by Dr. C.H. Weaver M.D. updated 8/2019
Lynparza (olaparib) is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of selected patients with ovarian, fallopian tube, or primary peritoneal cancer. Lynparza was the first PARP inhibitor approved for treating ovarian cancer and can be effectively used as part of initial treatment or in women with recurrent disease. Lynparza's approval is for patients with specific abnormalities in the BRCA gene and is an example of how a greater understanding of the underlying mechanisms of disease can lead to targeted, more personalized cancer treatment with precision cancer medicines.(1)
About Lynparza (olaparib)
The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.
PARP inhibitors are thought to have the greatest effect in women with mutations of the BRCA genes which occur in about 15% of ovarian-cancer patients. But recent research, still ongoing, indicates that the drugs may benefit an additional 35% of patients with different genetic profiles as well.
Genomic analyses for BRCA and other genomic abnormalities can be performed with a companion diagnostic that will detect the presence of mutations in the BRCA genes (gBRCAm) in blood samples from patients with ovarian cancer.(1-4)
The initial studies indicated that approximately 41% of women with advanced BRCA mutated ovarian cancer achieved objective responses. and over 60% of women with "platinum sensitive" disease responded to treatment with Lynparza Furthermore, the objective response rate among women with ovarian cancer, but without BRCA mutations, was 23.9%.(2,4) A series of comparative trials know as SOLO were initiated to confirm the benefits of Lynparza.
SOLO-1 Clinical Trial: Lynparza delays cancer progression and prolongs survival when used as initial treatment in women with a BRCA 1 or 2 mutation
Two-year maintenance therapy with Lynparza significantly delays time to cancer progression and prolongs survival when used as part of the initial treatment strategy for advanced ovarian cancer in women with a BRCA 1 or 2 mutation. The results were presented at the European Society of Medical Oncology 2018 annual meeting, published in the prestigious New England Journal of Medicine, and updated at the June 2019 American Society of Clinical Oncology Meeting.
In the “SOLO-1” clinical trial women with newly diagnosed BRCA positive advanced ovarian cancer who were either in remission or with stable disease after platinum based chemotherapy were treated with either Lynparza 300 mg twice daily or a placebo for 2 years or until their cancer progressed, which ever came first. Patients with no evidence of disease at 2 years stopped treatment, while those with a partial response could continue treatment.
Overall the therapy was well tolerated. Patients treated with Lynparza did not experience a change in health-related quality of life scores while on treatment. Importantly 60% of Lynparza treated patients survived without cancer progression 3 years from the initiation of treatment compared to only 27% of those treated without the maintenance therapy. A more specific update was provided at ASCO 2019. (3,4)
- 53% of women with BRCA1-mutated cancer treated with Lynparza survived without cancer progression 3 years compared to 26% receiving placebo.
- 80% of women with BRCA2-mutated cancer survived without caner progression compared to 29% treated with placebo.
The study authors believe that Lynparza maintenance when used as part of initial may actually lead to the cure of additional patients improving the overall outlook for ovarian cancer treatment. It also shifts how physicians must think about ovarian cancer treatment; genetic testing for BRCA will need to be done much earlier as part of the initial treatment evaluation.
What is the best maintenance therapy?
Standard first-line therapy in many countries includes chemotherapy plus Avastin (bevacizumab) maintenance but the question remains whether maintenance with Lynparza alone or in combination with Avastin could be preferable. This question is being addressed by the PAOLA-1 clinical trial.
PAOLA-1 is a randomized phase III clinical trial testing the effectiveness and safety of Lynparza + Avastin compared to Avastin alone, as a 1st-line maintenance treatment for newly-diagnosed advanced stage III-IV high grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to 1st-line treatment with platinum-based chemotherapy and Avastin.
In August 2019 the trial was reported to have met its primary endpoint in the intent-to-treat population with a statistically-significant and clinically-meaningful improvement by increasing the time women taking Lynparza + Avastin survived without disease progression or death compared to those taking Avastin alone. The full trial results, including biomarker sub-group analyses, will be presented at a forthcoming medical meeting. (9)
Strategies to Improve Ovarian Cancer Treatment with Lynparza Combinations
SOLO-2 Clinical Trial: Lynparza™ Demonstrates Survival Benefit in Relapsed Ovarian Cancer
The phase III SOLO-2 clinical trial was designed to determine the effectiveness of Lynparza oral therapy for the maintenance treatment of platinum-sensitive relapsed, BRCA-mutated ovarian cancer. SOLO-2 demonstrated a clinically-meaningful improvement in survival free of cancer progression.(7)
Importantly, the median time to cancer progression for Lynparza–treated patients substantially exceeded that observed in a previous study in patients with platinum-sensitive relapsed ovarian cancer.(y)
SOLO-3 Clinical Trial: Lynparza superior to chemotherapy for treatment of BRCA-mutated relapsed ovarian cancer
In the SOLO-3 clinical trial 200 women with BRCA-mutated, platinum-sensitive relapsed ovarian cancer were treated with Lynparza (n = 178) or the physician’s choice of chemotherapy (n = 88) until evidence of cancer progression. Physician choice included paclitaxel (n = 20), topotecan (n = 8), gemcitabine (n = 13) or pegylated liposomal doxorubicin (n = 47).(5,6)
Overall Lynparza treatment was well tolerated and 72% of Lynparza treated patients responded to treatment compared to 51% of those receiving chemotherapy. The time until cancer progression was 13.4 months with Lynparza compared to 9.2 months with chemotherapy.
To assess the safety and efficacy of Lynparza in ovarian cancer, researchers initially conducted a phase II clinical trial of 265 women with relapsed, platinum-sensitive, serous ovarian cancer. After treatment with chemotherapy, women were assigned to further treatment (maintenance therapy) with either Lynparza or a placebo.
- Women in the Lynparza group remained free of cancer progression longer than women in the placebo group: median progression-free survival was 8.4 months in the Lynparza group and 4.8 months in the placebo group.
Common side effects of Lynparza included nausea, fatigue, vomiting, diarrhea, distorted taste (dysgeusia), indigestion (dyspepsia), headache, decreased appetite, common cold-like symptoms (nasopharyngitis), cough, joint paint (arthralgia), musculoskeletal pain, muscle pain (myalgia), back pain, rash (dermatitis) and abdominal pain. Serious side effects included the development of myelodysplastic syndrome, a condition where the bone marrow is unable to produce enough functioning blood cells; acute myeloid leukemia, a bone marrow cancer; and lung inflammation.
- National Institutes of Health. Olaparib Treatment in BRCA Mutated Ovarian Cancer Patients After Complete or Partial Response to Platinum Chemotherapy. Available at: http://clinicaltrials.gov/show/NCT01874353. Last accessed October 2016.
- Gelmon KA, Hirte HW, Robidoux A, et al. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract 3002.
- FDA Approval Letter. U.S. Food and Drug Administration, Silver Spring, MD. Available Online. Accessed July, 2016.
- Fong PC, Yap TA, Boss DS, et al. Poly (ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer correlating With Platinum-Free Interval. Journal of Clinical Oncology [early online publication]. April 20, 2010.
- Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. New England Journal of Medicine. Early online publication March 27, 2012.
- Penson RT, et al. Abstract 5506. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.