Olaparib prolongs progression-free survival in BRCA germline mutated pancreatic cancer

For the first time, a biomarker-based therapeutic approach in pancreatic cancer has been able to prolong progression-free survival (PFS).

New study garners critical discussion at ASCO 2019

For the first time, a biomarker-based therapeutic approach in pancreatic cancer has been able to prolong progression-free survival (PFS). In the Phase III POLO trial, treatment with PARP inhibitor olaparib (Lynparza), extended PFS in patients with metastatic pancreatic carcinoma and BRCA gene mutations in the germline from 3.8 months under placebo to 7.4 months.

Hedy L. Kindler, Head of Gastroenterological Oncology, University of Chicago, presented the results of the POLO (Pancreas Cancer Olaparib Ongoing) trial at the plenary session on June 2nd at the ASCO (American Society of Clinical Oncology) Annual Meeting 2019 (Source 1), and published them in parallel in the New England Journal of Medicine (Source 2).

Metastatic pancreatic carcinoma responds particularly poorly to treatment. The current therapy standard is treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel, with which a PFS of about 6 months and overall survival (OS) of 8 to 12 months can be achieved. Less than 10% of patients live 5 years after diagnosis. A germline mutation of BRCA1 and/or BRCA2 can be detected in about 4 to 7% of pancreatic carcinoma. In these cases, an improved response to platinum-containing chemotherapy could be seen.

The BRCA genes code for proteins involved in the repair of DNA double-strand breaks. Cells with mutated BRCA genes and defective DNA repair mechanisms are sensitive to inhibitors of the poly adenosine-diphosphate-ribose polymerase (PARP), thereby preventing the repair of DNA damage in the cells caused, for example, by chemotherapy. PARP inhibitors are primarily used in post-chemotherapy maintenance therapy to slow disease progression without further compromising the quality of life.

Positive effects with Olaparib

The PARP inhibitor olaparib achieved a median PFS of 4.6 months and a response rate of 21.7% in a Phase II study in 23 patients with BRCA germline mutations and severely pretreated pancreatic cancer (source 3). Therefore, Kindler and her colleagues now investigated the efficacy of maintenance therapy with olaparib in patients with BRCA germline mutations and metastatic pancreatic carcinoma in the multicenter randomized double-blind phase III trial POLO, which had not progressed in at least 16 weeks of platinum-containing first-line therapy. Of 3,315 screened patients, 247 (7.5%) exhibited a BRCA germline mutation, of which 154 were included in the study.

In 119 centers in 12 countries, patients received 3:2 randomized maintenance therapy with oral olaparib (300 mg twice daily) (n = 92) or placebo (n = 62). Treatment was initiated 4 to 8 weeks after the last dose of first-line chemotherapy and continued until radiological progression or unacceptable side effects occurred. The primary endpoint of the study was PFS, secondary endpoints included time to second progression (PFS2),  overall response rate (ORR), quality of life, safety and tolerability, and overall survival (OS).

Olaparib extends PFS

The primary endpoint PFS was analyzed after disease progression or death in 104 of the 154 patients. No progression had occurred in 30 Olaparib and 12 placebo patients. The median PFS was significantly longer in the olaparib group (7.4 months) than in the placebo group (6.2 months) (hazard ratio 0.53, p = 0.0038). Six months after randomization, the Olaparib treatment doubled the proportion of patients without disease progression at 6, 12, 18 and 24 months. The effects were detectable in all predefined subgroups.

An interim analysis of the OS (46% data maturity) showed a median OS of 18.9 months for olaparib and 18.1 months for placebo. The final OS analysis is planned after 106 deaths with a data maturity of 69%.

The interim analysis of PFS2 (data maturity 46 %) showed a median value of 13.2 months in the olaparib group and 9.2 months in the placebo group with an HR of 0.76 (p = 0.26).

The ORR in the Olaparib group was 23.1%, with two patients achieving a complete response that had persisted until the time of data analysis. The ORR under placebo was 11.5%. The median time to response in the Olaparib group was 5.4 months, the median time of response was 24.9 months. In the placebo group, it took 3.6 months to respond and 3.7 months to respond. The quality of life had not changed in either study arm.

The therapy lasted 6.0 months in the Olaparib group and 3.7 months in the placebo group. Severe adverse effects were observed in 24% of olaparib patients and 15% of placebo patients.

Targeted therapy causes high costs

Wells Messersmith, from the University of Colorado Cancer Center, and discussant of the POLO trial in the plenary session at the ASCO annual meeting, pointed out that no targeted therapy for pancreatic cancer has been successful so far. However, preclinical and early clinical data had indicated that the use of a PARP inhibitor may be useful in patients with BRCA germline mutations. POLO is now the first successful biomarker-based study and the first successful study of maintenance therapy for this disease. He described the doubling of the PFS rate by olaparib after 6 and 12 months as "considerable" for pancreatic carcinoma. Due to the curve, however, he fears the development of resistance, as with many targeted therapies. The side effects are "manageable" compared to cytotoxic chemotherapy.

Critically he saw the still missing data on the OS, he does not believe that the final OS analysis will result in a survival advantage for Olaparib. He also questioned the use of placebo after only 16 weeks of first-line therapy for this aggressive disease. Most oncologists would continue first-line therapy indefinitely. It is also open how patients with somatic BRCA mutations can be treated.

In his opinion, however, based on the POLO results, all patients with advanced pancreatic carcinoma should now be tested by molecular genetics as standard, and this should also be changed accordingly in guidelines. In addition, maintenance therapy with olaparib should now be an option for patients with germline mutations of the BRCA gene.

However, the financial toxicity of the therapy should not be forgotten. Messersmith calculated that one month of treatment with olaparib (300 mg twice daily) in the USA costs 16,830 US dollars. For the POLO trial, this meant that 7.4 months of median progression-free survival required drug costs of 124,540 US dollars.

Sources:
1. Kindler, HL, et al. Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial. 2019 ASCO Annual Meeting, Chicago, 31 May to 4 June 201, Abstract LBA4. https://abstracts.asco.org/239/AbstView_239_249933.html
2. Golan T, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. published online on June 2, 2019. https://www.nejm.org/doi/full/10.1056/NEJMoa1903387
3. Kaufman B, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015,33:244-50. https://ascopubs.org/doi/full/10.1200/JCO.2014.56.2728

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