AstraZeneca and MSD's Lynparza (olaparib) demonstrated a long-term progression-free survival (PFS) benefit versus placebo as a 1st-line maintenance treatment in patients with newly diagnosed, advanced BRCA-mutated (BRCAm) ovarian cancer who had a complete or partial response following platinum-based chemotherapy.

Ovarian cancer is the eighth most common cause of cancer death in women worldwide and in 2018, there were nearly 300,000 new patients diagnosed and around 185,000 deaths globally.[1] Approximately 22% of patients with ovarian cancer have a BRCA1/2 mutation.[2]Five-year follow-up data from the SOLO-1 Phase III trial showed Lynparza reduced the risk of disease progression or death by 67% (based on a hazard ratio [HR] of 0.33; 95% confidence interval [CI] 0.25-0.43) and improved PFS to a median of 56.0 months versus 13.8 months for placebo. At five years, 48.3% of patients treated with Lynparza remained free from disease progression versus 20.5% on placebo. The median duration of treatment with Lynparza was 24.6 months versus 13.9 months with placebo.

Susana Banerjee, one of the investigators from the SOLO-1 trial and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Reader at The Institute of Cancer Research, London, said: "For patients with newly-diagnosed BRCA-mutated advanced ovarian cancer, the benefit derived from two years of maintenance treatment with Lynparza continued long after treatment ended. After five years, almost half of women were free of cancer progression. These results represent a significant step forward in the treatment of BRCA-mutated advanced ovarian cancer."

José Baselga, Executive Vice President, Oncology R&D, said: "Once a patient's ovarian cancer recurs, it historically has been incurable. Even at an advanced stage, we have shown that maintenance treatment with Lynparza can help patients achieve sustained remission. Today's results further underline the critical importance of identifying a patient's biomarker status at the time of diagnosis to offer a treatment that may help delay disease progression."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "This is the first trial of a PARP inhibitor to read out a five year follow up and showed Lynparza improved progression-free survival to over four and half years versus 13.8 months with placebo following response to 1st-line platinum-based chemotherapy. This latest data represents a major and significant milestone in a disease which has historically had such a poor prognosis."

Summary of results

Progression Recurrence
-free -free
survival survival*
LynparzaN=260 Placebo LynparzaN=189 Placebo
N=131 N=101
Events, n (%) 118 (45) 100 (76) 79 (42) 74 (73)
Median, m 56.0 13.8 NR 15.3
HR (95% CI) 0.33 0.37
(0.25-0.43) (0.27-0.52)
Patients
progression
or recurrence
free at
timepoint, %
(Kaplan-Meier
estimates)
1y 87.7 51.4 91.0 58.0
2y 73.6 34.6 77.2 39.0
3y 60.1 26.9 64.0 28.9
4y 52.3 21.5 55.2 23.0
5y 48.3 20.5 51.9 21.8
*Defined post
hoc as time
from
randomization
to disease
recurrence*
or death
for patients
in complete
response† to
platinum
-based
chemotherapy
at baseline;
patients had
CR at
baseline
based on
electronic
case report
form data.
CI,
confidence
interval; HR,
hazard ratio;
NR, not
reached

The safety profile of Lynparza was consistent with previous observations. The most common adverse events (AEs) ≥20% were nausea (77%), fatigue/asthenia (63%), vomiting (40%), anaemia (39%) and diarrhoea (34%). The most common ≥ grade 3 AEs were anaemia (22%) and neutropenia (9%). 12% of patients on Lynparza discontinued treatment due to an AE.

The results were presented on Friday 18 September during the 2020 European Society of Medical Oncology virtual congress.

The SOLO-1 Phase III trial met the primary endpoint of PFS in June 2018 (https://www.astrazeneca.com/media-centre/press-releases/2018/solo-1-phase-III-trial-demonstrates-lynparza-maintenance-therapy-cut-risk-of-disease-progression-or-death-by-70-percent-in-patients-with-newly-diagnosed-advanced-brca-mutated-ovarian-cancer.html), which formed the basis of approvals in the US, the EU, Japan, China, and several other countries.

Ovarian cancer

For newly diagnosed patients with advanced ovarian cancer, the primary aim of first-line treatment is to delay progression of the disease for as long as possible and maintain the patient's quality of life with the intent of achieving complete remission.[3-6]

About SOLO-1

SOLO-1 was a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial to evaluate the efficacy and safety of Lynparza tablets (300mg twice daily) as a maintenance monotherapy compared with placebo in patients with newly-diagnosed BRCAm advanced ovarian cancer following first-line platinum-based chemotherapy. The trial randomised 391 patients with a deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutation who were in clinical complete or partial response following platinum-based chemotherapy.
 

Patients were randomised (2:1) to receive Lynparza or placebo for up to two years or until disease progression. Patients who had a partial response at two years were permitted to stay on therapy at the investigator's discretion. The primary endpoint was PFS and key secondary endpoints included time to second disease progression or death, time to first subsequent treatment and overall survival.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US as a 1st-line maintenance treatment with bevacizumab for patients with homologous recombination deficiency (HRD)-positive advanced ovarian cancer. Lynparza is approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US and several other countries for the treatment of germline BRCA-mutated metastatic pancreatic cancer. Lynparza is approved in the US for HRR gene-mutated metastatic castration-resistant prostate cancer. Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration 

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world's first PARP inhibitor, and Koselugo (selumetinib), a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms - Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates - and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com (http://www.astrazeneca.com/) and follow the Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca).

References

1.The World Health Organization. IARC. Globocan 2018. Available at: http://gco.iarc.fr/ [Accessed September 2020].

2.da Cunha Colombo Bonadio et al. (2018). Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics (Sao Paulo). 2018;73(suppl 1):e450s.

3.Moore, K. (2018). Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. New England Journal of Medicine. 379(26), pp.2495-2505.

4.Raja et al. 2012. Optimal first-line treatment in ovarian cancer. Annals of Oncology. 23 Suppl 10, x118-127.

5.NHS Choices, Ovarian Cancer Available at: https://www.nhs.uk/conditions/ovarian-cancer/treatment/   [Accessed September 2020].

6.Ledermann et al. (2013). Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 24, pp.vi24-vi32.