People with newly diagnosed advanced ovarian cancer without BRCA mutations, who received durvalumab (Imfinzi®; AstraZenea) and the the poly(ADP-ribose) polymerase inhibitor olaparib (Lynparza®; AstraZeneca), in addition to the standard of care had improved progression-free survival compared with those who received the standard of care only. [1]

This is the conclusion of an interim analysis of the DUO-O study ( identifier: NCT03737643), an international phase III randomized clinical trial funded by AstraZeneca. The research is presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2 – 6, 2023 in Chicago, Illinois.

Common cancer
Ovarian cancer is the eighth most common cancer in women worldwide.[2] There were more than 313,000 new cases of ovarian cancer in 2020, and over 207,000 deaths. The 5-year survival rate of newly diagnosed advanced ovarian cancer patients has typically been 30-50%. [3][4] Roughly half of women with advanced ovarian cancer have homologous recombination deficiency (HRD)-positive tumors including those with a BRCA mutation and up to one in five women have a BRCA mutation. [5][6][7] The primary aim of 1st-line treatment is to delay disease progression for as long as possible with the intent to achieve long-term remission.[8][9][10]

Study Design
The current standard of care includes chemotherapy (paclitaxel/carboplatin) and bevacizumab, an anti-angiogenic agent. Durvalumab is a checkpoint inhibitor and olaparib is a PARP inhibitor, which blocks a certain cell-repair mechanism. Two recent studies have shown that maintenance olaparib benefits newly diagnosed patients with a BRCA mutation and that bevacizumab benefits patients with HRD-positive tumors.

In patients with tumors that are HRD-positive, cancer cells have a harder time repairing themselves which means certain treatments, such as PARP inhibitors, are more likely to be effective. This led researchers to explore the novel combination of bevacizumab and durvalumab with the addition of olaparib to the maintenance therapy regimen to see if it would enhance the anti-tumor effect.

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The Phase 3 DUO-O trial ( identifier: NCT03737643) evaluated carboplatin + paclitaxel + bevacizumab + durvalumab, followed by maintenance bevacizumab + durvalumab + olaparib, in patients with non-tBRCAm advanced ovarian cancer in the first-line setting.

Rationale behind the scenes
Results from theIn SOLO1/GOG 3004 study ( identifier: NCT01844986) have demonstrated that maintenance therapy with olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. [11]. Furthermore, the PAOLA-1/ENGOT-ov25 study ( identifier: NCT02477644) demonstrated that adding olaparib to maintenance bevacizumab after first-line (1L) platinum-based chemotherapy (PBC) + bevacizumab led to a significant progression-free survival (PFS) benefit in the treatment of patients with advanced ovarian cancer (HR 0.59, 95% CI 0.49–0.72; P<0.001), particularly in patients with homologous recombination deficiency (HRD+; BRCA1/2 mutation [BRCAm] and/or genomic instability. [12] However, there is still a major unmet medical need.

The The MEDIOLA study ( identifier: NCT02734004) evaluated the efficacy and safety of olaparib + durvalumab (O+D doublet cohort) and olaparib + durvalumab + bevacizumab (O+D+B triplet cohort) in patients with non-germline BRCA-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC).

Based on 56 weeks of available data for this study, the investigators of this study concluded that the triplet cohort of olaparib + durvalumab + bevacizumab demonstrated promising efficacy in patients with non-gBRCAm platinum-sensitive relapsed ovarian cancer, with a consistent safety profiles of both the doublet cohort of olaparib + durvalumab and the triplet cohort compared with that expected for the single agents and without new safety signals with longer follow-up.

Study results
In the trial, newly diagnosed patients with advanced high-grade epithelial ovarian cancer without BRCA mutations who received the standard of care (upfront paclitaxel/carboplatin and bevacizumab, plus maintenance bevacizumab) plus upfront durvalumab and maintenance durvalumab and olaparib had improvement in PFS compared to patients who received the standard of care. Of patients with HRD-positive tumors in the durvalumab + olaparib group, the risk of the disease progressing was 51% less than for those who received the standard-of-care. In addition, for patients in the intent-to-treat group who received durvalumab + olaparib, the risk of the disease progressing was 37% less than for those who received the standard of care. In the durvalumab + olaparib arm, the risk of the disease progressing was 32% lower in all subsets of patients, including both HRD-positive and negative patients, compared to the standard-of-care arm.

“While there has been significant progress for patients with advanced ovarian cancer, an unmet need still remains. Our trial results provide encouraging evidence that we can find new treatment approaches for patients with advanced disease,” said Philipp Harter, MD, PhD, director in the Department of Gynecology and Gynecologic Oncology at the Evangelische Kliniken Essen-Mitte hospital in Essen, Germany.

