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Maintenance olaparib significantly delays progression of BRCA-mutated pancreatic cancer
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CHICAGO — Maintenance therapy with olaparib significantly improved PFS among patients with metastatic pancreatic cancer who harbor germline BRCA mutations, according to results of the randomized phase 3 POLO trial presented during the plenary session at ASCO Annual Meeting.
Results showed toxicity consistent with the known profile for olaparib (Lynparza; AstraZeneca, Merck), a first-in-class poly(ADP-ribose) polymerase (PARP) inhibitor.
The international, double-blind POLO study served as the first phase 3 trial to validate biomarker-driven treatment for patients with pancreatic cancer.
“The results of this are incredibly exciting,” Michael J. Hall, MD, MS, chairman and associate professor in the department of clinical genetics at Fox Chase Cancer Center, and co-author of the study, told HemOnc Today. “This is a very tough disease, and unfortunately for most patients we have to use multiagent chemotherapy, which can really beat them up. You are trying to extend their life, but you are also ruining their life in a way. What we showed in this study is that a single oral therapy can extend DFS for a small subset of patients. Hopefully that will be expanding as we move forward.”
Previous studies have demonstrated that patients with pancreatic cancer who have germline BRCA1 or BRCA2 mutations — which represents about 4% to 7% of patients with metastatic pancreatic cancer — respond positively to olaparib; however, none of those were phase 3 trials.
Hall and colleagues randomly assigned 154 patients (median age, 57 years) with pancreatic adenocarcinoma and a germline BRCA mutation to 300 mg twice-daily maintenance olaparib (n = 92) or placebo (n = 62). Two-thirds of patients harbored BRCA2 mutations, and the others had BRCA1 mutations.
All patients previously received at least 16 weeks of first-line platinum-based chemotherapy for metastatic disease and did not have progression.
Treatment with olaparib or placebo began 4 to 8 weeks after the last chemotherapy dose. Median treatment duration was 6 months for olaparib and 3.7 months for placebo.
PFS served as the study’s primary endpoint.
Results showed that patients in the olaparib arm demonstrated significantly longer PFS compared with patients in the placebo arm (7.4 months vs. 3.8 months; HR = 0.53; 95% CI, 0.35-0.82).
These results were consistent regardless of response to previous chemotherapy.
At 6 months, the percentage of progression-free patients in the olaparib arm was double that of the placebo arm (53% vs. 23%). This PFS trend continued at 1 year (33.7% vs. 14.5%), 18 months (27.6% vs. 9.6%) and 2 years (22.1% vs. 9.6%).
The interim OS analysis, at 46% maturity, showed an HR of 0.91 (95% CI, 0.56-1.46), with a median OS of 18.9 months in the olaparib group and 18.1 months in the placebo group.
Researchers also evaluated time to second progression, which may be suggestive of durability of treatment benefit beyond progression. Results showed median PFS2 of 13.2 months in the olaparib arm and 9.2 months in the placebo arm (HR = 0.76; 95% CI, 0.46-1.23).
Objective response rate among patients with measurable disease was 23.1% with olaparib and 11.5% with placebo.
Two patients assigned olaparib achieved complete response, which were ongoing at the time of the data cutoff. Median duration of response was 24.9 months with olaparib and 3.7 months with placebo.
Median time to the onset of response was 5.4 months with olaparib and 3.6 months with placebo.
“What’s interesting about olaparib is that the responses took a while,” Hall told HemOnc Today. “We didn’t see the disease immediately start to shrink away, so these types of drugs work much more slowly and surely on these BRCA-deficient tumors.”
Grade 3 or higher adverse events occurred in 40% of patients in the olaparib arm and 23% in the placebo arm. A small percentage of patients in each arm (5.5% olaparib; 1.7% placebo) stopped treatment because of adverse events.
The most common adverse events associated with olaparib included fatigue (60.4%), nausea (45.1%), diarrhea and abdominal pain (28.6% each), and anemia (27.5%).
“Chemotherapy is always going to have a role in treating this ... it’s like throwing a huge roadblock in front of a very aggressive disease,” Hall said. “Understanding that mechanism and the role of the immune system in these kinds of tumors is very important. There is a lot of science and research ahead of us.” – by John DeRosier
Reference:
Kindler HL, et al. Abstract LBA4. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Hall reports research funding and travel accommodations from AstraZeneca, Caris Life Sciences, Foundation Medicine and Myriad Genetics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Davendra P.S. Sohal, MD, MPH
This remarkable study featured several first-of-its-kind approaches to treatment of metastatic pancreatic cancer, including screening for germline alterations in BRCA1 and BRCA2, the use of olaparib based on germline findings, and the testing of maintenance therapy. The combination of these various “firsts” answers several important questions.
This demonstrates, in a prospective, worldwide setting — that germline alterations are not rare. In fact, this focused only on BRCA1 and BRCA2, and found 7.5% of those screened to harbor a germline mutation. Adding all other potentially germline genes can yield even more carriers. This supports the growing evidence of prevalence of germline mutations in pancreatic cancer and for consideration of routine testing.
It also demonstrated the feasibility of such an effort worldwide, as well as the acceptability of a maintenance-therapy concept in this dreaded disease.
Most importantly, it demonstrated the therapeutic utility of a drug targeting a germline alteration in pancreatic cancer. While pembrolizumab (Keytruda, Merck) for microsatellite instability-high tumors and larotrectinib (Vitrakvi; Bayer, Loxo Oncology) for NTRK fusion-harboring tumors have been approved as targeted therapies spanning all cancers, this is the first instance of a precision oncology approach working in pancreatic cancer.
In terms of practice-changing implications, this study now provides an option for patients with metastatic pancreatic cancer harboring a germline BRCA1 and/or BRCA2 alterations. If they are on a platinum-based regimen, typically FOLFIRINOX, and have achieved response or at least stable disease after 4 months of treatment, they have the option of switching to olaparib as maintenance therapy. However, there are two major caveats:
- This was a placebo-controlled trial. We cannot infer that olaparib is better than maintenance chemotherapy. There could be a proportion of patients who would do well on continued chemotherapy, with dose and schedule modifications to minimize toxicities — the usual approach that we follow in clinic. In fact, a 10% response rate and a 23% 6-month PFS rate in the placebo arm points to continued benefit from prior platinum-based therapy.
- While PFS was improved, OS was not. The latter endpoint results are immature, but the OS curves are almost identical, making it highly unlikely that they will diverge meaningfully with more follow-up. This is likely due to second-line therapies — 71% of patients progressing on placebo received platinum-based therapies, and 15% received olaparib. This indicates that resumption of chemotherapy provided meaningful survival benefit, which highlights the earlier point — simply remaining on a platinum is a very valid approach.
Going forward, practicing oncologists should test patients with metastatic pancreatic cancer for germline alterations. If a BRCA1 or BRCA2 mutation is found, and the patient has responding or stable disease on platinum-based chemotherapy, there is now the option of switching to olaparib as maintenance after 4 months of chemotherapy. This decision must be individualized. If disease progresses on olaparib, going back to platinum-containing chemotherapy (or another regimen if neuropathy precludes further platinum use) remains a valid option.
Finally, we do not know if platinum-refractory disease can respond to olaparib — that will probably require further clinical trials.
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