Pant Pushes for De-Escalated Options, Targeted Therapy in Pancreatic Cancer

Shubham Pant, MD

Chemotherapy has been a mainstay in advanced pancreatic cancer, but it can be challenging for patients to tolerate, according to Shubham Pant, MD, who added that de-escalated maintenance approaches could be one way to help patients preserve their quantity and quality of life.

For example, data from the phase II PRODIGE 35-PANOPTIMOX trial showed comparable overall survival (OS) among previously untreated patients with advanced disease who received 6 months of FOLFIRINOX versus 4 months of FOLFIRINOX followed by 5-fluorouracil/leucovorin (LV5FU2). The median OS was 10.1 months in the continuous FOLFIRINOX arm versus 11.0 months in the FOLFIRNOX/LV5FU2 arm.¹

“Maintenance chemotherapy is certainly appropriate for patients who are experiencing toxicity, especially neuropathy with oxaliplatin,” said Pant.

Moreover, in the phase III POLO trial, maintenance therapy with olaparib (Lynparza) demonstrated a significant progression-free survival (PFS) advantage over placebo in patients with germline BRCA-mutated metastatic disease. The median PFS was 7.4 months with olaparib versus 3.8 months with placebo, which translated to a 47% reduction in the risk of progression or death with the PARP inhibitor (HR, 0.53; 95% CI, 0.35-0.82; P =.004).² Additionally, maintenance olaparib prolonged the time to worsening of pain versus placebo, according to health-related quality-of-life findings presented at the 2019 ESMO Congress.³ In December 2019, the FDA approved olaparib for patients with germline BRCA-mutant pancreatic cancer whose disease has not progressed on ≥16 weeks of frontline platinum-based chemotherapy, based on the POLO findings.

Ongoing investigations into other DNA damage repair genes, such as PALB2 and RAD51, could expand the utility of PARP inhibitors even further, added Pant.

“One of the important things we forget is that the patient’s performance status goes down while they're getting treated. They may stop eating, they may lose a lot of lean body muscle mass,” said Pant. “Many newer therapeutics are being developed to improve the performance status of these patients while they're receiving chemotherapy.”

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Gastrointestinal Malignancies, Pant, associate professor in the Department of Investigational Cancer Therapeutics in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed frontline treatment selection in metastatic pancreatic cancer and shed light on some of the latest research being done in the space.

OncLive^®: Could you discuss some of the latest research efforts in metastatic pancreatic cancer?

Pant: A lot of new research is being done in metastatic pancreatic cancer. We have frontline therapies in metastatic disease, some which have been around for some time. These options include modified FOLFIRINOX and the combination of gemcitabine and nab-paclitaxel (Abraxane). I also discussed maintenance chemotherapy. Patients who are treated with chemotherapy develop toxicities, so we need to de-escalate treatment a little bit and put them on maintenance therapy.

[In my presentation], I also shed some light on the DNA damage-repair (DDR) pathway in pancreatic cancer. I mainly discussed how olaparib is used in patients with germline BRCA1/2 mutations.

How do you approach frontline treatment in practice?

We have to [select treatment on an individualized level]. Typically, the 2 frontline regimens are modified FOLIFRINOX or the combination of gemcitabine and nab-paclitaxel. We tend to use modified FOLFIRINOX in more robust patients with a better performance status. We tend to go with gemcitabine/nab-paclitaxel in patients who have a performance status of 2.

Could you highlight some of the clinical trials that have evaluated maintenance chemotherapy?

One of the trials I discussed was the PRODIGE 35-PANOPTIMOX trial, which evaluated de-escalated chemotherapy [followed by LV5FU2]. The investigators showed comparable PFS between [FOLFIRINOX/LV5FU2] and continued modified FOLFIRINOX.

What does treatment in later-line settings look like?

Pancreatic cancer is a debilitating disease. Many times, we cannot give patients second-line therapy, so we really have to pick and choose to see which patients are strong enough [to receive second-line therapy] and whether [the treatment] will improve the quality or quantity of their life. Those are the benchmarks I look at to see if patients can benefit from [additional treatment]. [If the answer is yes], I’ll consider giving them second-line therapy.

Could you discuss some of the exciting data we have seen with PARP inhibitors in the field?

Patients who have germline BRCA1/2 mutations can receive olaparib maintenance therapy after completing 4 months of platinum-based therapy. Patients [who receive these agents] have better PFS versus placebo. [Olaparib was recently approved for use as a maintenance therapy setting in this setting], and I'm excited to offer that option to my patients.

Could we expand the utility of PARP inhibitors to patients with other DDR alterations?

That's a great question. The DDR [pathway] encompasses a number of genes. There are some initial data on PALB2, which is a DDR gene. Other DDR genes might not be so affected by [PARP], but trials are ongoing right now. Clinical trials are evaluating RAD51, which is one of the other DDR genes. ATR inhibitors, which target resistance mechanisms to PARP, could be coming down the pike as monotherapy and in combination with other PARP agents.

Could you shed light on the work being done with immunotherapy?

There's a lot of interest in immunotherapy. This approach has not really worked well in pancreatic cancer, but I believe combination immunotherapy, especially with agents that target the tumor microenvironment and make it less immunosuppressive, is very exciting.

What is the biggest challenge faced in pancreatic cancer?

We’re doing many trials in which we are measuring through Fitbits and other [measures] how patients go through chemotherapy and whether their performance status improves while they're receiving active therapy or some kind of targeted therapy.

What are other targets of interest in pancreatic cancer?

We are also trying to target KRAS [mutations]. A targeted therapy for this target is the holy grail of therapy because 90% of patients have KRAS mutations. We are developing new therapies downstream from KRAS and directly targeting KRAS; this [research] will hopefully impact treatment in the next decade.

References

1. Dahan L, Phelip JM, Malicot KL, et al. FOLFIRINOX until progression, FOLFIRINOX with maintenance treatment, or sequential treatment with gemcitabine and FOLFIRI.3 for first-line treatment of metastatic pancreatic cancer: a randomized phase II trial (PRODIGE 35-PANOPTIMOX). J Clin Oncol. 2018;36(suppl 15; abstr 4000). doi: 10.1200/JCO.2018.36.15_suppl.4000
2. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327. doi: 10.1056/NEJMoa1903387
3. Hammel P, Kindler HL, Reni M, et al. Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib. Ann Oncol. 2019;30(12):1959-1968. doi: 10.1093/annonc/mdz406