An estimated 19,710 new cases of ovarian cancer will be diagnosed in the United States in 2023, and an estimated 13,270 deaths due to the disease will occur. Only 20% of all cases of ovarian cancer are found early. When disease is detected at stage III or higher, survival rates can be as low as 30%. About half of the patients who are diagnosed with ovarian cancer are 63 years or older, and it is more common in White people than in Black people.1

Next Steps
Researchers will formally assess overall survival and other secondary endpoints in a subsequent analysis.

Clinical trial
Durvalumab Treatment in Combination With Chemotherapy and Bevacizumab, Followed by Maintenance Durvalumab, Bevacizumab and Olaparib Treatment in Advanced Ovarian Cancer Patients (DUO-O) – NCT03737643
Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy. (SOLO-1) – NCT01844986
Platine, Avastin and OLAparib in 1st Line (PAOLA-1) – NCT02477644
A Phase I/II Study of MEDI4736 in Combination With Olaparib in Patients With Advanced Solid Tumors. (MEDIOLA) – NCT02734004

Highlights of prescribing information
Durvalumab (Imfinzi®; AstraZenea)[Prescribing Information]
Olaparib (Lynparza®; AstraZeneca)[Prescribing Information]

[1] Harter P, Trillsch F, Okamoto A, Reuss A, Kim JW, Rubio-Pérez MJ, Vardar MA. et al. Durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev), followed by maintenance durvalumab, bev, and olaparib in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumor BRCA1/2 mutation (non-tBRCAm): Results from the randomized, placebo (pbo)-controlled phase III DUO-O trial. J Clin Oncol 41, 2023 (suppl 17; abstr LBA5506) DOI 10.1200/JCO.2023.41.17_suppl.LBA5506
[2] World Cancer Research Fund International. Ovarian Cancer Statistics. Online. Last accessed on June 3, 2023.
[3] Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018 Jul;68(4):284-296. doi: 10.3322/caac.21456. Epub 2018 May 29. PMID: 29809280; PMCID: PMC6621554.
[4] National Cancer Institute. Cancer Stat Facts: Ovarian Cancer. Available at Online. Last accessed on June 3, 2023.
[5] Pothuri B. BRCA1- and BRCA2-related mutations: therapeutic implications in ovarian cancer. Ann Oncol. 2013 Nov;24 Suppl 8:viii22-viii27. doi: 10.1093/annonc/mdt307. PMID: 24131965.
[6] Moschetta M, George A, Kaye SB, Banerjee S. BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer. Ann Oncol. 2016 Aug;27(8):1449-55. doi: 10.1093/annonc/mdw142. Epub 2016 Mar 31. PMID: 27037296.
[7] da Cunha Colombo Bonadio RR, Fogace RN, Miranda VC, Diz MDPE. Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics (Sao Paulo). 2018 Aug 20;73(suppl 1):e450s. doi: 10.6061/clinics/2018/e450s. PMID: 30133561; PMCID: PMC6096977.
[8] Raja FA, Chopra N, Ledermann JA. Optimal first-line treatment in ovarian cancer. Ann Oncol. 2012 Sep;23 Suppl 10:x118-27. doi: 10.1093/annonc/mds315. PMID: 22987945.
[9] NHS Choices, Ovarian Cancer Available at Online. Last accessed on June 3, 2023.
[10] Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C; ESMO Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi24-32. doi: 10.1093/annonc/mdt333. Erratum in: Ann Oncol. 2018 Oct 1;29(Suppl 4):iv259. PMID: 24078660.
[11] DiSilvestro P, Banerjee S, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Oza A, González-Martín A, Aghajanian C, Bradley W, Mathews C, Liu J, McNamara J, Lowe ES, Ah-See ML, Moore KN; SOLO1 Investigators. Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial. J Clin Oncol. 2023 Jan 20;41(3):609-617. doi: 10.1200/JCO.22.01549. Epub 2022 Sep 9. PMID: 36082969; PMCID: PMC9870219.
[12] Ray-Coquard IL, Leary A, Pignata S, Cropet C, Gonzalez Martin AJ, Bogner G, Yoshida H,  Vergote IB, et al. LBA29 – Final overall survival (OS) results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC). Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
[13] Banerjee1 S, Imbimbo M, Roxburgh P, Kim J, Kim MH, Plummer R, Stemmer S, You B, et al.529MO – Phase II study of olaparib plus durvalumab with or without bevacizumab (MEDIOLA): Final analysis of overall survival in patients with non-germline BRCA-mutated platinum-sensitive relapsed ovarian cancer. Annals of Oncology (2022) 33 (suppl_7): S235-S282. 10.1016/annonc/annonc1054.

Featured image: General views of the Annual Meeting of the American Association of Clinical Oncology (ASCO) – held in the McCormick Place in Chicago, Ill. Courtesy: © 2019 – 2023 ASCO/Max Gersh. Used with permission.

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