covers the past and present standards of care, as well as upcoming therapeutic options, for World Ovarian Cancer Day.
Barbara Buttin, MD, is a board-certified and fellowship-trained gynecologic oncologist at Cancer Treatment Centers of America® (CTCA) Chicago.
Over 70% of women with ovarian cancer present in advanced stages (III and IV) because early detection remains elusive. The 5-year relative survival for advanced ovarian cancer is only 30.8%. This is mostly due to high rates of recurrence and ultimate development of chemotherapy resistance. Successful initial treatment for ovarian cancer requires a combination of cytoreductive surgery and platinum/taxane-based chemotherapy. With these measures, 70% of patients achieve remission. However, a majority of those in remission will relapse and ultimately die of their disease.1
Fortunately, the last 15 years have changed the treatment landscape of ovarian cancer to a much larger playing field and the future for these patients finally looks much brighter today than it has in years past.
It All Began With Intraperitoneal Chemotherapy
In 2006, the National Cancer Institute published a clinical advisory stating that intraperitoneal (IP) chemotherapy should be considered for all women with optimally cytoreduced, stage III ovarian cancer.2 This was based on the results of the GOG-0172 trial (NCT00003322) that demonstrated a 16-month longer median overall survival (OS) in the intravenous (IV)/IP chemotherapy arm compared with the IV chemotherapy arm.3 For patients with no evidence of disease at the completion of initial chemotherapy, this survival benefit persisted beyond 10 years, where median OS in that patient population is now reported at 127.6 months (approximately 10.5 years). This treatment remains a viable option for a select patient population.
Incorporation of Bevacizumab – The Next Innovation
In 2011, 2 phase 3 trials were published incorporating bevacizumab (Avastin) into carboplatin and paclitaxel IV chemotherapy for ovarian cancer with bevacizumab maintenance. One study, ICON7 (ISRCTN91273375),4 was conducted in Europe and the other, GOG-0218 (NCT00262847),5 was conducted in the United States. The patient population was primarily stage III with higher residual disease (>1 cm) and stage IV. For both studies, the addition of bevacizumab increased median progression-free survival (PFS) by 2 to 4 months without OS benefit.
Nonetheless, these studies led to the approval of bevacizumab as an adjunct to frontline chemotherapy with potential maintenance for advanced high-risk ovarian cancer in Europe and eventually the United States. However, when analyzing both studies for the most high-risk subgroups (suboptimally cytoreduced stage III and stage IV), an OS benefit could be demonstrated emphasizing the value of antiangiogenic therapy in ovarian cancer.6,7 Bevacizumab is also approved alone and in combination with second- or third-line chemotherapy for recurrent platinum-sensitive and -resistant disease.
Insights From the Cancer Genome Atlas Project
Also in 2011, the Cancer Genome Atlas Project for ovarian serous carcinoma was published measuring genomic and epigenomic abnormalities on high grade serous ovarian carcinomas (HGSCs) and opened the door to the era of targeted therapies.8 While 13% of HGSC of the ovary/fallopian tubes or peritoneum were presumed to be related to germline mutations in BRCA1/2 with a smaller percentage accounted for by other related mutations, this study found that almost 50% of these cancers exhibit some form of defect in homologous recombination (HRD). At that point, the development of PARP inhibitors became the next innovation in the treatment of ovarian cancer.
PARP Inhibition Approved for Ovarian Cancer
To date, 3 types of PARP inhibitors are FDA approved for ovarian cancer in various clinical settings and research continues to extend the spectrum of applicability for these oral drugs: olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca).
Olaparib is currently indicated for frontline maintenance for patients with complete or partial response to platinum-based chemotherapy who have a germline or somatic BRCA mutation based on the SOLO1 trial data (NCT01844986) showing a median PFS of 56.0 months versus 13.8 months in the treatment and placebo arms, respectively.9 Olaparib is also indicated in conjunction with bevacizumab for patients who had bevacizumab during their chemotherapy with response and have evidence of HRD based on the PAOLA-1 trial data (NCT02477644), with a median PFS of 37.2 versus 17.7 months.10 Lastly, it can also be used in third line or greater in all patients with a response to platinum therapy.
Niraparib showed benefit as a maintenance agent in frontline platinum responders not just in the BRCA/HRD population but also in the homologous recombination proficient (HRP)/BRCA wild-type patients as demonstrated in the PRIMA study (NCT02655016).11 This trial enrolled a more varied patient population, including patients with residual disease, stage IV disease and those that had received neoadjuvant chemotherapy. For the whole population, median PFS was 13.8 months versus 8.2 months, equivalent to a 38% reduction in risk of progression or death, with a 32% such risk reduction in the HRP population and a 60% risk reduction for the BRCA-mutated population. Niraparib is taken once daily versus twice daily for olaparib, and adverse event profile is slightly different with more notable cytopenias.
In platinum sensitive recurrence, niraparib is also indicated to prolong median PFS as demonstrated in the NOVA trial (NCT01847274).12 Again, the largest benefit was found in the BRCA mutant cohort (21 versus 5.5 months), followed by the HRD+ patients (12.9 versus 3.8 months), and 9.3 versus 3.9 months in the overall non–BRCA-mutant cohort.
