Olaparib Expands Options in Metastatic Pancreatic Cancer

A. Craig Lockhart, MD, MHS

The metastatic pancreatic cancer paradigm has expanded to include frontline maintenance therapy with the PARP inhibitor olaparib (Lynparza), as it recently received the green light from the FDA with a December 2019 approval.

"Olaparib gives us an opportunity to have a maintenance therapy that is a little less toxic than standard chemotherapy," said A. Craig Lockhart, MD, MHS. "Anything new that comes along that we can administer to our patients and provide them with potentially better quality of life is an important development." 

The approval, which is specific to adult patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on ≥16 weeks of a first-line platinum-based chemotherapy regimen, was based on results from the phase III POLO trial. Data showed that the median progression-free survival (PFS) was 7.4 months with olaparib versus 3.8 months with placebo for this patient population (HR, 0.53; 95% CI, 0.35-0.81; P = .0035).¹ No disease progression was seen in 22.1% of patients who received olaparib compared with 9.6% with placebo after 2 years.

The approval quickly followed the December 2019 decision by the FDA’s Oncologic Drugs Advisory Committee to vote in favor of olaparib tablets as maintenance therapy for this patient population.²

In an interview during the 2019 OncLive State of the Science Summit on Gastrointestinal Malignancies, Lockhart, a professor and associate director for Regional and Strategic Clinical Research Affiliations, Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed the current treatment landscape of pancreatic cancer and how the introduction of olaparib in the frontline maintenance setting may benefit patients.

OncLive:  What does the current treatment landscape look like for metastatic pancreatic cancer?

Lockhart: Pancreas cancer is very difficult to begin with. Patients can present with a consolidation of symptoms including alterations in their liver function and elevated bilirubin. Many of those factors can dictate the kinds of treatment these patients should receive. Currently, we have 2 frontline strategies: FOLFIRINOX, and gemcitabine with nab-paclitaxel (Abraxane). 

How we choose between the 2 [strategies] tends to be somewhat arbitrary; however, some physicians do have their reasons, including age and performance status. Bilirubin level is a factor to consider because FOLFIRINOX is not generally given to patients with a bilirubin level of >1.5 [mg/dL]. 

Patients with a BRCA1/2  germline [mutation] are supposed to be more responsive to platinum-based agents. Perhaps FOLFIRINOX should be considered in that setting rather than gemcitabine/nab-paclitaxel. 

There are some data suggesting that gemcitabine/nab-paclitaxel may be a better backbone to add another drug onto frontline therapy, but I've done clinical trials where either [FOLFIRINOX or gemcitabine/nab-paclitaxel has served as a backbone]. 

We need to be able to better choose our patients, as far as which regimen to consider. What you choose upfront [influences] what you choose in the second-line setting. Not all patients with pancreatic cancer get onto second-line therapy, but a substantial percentage do. If you pick FOLFIRINOX up front, you may consider gemcitabine/nab-paclitaxel in the second-line setting. If you choose gemcitabine/nab-paclitaxel up front, FOLFIRINOX or another 5-fluorouracil (5-FU)—based regimen, such as nanoliposomal irinotecan, could follow.  

Pancreas tumors often become resistant to therapy, so it is important to think about the road in terms of second-line options. 

What agents are being utilized in the maintenance setting? 

FOLFIRINOX is hard to take for a long period of time. Maintenance options should be considered. There is a maintenance strategy with gemcitabine/nab-paclitaxel that may be useful. 

We have recent data with olaparib (Lynparza) for patients who have BRCA1/2  mutations. Though these patients represent a small percentage of the general population, they should be considered for maintenance therapy with olaparib to reduce the toxicities of long-term chemotherapy. 

What are your thoughts on the recent ODAC vote of olaparib for maintenance of pancreatic cancer?*

I'm not surprised that olaparib was [voted for approval] in that setting. We have so few options for patients with pancreatic cancers. Our 2 best chemotherapy options in the frontline setting have considerable toxicity associated with them. For the majority of patients, those therapies cannot be given for extended periods of time. Even the second-line setting, nanoliposomal irinotecan plus 5-FU is associated with diarrhea. All of our options in pancreatic cancer have a fair amount of toxicity associated with them. Adjustments can be made, but these patients may not be robust from the beginning. 

Could you discuss the importance of the NAPOLI-1 trial?

The NAPOLI-1 data reported out about 3 years ago. We now have longer-term follow-up on the patients from that study. The PFS and overall survival (OS) data are essentially identical to what was presented previously. 

In part of the analysis, investigators were trying to figure out which patients tended to have longer-term benefit from nanoliposomal irinotecan plus 5-FU. Generally, the data were not unexpected. Younger patients, those with fewer liver metastases, and those with better performance status [had better long-term benefit]. This suggests which patients may benefit the most from nanoliposomal irinotecan plus 5-FU. 

*Editor’s Note: This interview took place prior to the December 2019 FDA approval of olaparib for the maintenance treatment of adult patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

References

1. Kindler HL, Hammel P, Reni M, 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. J Clin Oncol. 2019;37(suppl; abstr LBA4). doi: 10.1200/JCO.2019.37.18_suppl.LBA4.
2. NDA 208558/Supplement 10 Lynparza (olaparib) tablets AstraZeneca [ODAC briefing document]. FDA. Published December 17, 2019. https://bit.ly/2syDPsI. Accessed December 17, 2019.