General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.
General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

Detailed results from the Phase III PAOLA-1 trial* (NCT02477644) confirms that olaparib (Lynparza®; AstraZeneca and Merck/MSD), a poly (ADP-ribose) polymerase (PARP) inhibitor, added to bevacizumab (Avastin®; Genentech/Roche) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in women with newly-diagnosed advanced ovarian cancer who had a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab.[1]

Ovarian cancer the eighth most common cause of death from cancer in women worldwide, with a five-year survival rate of approximately 19%. Globally, in 2018, there were nearly 300,000 new cases diagnosed and around 185,000 deaths. According to the American Cancer Society, a woman’s risk of getting ovarian cancer during her lifetime is about 1 in 78, while her lifetime chance of dying from ovarian cancer is about 1 in 108. These statistics, however, don’t count low malignant potential ovarian tumors.[2]

Compared to standard of care
The PAOLA-1 trial is te first phase III trial that compared olaparib when added to standard-of-care (SoC) bevacizumab vs. bevacizumab alone in women in the first-line maintenance setting, irrespective of their genetic biomarker status or outcome from previous surgery.

This international, academic-led trial enrolled 806 patients with stage III/IV ovarian cancer and partial or complete response to standard platinum-based chemotherapy and bevacizumab.

Investigator-assessed results showed olaparib added to bevacizumab reduced the risk of disease progression or death by 41% and improved PFS to a median of 22.1 months versus 16.6 months for those treated with bevacizumab alone (HR 0.59 [95% CI, 0.49-0.72], p<0.0001).

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After completing first-line chemotherapy, patients were randomly allocated 2:1 to olaparib or placebo, both on top of bevacizumab. They received olaparib for up to 24 months and bevacizumab for 15 months in total. The primary outcome was investigator-assessed progression free survival.

José Baselga, MD, Ph.D, MD, Ph.D, the former Physician-in-Chief at the Memorial Sloan Kettering Cancer Center and current executive vice president, Oncology R&D, at AstraZeneca.

The sensitivity analysis of blinded independent central review (BICR) of PFS was consistent, showing a similar improvement with a median of 26.1 months for olaparib added to bevacizumab versus 18.3 months for bevacizumab alone (HR 0.63 [95% CI, 0.51-0.77], p<0.0001).

The safety and tolerability profile of olaparib and bevacizumab were consistent with those known from previous trials for each medicine.

The results were presented at during the Presidential Symposium of the 2019 European Society of Medical Oncology (ESMO) congress being held in Barcelona, Spain (Abstract #LBA2_PR).[1]

“This trial was designed to reflect everyday clinical practice and used a global standard-of-care treatment with [olaparib]. We are working with regulatory authorities to bring [olaparib] to these patients as quickly as possible,” noted José Baselga, MD, Ph.D, the former Physician-in-Chief at the Memorial Sloan Kettering Cancer Center and current executive vice president, Oncology R&D, at AstraZeneca.

“PAOLA-1 is the second positive Phase III trial involving [olaparib] in the first-line maintenance setting for advanced ovarian cancer. Following the positive SOLO-1 trial, we are encouraged by the PAOLA-1 results which reaffirm AstraZeneca and Merck’s ongoing commitment to explore potential treatment options for more women with ovarian cancer,” Roy Baynes, MD, Ph.D, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories.

Prof Isabelle Ray-Coquard, Centre Leon Bérard, Université Claude Bernard, Lyon, and president of the GINECO group France.

“The goal of first-line, including maintenance treatment for women with newly-diagnosed advanced ovarian cancer, is to delay relapse. Unfortunately, the risk of relapse is high, as two out of three women relapse within three years of initial diagnosis,” explained study author Isabelle Ray Coquard, MD, Ph.D, who is the principal investigator of the PAOLA-1 trial and medical oncologist, Department of Medical Oncology at the Clinical Science Institute of the Léon Bérard Centre and President of the GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein) group.

“This study reports the greatest hazard ratio (0.59) and longest progression free survival we have ever seen,” Ray-Coquard said.

