Shots:

• Dr. Susan talked about the results from the SOLO-1 P-III trial of Lynparza in patients with BRCA mutated (BRCAm) newly diagnosed advanced ovarian cancer presented at ESMO’22
• Dr. Susan also spoke about the overall survival of this 7-year follow-up study.The 7-year follow-up of SOLO-1 showed that olaparib provided a clinically meaningful improvement in OS over placebo in patients with BRCAm newly diagnosed advanced ovarian cancer
• This data provide the longest follow-up for any PARP inhibitor in this setting and support the use of maintenance olaparib to achieve long-term remission and enhance the potential for cure

Smriti: Can we talk about Lynparza (its MOA, ROA, formulations, strength, etc.)?

Susana Banerjee: Olaparib (Lynparza) is a PARP inhibitor. By inhibiting PARP1, an enzyme involved in DNA repair, olaparib leads to the generation of DNA double-strand breaks.

The impact on tumor cells depends on whether the homologous recombination repair (HRR) pathway is functioning. In HRR-proficient cells, these DNA double-strand breaks can be repaired. In HRR-deficient cells, such as those with a BRCA mutation, DNA damage accumulates, and genomic instability is increased, ultimately leading to tumor cell death. 

Oral tablets of olaparib are taken twice a day, with a starting dose of 300mg. 

Smriti: Who is Lynparza prescribed to and how is it used?

Susana Banerjee: I am going to focus on the use in ovarian cancer. Olaparib is approved by the European Medicines Agency (EMA) in 3 indications as maintenance therapy in ovarian cancer.

As indicated on the EMA website, olaparib is approved as maintenance therapy (continuing treatment after initial treatment) of high-grade cancers of the ovaries, fallopian tubes, and the peritoneum in:

1. women whose cancer has come back (relapsed) after previous treatment and in whom platinum-based chemotherapy has shrunk or cleared cancer;
2. women newly diagnosed with advanced cancer with mutations in BRCA1 or  BRCA2 genes who have been treated with platinum-based chemotherapy and in whom this treatment has shrunk or cleared cancer;
3. women with advanced cancer that is homologous recombination deficiency (HRD)-positive where one of the mechanisms to repair damaged DNA does not work, which can be due to a defect in certain genes such as BRCA1 and BRCA2 and in whom platinum-based chemotherapy in combination with  bevacizumab has shrunk or cleared the cancer

Smriti: Can we tell us a little bit about the SOLO-1 trial that led to the Lynparza approval?

Susana Banerjee: The SOLO1 trial is a landmark study of olaparib which has led to a paradigm shift in the treatment of women with advanced ovarian cancer. It is the first trial to report the benefit of a maintenance PARP inhibitor in women with newly diagnosed advanced ovarian cancer and a BRCA mutation.

SOLO-1 is the first, double-blind, randomized, prospective phase III trial evaluating 1st-line olaparib maintenance therapy after platinum-based chemotherapy in newly diagnosed advanced ovarian cancer (FIGO stage III-IV) with a BRCA mutation.

We presented the primary results at ESMO 2018, also published in the New England Journal of Medicine. These results showed that two years of maintenance therapy with olaparib led to a substantial improvement in progression-free survival (PFS) in newly diagnosed patients with advanced ovarian cancer and a BRCA1 or 2 mutations.

This led to a change in clinical practice.

On behalf of my co-authors, I presented the five-year follow-up at ESMO 2020, as published in Lancet Oncology, which showed that the median PFS was 56 months with olaparib compared to 13.8 months in the placebo arm. What is particularly ground-breaking here is that the benefit of olaparib was sustained after stopping olaparib for two years. 

Smriti: The overall survival at 7 years was presented at ESMO’22. Can we talk about the findings?

Susana Banerjee: The SOLO-1 Phase III trial, which assessed olaparib as maintenance therapy in patients with BRCA-mutated advanced ovarian cancer following platinum-based chemotherapy, is the first monotherapy study to demonstrate a clinically meaningful improvement in overall survival (OS) at seven years with PARP inhibitor maintenance therapy in the 1st-line setting.

