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Olaparib maintenance increases PFS in HRD-positive advanced ovarian cancer regardless of BRCA status

Prof. Isabelle Ray-Coquard
Centre Leon Bérard, Université Claude Bernard, Lyon
France
26 Nov 2019

Ovarian cancer is the most lethal gynaecological tumour. Results of the PAOLA-1/ENGOT-ov25 trial, presented recently at the European Society for Medical Oncology (ESMO) Congress 2019, showed that the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib improves progression-free survival (PFS) in advanced ovarian cancer patients with homologous recombination repair deficiency (HRD) with or without BRCA mutations.

PAOLA-1/ENGOT-ov25 trial

The majority of ovarian cancer patients are diagnosed at an advanced stage. Despite good response to first-line treatment, most patients usually relapse <2 years after diagnosis. 

The current standard of care (SoC) for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone. [Ray-Coquard I, et al, ESMO 2019, abstract LBA2_PR]

“Olaparib showed an unprecedented PFS benefit as first-line maintenance monotherapy for patients with a BRCA mutation. However, HRD is not limited to BRCA genes and is present in approximately 50 percent of high-grade serous ovarian tumours,” said PAOLA-1/ENGOT-ov25 study author Professor Isabelle Ray-Coquard of Centre Leon Bérard, Université Claude Bernard, Lyon, France. [N Engl J Med 2018;379:2495-2505; Nature 2011;474:609-615]

“In platinum-sensitive relapse, PARP inhibitor activity was observed in patients with or without BRCA mutations,” noted Ray-Coquard. [Lancet Oncol

2014;15:852-861; Br J Cancer 2018;119:1075-1785] “This activity increased when PARP inhibitor was used in combination with an antiangiogenic agent.” [J Clin Oncol 2019;37(Suppl):abstract 5505; Ann Oncol 2019;30:551-557]

PAOLA-1/ENGOT-ov25 is the first phase III trial to examine the efficacy and safety of a PARP inhibitor plus bevacizumab as first-line maintenance therapy in patients with advanced ovarian cancer regardless of BRCA mutation status. 

This international, academic-led trial enrolled 806 patients with stage III/IV ovarian cancer with partial or complete response to standard platinum-based chemotherapy and bevacizumab. After completing first-line chemotherapy, patients were randomized 2:1 to receive olaparib (n=537; median age, 61 years) or placebo (n=269; median age, 60 years), both in addition to bevacizumab. They received olaparib for up to 24 months and bevacizumab for 15 months in total. 

The primary outcome was investigator-assessed PFS. Secondary endpoints were time to first subsequent treatment (TFST), time to second subsequent treatment (TSST), PFS2 (time from randomization to disease progression on subsequent-line treatment or death from any cause), overall survival (OS), safety and tolerability, and health-related quality of life (HRQoL).

Efficacy outcomes

In the intent-to-treat (ITT) population, first-line maintenance therapy with olaparib plus bevacizumab produced a 5.5-month improvement in PFS vs bevacizumab alone (median, 22.1 months vs 16.6 months; hazard ratio [HR], 0.59; 95 percent confidence interval [CI], 0.49 to 0.72; p<0.0001), after a median follow-up of 24 months in the olaparib arm and 22.7 months in the placebo arm.  

Median time from first cycle of chemotherapy to randomization was 7 months. “Therefore, patients who received olaparib plus bevacizumab were relapse-free for almost 30 months,” remarked Ray-Coquard.

At baseline, half of the patients had undergone debulking surgery, 60 percent of whom had no residual disease. Approximately 40 percent had interval cytoreductive surgery, 70 percent of whom had no residual disease.

Approximately half of the patients were HRD-positive, 29 percent had a BRCA mutation, and 19 percent were HRD-positive and BRCA wild-type (wt). 

“Patient selection was not restricted by surgical outcome or BRCA mutation status. Therefore, participants represent the general population of women with advanced ovarian cancer,” commented Ray-Coquard. 

“Olaparib’s PFS benefit was observed in all clinical subgroups,” she noted. In prespecified subgroup analyses, the benefit was even more pronounced in patients with HRD and a BRCA mutation, with median PFS reaching 37.2 months in both olaparib-treated subgroups vs 21.7 months (HR, 0.31; 95 percent CI, 0.20 to 0.47) and 17.7 months (HR, 0.33; 95 percent CI, 0.25 to 0.45) in respective placebo subgroups. 

“Interestingly, PFS was extended by 11.5 months in HRD-positive BRCA wt patients treated with olaparib plus bevacizumab vs bevacizumab alone [median, 28.1 months vs 16.6 months; HR, 0.43; 95 percent CI, 0.28 to 0.66].” said Ray-Coquard. (Figure)

352en2

“These results in HRD-positive patients without a BRCA mutation identify, for the first time, a new patient population with a significant clinical benefit from olaparib when added to bevacizumab,” stated Ray-Coquard.

Longer PFS after first-line therapy increases the probability of response to a new line of chemotherapy. “While PFS2 data are still immature, at 39 percent maturity, we saw a HR of 0.86 [95 percent CI, 0.69 to 1.09] in favour of olaparib,” she said.

Safety outcomes

“Adverse events [AEs] in the combination arm were similar to those observed with olaparib monotherapy in previous clinical trials,” said Ray-Coquard. “Compared with placebo, the addition of olaparib to bevacizumab produced a higher incidence of fatigue/asthenia, nausea and anaemia.”

Grade ≥3 AEs were reported by 57 percent of patients in the olaparib arm vs 51 percent of those in the placebo arm, the most common being hypertension (19 percent vs 30 percent) and anaemia (17 percent vs <1 percent). 

“There was no increase in the incidence of bevacizumab-related AEs, in particular, low- or high-grade hypertension,” noted Ray-Coquard.

Dose interruptions, reductions and discontinuations were more common in the olaparib vs placebo arm (54 percent vs 24 percent, 41 percent vs 7 percent and 20 vs 6 percent).

“AEs of special interest for olaparib, such as myelodysplasia, leukaemia and new primary malignancies, were similar to those observed in previous trials of olaparib,” said Ray-Coquard. 

“Health-related quality of life [HRQoL], assessed using global health status/QoL questionnaire, was maintained in both arms without any difference,” she added.  

Conclusion

“The POALA-1/ENGOT-ov25 population is representative of the majority of patients with advanced ovarian cancer,” said Ray-Coquard. “The trial met its primary endpoint and demonstrated a significant improvement in PFS with olaparib vs placebo, both added to first-line SoC bevacizumab maintenance treatment.”

“The results also revealed a new population of HRD-positive patients, outside of BRCA mutations, who experienced substantial benefit from maintenance therapy with olaparib and bevacizumab,” she added.

“The safety profile of olaparib plus bevacizumab was generally consistent with previous trials of each drug as monotherapy. The addition of olaparib did not impact bevacizumab’s tolerability and patients’ HRQoL,” she noted.

“The main goal in ovarian cancer treatment is to avoid relapse after first-line therapy. Otherwise, the probability of cure is quite low,” commented discussant Dr Ana Oaknin of Vall d´Hebron Institute of Oncology, Barcelona, Spain. “The combination of olaparib and bevacizumab as maintenance therapy should become a new SoC for patients with advanced ovarian cancer.”

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