The ARIEL3 trial (NCT01968213) showed similar results for rucaparib and had an even larger proportion of BRCA wild-type patients enrolled.13 The HRP/non-BRCA patients experienced a 42% reduction in the risk of disease progression or death that persisted over time. Since time in remission becomes shorter and shorter in recurrent ovarian cancer, offering a PARP inhibitor to all patients with platinum-sensitive recurrence now makes sense.
Hematologic toxicity is the most concerning for these drugs with a small but significant risk for acute myeloid leukemia and myeloid dysplastic syndrome that is highest with olaparib (up to 1.5%) and lower for rucaparib (1.1%) and niraparib (0.8%).
Newest Developments and Ongoing Research
While PFS in upfront maintenance and in platinum-sensitive recurrence has increased significantly, allowing patients with ovarian cancer to live longer with improved quality of life, other treatment strategies are being investigated to further improve OS and help engage the immune system in the fight against ovarian cancer. Additionally, patients with platinum-resistant tumors are in desperate need of novel treatment strategies. Up to now, single-agent checkpoint inhibitor studies have shown underwhelming results in ovarian cancer.
Attention is now being focused on adding immunotherapy to chemotherapy in the neoadjuvant setting. Park, et al, presented a study by the Korean Gynecologic Oncology Group at the 2021 American Society of Clinical Oncology annual meeting demonstrating that the addition of durvalumab (Imfinzi) and tremelimumab to neoadjuvant chemotherapy showed encouraging responses and an encouraging safety profile (KGOG 3046 trial; NCT03899610).14 Patients in this phase 2 study had mostly high-grade serous carcinomas, stage IIIC or IV, and received the aforementioned drugs in addition to 3 cycles of carboplatin and paclitaxel prior to cytoreductive surgery.
One ongoing trial is investigating the combination of PARP inhibitors and CTLA-4 blockade for synergy (NCT02571725). Additionally, a phase 2 study (NCT02853318) of pembrolizumab (Keytruda), bevacizumab, and oral metronomic cyclophosphamide in a mixed, recurrent ovarian cancer population showed an objective response rate of 47.5%, and a 95% clinical benefit rate with tolerable toxicities of fatigue, diarrhea, and hypertension.15
Other promising new treatment approaches include cortisol modulating agents such as relacorilant that appeared to improve survival in a platinum-resistant population receiving nab-paclitaxel in a phase 2 study (NCT03776812).16 The antibody-drug conjugate mirvetuximab soravtansine—comprising a folate receptor (FR-alpha) binding antibody, cleavable linker and the maytansinoid payload DM4, a potent tubulin-targeting agent to kill targeted cancer cells—showed durable efficacy in ovarian cancers that express the receptor. The SORAYA trial (NCT04296890) showed a response rate of 32.4% in a population of women with platinum-resistant ovarian cancer who had received 1 to 3 prior therapies including bevacizumab and PARP inhibitors. Duration of response was 5.9 months, including several complete responders, and toxicities were tolerable.17
As a gynecologic oncologist who treats many women diagnosed with ovarian, fallopian tube, and peritoneal carcinoma, I am excited by the potential implications of these and other initiatives. Undoubtedly, outcomes are improving, and the future is bright.
1. Cancer Facts & Figures 2022. American Cancer Society. Accessed May 3, 2022. https://bit.ly/38P5pXF
2. Trimble EL, Alvarez RD. Intraperitoneal chemotherapy and the NCI clinical announcement. Gynecol Oncol. 2006;103(2):S18-S19. doi:10.1016/j.ygyno.2006.08.020
3. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34-43. doi:10.1056/NEJMoa052985
4. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer [published correction appears in N Engl J Med. 2012 Jan 19;366(3):284]. N Engl J Med. 2011;365(26):2484-2496. doi:10.1056/NEJMoa1103799
5. 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
6. Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16(8):928-936. doi:10.1016/S1470-2045(15)00086-8
7. Tewari KS, Burger RA, Enserro D, et al. Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer. J Clin Oncol. 2019;37(26):2317-2328. doi:10.1200/JCO.19.01009
8. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615. doi:10.1038/nature10166
9. Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1721-1731. doi:10.1016/S1470-2045(21)00531-3
10. 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
11. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962
12. Del Campo JM, Matulonis UA, Malander S, et al. Niraparib maintenance therapy in patients with recurrent ovarian cancer after a partial response to the last platinum-based chemotherapy in the ENGOT-OV16/NOVA trial. J Clin Oncol. 2019;37(32):2968-2973. doi:10.1200/JCO.18.02238
13. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961. doi:10.1016/S0140-6736(17)32440-6
14. Park J, Park E, Joung Je-Gun, et al. A phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer (KGOG 3046/ TRU-D). Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; Virtual. Accessed April 12, 2022. https://bit.ly/3KExhvZ
15. Zsiros E, Lynam S, Attwood KM, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial. JAMA Oncol. 2021;7(1):78-85. doi:10.1001/jamaoncol.2020.5945
16. Colombo N, Nguyen DD, Fleming GF, et al. Relacorilant, a selective glucocorticoid receptor modulator, in combination with nab-paclitaxel improves progression-free survival in patients with recurrent platinum-resistant ovarian cancer: a 3-arm, randomized, open label, phase II study. ESMO Congress 2021; September 16-21, 2021; virtual. Abstract 721O.
17. Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression results from the SORAYA study. Presented at: 2022 SGO Annual Meeting on Womens’ Cancers; March 18-21, 2022; Phoenix, AZ. Abstract 242.