67% of newly diagnosed BRCA-mutated advanced ovarian cancer patients treated with olaparib were alive after seven years versus 47% of placebo patients (44% of whom had a subsequent PARP inhibitor) and 45% of olaparib patients had not been required to receive a subsequent treatment versus 21% of placebo patients. The median OS was 75.2 months with placebo but was not reached for the olaparib group as over half of them were alive at seven years. 

Furthermore, there was a 45% reduction in the risk of death for patients treated with olaparib versus those given a placebo (HR 0.55 (95% CI 0.40–0.76); P=0.0004*) 

It was also positive to see that after seven years of follow-up, the safety and tolerability profile of maintenance olaparib was consistent with that reported at previous data cutoffs, with no new safety signals identified. This further supports the use of maintenance olaparib with the goal of achieving long-term remission and enhancing the potential for cure in this setting

Smriti: How are these results useful for physicians and patients?

Susana Banerjee: SOLO-1 is currently the longest follow-up study for any PARP inhibitor in newly diagnosed advanced ovarian cancer and the first report of long-term OS data for any PARP inhibitor in this setting. 

As a clinician, I have seen first-hand the impact this has on my patients.

The results show that it is possible to improve OS and suggests that more women may be achieving a cure. It gives physicians and patients confidence in the benefits of olaparib monotherapy and the long-term safety of this treatment. Importantly, it shows that patients with no disease at two years, can stop olaparib treatment and still have the potential to derive OS benefits seven years after diagnosis. 

Smriti: What are the other lines in which Lynparza is being assessed for ovarian cancer patients (mono and combination both)?

Susana Banerjee: Olaparib with bevacizumab as maintenance therapy was assessed in the PAOLA-1 trial, which was also presented at ESMO 2022. These results provided a clinically meaningful improvement in OS in newly diagnosed HRD+ patients with advanced high-grade serous ovarian cancer at a five-year follow-up.

I presented the results of the MEDIOLA trial at ESMO 2022, in which olaparib plus durvalumab and bevacizumab demonstrated encouraging clinical activity in women with non-germline BRCA-mutated platinum-sensitive recurrent ovarian cancer, with a median OS of 31.9 months and a 56-week disease control rate of 38.7%.

Olaparib plus durvalumab and bevacizumab is under investigation as 1st-line maintenance treatment in patients with non-BRCA mutated advanced ovarian cancer in the Phase III DUO-O study.

Olaparib combinations are being assessed in recurrent, platinum-sensitive diseases as maintenance therapy.

Smriti: SOLO-1 talks about BRCA MUT OC patients, Is Lynparza being assessed in other subgroups also of Ovarian cancer?

Susana Banerjee: Olaparib is being assessed in other subgroups than BRCAm ovarian cancer patients. 

In PAOLA-1, patients irrespective of BRCA status were assessed. The results from ESMO 2022 showed olaparib had the most significant impact on HRD+ patients, reducing the risk of death by 38% vs placebo. Olaparib also showed a minimal positive effect across the all-comer population, as the median OS was 56.5 months with olaparib plus bevacizumab versus 51.6 months with bevacizumab monotherapy.

The DUO-O study is evaluating the efficacy and safety of durvalumab in combination with standard of care platinum-based chemotherapy and bevacizumab followed by maintenance durvalumab and bevacizumab or durvalumab, bevacizumab and olaparib in patients with newly diagnosed advanced ovarian cancer. The intention to treat population is all comers, with BRCA testing being performed. The primary outcome measures are PFS in all non-tumor BRCA (tBRCA) and non-tBRCA HRD+ patients. 

Source: My.Dr.com

About the Author: 

Dr. Susan Banerjee is a consultant medical oncologist, research lead gynaecology unit at The Royal Marsden and a co-author of the SOLO-1 study. Dr Banerjee specialises in ovarian cancer and the systemic treatment of endometrial and cervical cancers.Dr Banerjee is an author of over 140 peer-reviewed publications including in the New England Journal of Medicine, Lancet, Lancet Oncology, Journal of Clinical Oncology and Annals of Oncology. She graduated from St John’s College, University of Cambridge, and completed her medical training at Royal Free Medical School.
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