“Patient selection was not restricted by surgical outcome or BRCA mutation status, so participants represent the general population of women with advanced ovarian cancer. Previous studies of relapse have suggested benefits from combining anti-angiogenic agents and PARP inhibitors  and today’s results appear to support this. In addition, olaparib did not increase side-effects compared to placebo.” [3][4]

“In PAOLA-1, the results of [olaparib] added to bevacizumab were significant and have the potential to change clinical practice in how women with advanced ovarian cancer are treated in the first-line maintenance setting,” Ray-Coquard noted.

Ray-Coquard also noted that randomization in PAOLA-1 started a median six weeks after the last cycle of chemotherapy, whereas most previous trials started randomisation with the first cycle of chemotherapy.

“It is an important point to consider when comparing the results to other data,” she concluded.

Commenting on the relevance of the published data, Ana Oaknin, MD, head of the Gynecological Tumor Unit at Vall dHebrón Institute of Oncology (VHIO), Barcelona, Spain, said: “The main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low. The combination of bevacizumab and olaparib as maintenance therapy should become a new standard of care for patients with advanced ovarian cancer. The PAOLA-1 trial did not include patients with no response to first-line chemotherapy, but this is a small group”

“This trial is a significant step forward in treatment for these women,” Oaknin concluded.

Exploraty Sub-group Analyses
The trial also included exploratory sub-group analyses including BRCA-mutated (BRCAm) and broader homologous recombination deficiency (HRD) populations, including patients with BRCA mutations,  one of many homologous recombination repair deficiencies which are found in up to half of newly diagnosed advanced ovarian cancer patients.

Homologous recombination deficiencies or HRDs cause genomic instability which can be detected using assays such as the Myriad My Choice HRD test.

In the BRCAm-positive sub-group, [olaparib] added to bevacizumab vs. bevacizumab alone resulted in median PFS of 37.2 months versus 21.7 months (HR 0.31 [95% CI, 0.20-0.47]) and 18.9 months versus 16 months in the non-BRCAm sub-group (HR 0.71 [95% CI, 0.58-0.88]). For the HRD-positive sub-group, median PFS for olaparib added to bevacizumab was 37.2 months versus 17.7 months with bevacizumab alone (HR 0.33 [95% CI, 0.25-0.45]). In the HRD-positive, non-BRCAm sub-group, there was a median PFS of 28.1 months with olaparib added to bevacizumab versus 16.6 months on bevacizumab alone (HR 0.43 [95% CI, 0.28-0.66]).

The HRD-negative/unknown sub-group results showed a median PFS of 16.9 months for olaparib added to bevacizumab vs. 16 months for bevacizumab alone (HR 0.92 [95% CI, 0.72-1.17]).

Current regulatory status
Olaparib, which is being jointly developed and commercialized by Merck and AstraZeneca, is currently approved in 64 countries, including those in the European Union, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. The drug is approved in the United States as first-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 38 countries, including the United Stated, countries in the EU, and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the European Union this includes locally advanced breast cancer. Olaparib has been used to treat over 25,000 patients worldwide.

Clinical trial
Platine, Avastin and OLAparib in 1st Line (PAOLA-1) – NCT02477644

[1] LBA2_PR ‘Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (prs) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev‘ will be presented by Isabelle L. Ray-Coquard during the Presidential Symposium I on Saturday, 28 September, 16:30 to 18:20 (CEST) in the Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019
[2] Key Statistics for Ovarian Cancer. American Cancer Society. Online. Last accessed September 27, 2019.
[3] Mirza MR, Åvall Lundqvist E, Birrer MJ, et al. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. Lancet Oncol. 2019. pii: S1470-2045(19)30515-7. doi: 10.1016/S1470-2045(19)30515-7.
[4] Liu JF, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Ann Oncol. 2019;30:551–557. doi: 10.1093/annonc/mdz018.

* The PAOLA-1 study is a double-blind Phase 3 clinical trial designed to evaluate the efficacy and safety of olaparib added to standard of care bevacizumab vs. bevacizumab alone, as a first-line maintenance treatment for newly-diagnosed advanced FIGO Stage III-IV high grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab. The intent-to-treat* population refers to all patients randomized in the trial.
The trial is an initiative of ENGOT (European Network of Gynaecological Oncological Trial groups) trial, sponsored by ARCAGY Research (Association de Recherche sur les CAncers dont GYnécologiques) on behalf of GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein). ARCAGY-GINECO is an academic group specialising in clinical and translational research in patients’ cancers and a member of the GCIG (Gynecologic Cancer InterGroup).

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