Two Years of Olaparib Delivers Sustained Remissions in BRCA+ Ovarian Cancer

Susana Banerjee, MBBS, MA, PhD, FRCP

Two years of frontline maintenance therapy with olaparib (Lynparza) continued to deliver sustained remissions in women with newly diagnosed BRCA-mutant advanced ovarian cancer who achieved a complete or partial response to first-line platinum-based chemotherapy, according to 5-year follow-up data from the phase 3 SOLO-1 trial, explained lead study author, Susana Banerjee, MBBS, MA, PhD, FRCP.

The median progression-free survival (PFS) was 56.0 months with olaparib (n = 260) versus 13.8 months with placebo (n = 131; HR, 0.33; 95% CI, 0.25-0.43). The 5-year PFS rates were 48.3% and 20.5%, respectively. Moreover, the median treatment duration was 24.6 months with olaparib versus 13.9 months with placebo, suggesting that the adverse effect profile of olaparib was not prohibitive for patient adherence. 

“The 5-year follow-up results from SOLO-1 provide further support for the use of maintenance olaparib as a standard first-line treatment for women with newly diagnosed BRCA-mutant ovarian cancer,” said Banerjee.

In an interview with OncLive, Banerjee, consultant medical oncologist, clinical research lead, Gynaecology Unit, The Royal Marsden NHS Foundation Trust, discussed the significance of the landmark SOLO-1 analysis and outlined the next steps for research with regard to PARP inhibition in ovarian cancer. 

OncLive: What is it about the mechanism of action of PARP inhibitors that promote efficacy in patients with cancer? 

Banerjee: Olaparib belongs to a class of drugs called PARP inhibitors. There are a number of PARP inhibitors, which are licensed. PARP inhibitors interfere with the DNA damage response in tumor cells, particularly those that harbor a deficiency in a particular type of DNA repair called homologous recombination, which includes mutations in BRCA1/2. The enzyme PARP is blocked by PARP inhibitors. Other mechanisms exist with PARP inhibitors as well. For example, inhibition of PARP with olaparib can lead to the trapping of PARP, bound to DNA single-strand breaks preventing repair and leading to the degeneration of DNA double-strand breaks, ultimately triggering cancer cell death. 

What was so groundbreaking about the initial readout of the SOLO-1 trial? 

The SOLO-1 trial was the first trial to report the efficacy of a maintenance PARP inhibitor in newly diagnosed advanced ovarian cancer. A majority of women diagnosed with ovarian cancer continue to be diagnosed at advanced stages. Less than half of patients with newly diagnosed advanced ovarian cancer survive for 5 years, and the risk of relapse remains high. Despite treatment improvements, recurrent ovarian cancer for the majority of patients is incurable.

PARP inhibitors have changed the treatment landscape of ovarian cancer in the recurrent setting. PARP inhibitors have significantly delayed the time until progression and recurrence and the time to next treatment. Bringing PARP inhibitor treatment into the first-line setting has the potential for greater benefit, in terms of accessing these treatments earlier and having longer [PFS]. 

The aim of first-line treatments include delaying disease recurrence or progression, but also increasing survival. The frontline treatment space in this setting presents the opportunity to increase the chances of cure. SOLO-1 is a randomized phase 3 trial, which recruited patients with newly diagnosed high-grade serous or endometrioid ovarian cancer. Patients also had a germline or somatic BRCA1/2 mutation and a clinical response following first-line treatment, so surgery and platinum-based chemotherapy. Patients were randomized in a 2:1 fashion to receive maintenance olaparib tablets or placebo. Of note, women with no evidence of disease stopped receiving the study treatment after 2 years. 

In the primary analysis, which was presented at the 2018 ESMO Congress presidential session and published in the New England Journal of Medicine, maintenance olaparib was shown to significantly reduce the risk of disease progression by 70% compared with placebo, with a hazard ratio of 0.3. The median PFS in the placebo arm was 13.8 months, but at the time had not been reached in the olaparib arm.  

Could you expand on the 5-year results that were presented at the 2020 ESMO Virtual Congress?

The updated analysis after 5 years of follow-up shows that the benefits of maintenance olaparib continues substantially beyond the end of treatment. The hazard ratio for [PFS] remains significant at 0.33, indicating a 67% reduction in disease progression or death for women in the olaparib arm. Almost half of patients in the olaparib arm remained progression free 5 years after randomization. The median [PFS] in the olaparib arm was 56 months compared with 13.8 months in the placebo arm, so an additional 3.5 years longer. More than double the number of patients were progression free after 5 years when treated with olaparib versus placebo, so 20.5% versus 48.3%. These are very exciting, encouraging results that will help us explain the potential benefits of maintenance olaparib in patients with BRCA mutations in our clinic.

Did anything surprise you about the safety profile with longer follow-up? 

The safety profile with olaparib remains consistent with what we’ve seen previously. It’s good to see what happens with longer-term follow-up. Of note, there were no new cases of myelodysplastic syndromes or acute myeloid leukemia with longer follow-up.

Where should future research efforts be focused on?

We’ve come a long way, but there’s a long way to go. Research efforts need to be [conducted] throughout the patient journey from better diagnosis to first-line treatment modalities [with] surgery and chemotherapy, targeted therapies, and maintenance strategies to treatments in the recurrent setting. A lot of work still needs to be done, in particular [with regard to] patient selection so that we can get the maximum benefits and minimize side effects.

In terms of PARP inhibitors, it is important to [expand their benefit] beyond patients with BRCA mutations. It’s also important to understand how best to treat women who have been treated with a PARP inhibitor because many more women are being treated PARP inhibitors globally at different settings. Basically, we are looking at PARP inhibitor resistance.

Did you encounter any challenges with this research?

In this particular study, recruitment went very well, which shows the benefits of good clinical trials that are conducted in this fashion. 

In terms of the challenges we’re facing today in the era of the novel coronavirus disease 2019, it’s the potential effect on clinical trials. In the initial surge, across cancer centers, globally, clinical trials were affected. But fortunately, we’re in a situation where clinical trials are reopening to recruitment. It’s really important to continue clinical trials and research, so that we can improve the standard of care for women with advanced ovarian cancer and all malignancies. Without clinical trials like SOLO-1, we wouldn’t have been able to change the standard of care, and it’s thanks to patients who have enrolled on these studies and participating cancer centers. 

Reference

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year follow-up (f/u) from SOLO1. Ann Oncol. 2020;31(supp 4):S613. doi:10.1016/j.annonc.2020.08.950