Brigid Stadinski, PhD

Outcomes in pancreatic cancer may be improving for the first time in decades. With pancreatic cancer projected to be the second leading cause of cancer-related deaths in the United States by the year 2030,

this projection brings welcome optimism to the field.

Recommended first-line therapy for patients with advanced pancreatic cancer and good performance status includes chemotherapy with gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) or FOLFIRINOX, a regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin.

Despite intervention, the median life expectancy for patients with metastatic pancreatic cancer is less than 1 year with current treatment.

Resistance to chemotherapy arises in part from the characteristic dense stroma surrounding pancreatic tumors.

It has been proposed that the stroma acts as a barrier to drug delivery by hindering blood vessel perfusion.

The tumor microenvironment (TME) also contributes to oncogenesis through deregulation of key signaling pathways and immunosuppression.

Furthermore, the presence of highly resistant cancer stem cells (CSCs), aberrant gene expression, and mutations facilitate chemoresistance.

Recent research has revealed that germline mutations in cancer predisposition genes are more common than initially thought and occurs in patients with and without a family history of the disease.9,10 In response, the National Comprehensive Cancer Network (NCCN) guidelines for pancreatic cancer were updated to recommend that germline testing be performed for any patient with pancreatic cancer, and that molecular analysis of tumors be considered in patients with metastatic disease.

Eileen M. O&rsquo;Reilly, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), explained to Targeted Therapies in Oncology (TTO) that the new guidelines are &ldquo;to have individuals undergo germline testing [to look] for genes associated with pancreas cancer predisposition and to determine the actionability of those and other genes with regard to treatment application and, similarly, to consider tumor-based or somatic profiling.&rdquo; O&rsquo;Reilly serves on the advisory board of the NCCN pancreas cancer panel and was a co-investigator on the research that informed the change. At MSKCC, she is associate director for clinical research, at the David M. Rubenstein Center for Pancreatic Cancer Research, and the Winthrop Rockefeller Chair of Medical Oncology.

An increased understanding of the key molecular players that impede effective pancreatic cancer treatment has led to novel regimens that target tumor genomic alterations, CSCs, the tumor stroma, and immunosuppression in the TME (

Clinical trials investigating such promising therapies signal a new age of research that may find ways to overcome drug resistance; this would translate to improved outcomes for patients with pancreatic cancer when such therapies are combined with standard chemotherapy.

John L. Marshall, MD, director of Georgetown University&rsquo;s Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, discussing the overall impact of these new therapeutic approaches, noted, &ldquo;We are shifting from a sense of futility in pancreas cancer to one of hope. This hope is coming from an increased recognition that there are cancer targets in pancreatic cancer, that drugs are working, and that we need to keep looking for more." Marshall, who is also chief of the Division of Hematology/Oncology, Medstar Georgetown University Hospital, and professor of medicine and oncology at Georgetown&rsquo;s Lombardi Comprehensive Cancer Center, added, "Broad molecular testing is valuable; it does yield therapeutic guidance and should be done in all patients with metastases. Linked to this, physicians need to keep abreast of the latest results and options so that they can guide their patients.&rdquo;

The BRCA1, BRCA2, and PALB2 proteins are involved in the repair of double-strand DNA breaks by the homologous recombination repair (HRR) pathway,

and loss-of-function mutations in the genes encoding them are linked to increased genomic instability.

PARP proteins are involved in the repair of single-strand DNA breaks. A class of antidrug agents called PARP inhibitors (PARPi) prevent this single-strand break repair, which subsequently leads to the accumulation of double-strand breaks. In HRRdeficient (HRD) cells, such as tumor cells lacking BRCA1/2, these PARPi-induced double-strand breaks can cause cell death in the absence of a repair mechanism, a process termed synthetic lethality.

Nontumor cells, which contain at least 1 normal copy of BRCA1/2, are able to repair the double-strand breaks through their intact HRR pathway and remain unharmed by the PARPi.

&ldquo;There is a critical need for the identification of specific molecular events guiding therapy decisions for patients with PDAC [pancreatic ductal adenocarcinoma],&rdquo; said Tanios Bekaii- Saab, MD, in an interview with TTO. He is medical director of the Cancer Clinical Research Office, and vice chair and section chief of medical oncology, Department of Internal Medicine at the Mayo Clinic in Phoenix, Arizona.

Among all PDAC cases, Bekaii-Saab added, &ldquo;25% have defects in genes mediating the DNA damage response, including close to 2% germline mutations in

; somatic mutations in the same genes; and defects in proteins regulating or participating in homologous recombination repair. As HRD tumors are associated with sensitivity to DNA-damaging agents such as PARPi, platinums, and topoisomerase-1 inhibitors, the successful development of HRD-targeted therapy has the potential to dramatically improve survival for a large subgroup of patients with PDAC.&rdquo;

Studies indicate that patients with loss-of-function mutations may have improved outcomes when treated with platinum-based chemotherapies.

Further, PDAC tumors associated with germline

mutations showed response to the PARPi olaparib (Lynparza) in a phase II study.

This research prompted the phase III POLO (Pancreas cancer OLaparib Ongoing) trial, designed to evaluate the efficacy of olaparib as maintenance therapy in patients with BRCA1/2-positive metastatic PDAC that is sensitive to first-line platinum-based chemotherapy (NCT02184195).13 In this double-blind, placebo-controlled study, patients were randomized to receive maintenance olaparib or placebo. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS) and adverse events (AEs).

Among the 154 patients who were evaluated, PFS was significantly longer in the olaparib group compared with the placebo group (7.4 vs 3.8 months; HR, 0.53; 95% CI, 0.35-0.82;

= .004). No difference in OS was observed between the 2 groups in an interim analysis, and the AE profile of maintenance olaparib was similar to that observed in other cancers.

O&rsquo;Reilly, who coauthored the POLO trial report, indicated that these data should bring about &ldquo;an approval for the first PARPi in pancreas cancer with olaparib.&rdquo; She added that the POLO trial serves as &ldquo;proof of principle that being able to select a subgroup of patients and apply a specific treatment can improve outcomes. It is encouraging that the data support the scientific underpinning of what platinum drugs and PARPi offer in the setting of germline BRCA mutations, and that such treatment can apply to pancreas cancer as it has to ovary, breast, and prostate cancer.&rdquo;

Several phase II clinical trials investigating the efficacy and safety of other PARPis, including veliparib (NCT02890355, NCT01585805) and rucaparib (Rubraca; NCT03140670) are currently underway.

Although veliparib did not show any confirmed response when evaluated as monotherapy in a phase II clinical study for

trials continue to assess its efficacy in combination with chemotherapy. One randomized phase II trial is investigating veliparib in combination with FOLFIRI (folinic acid/5-fluorouracil/irinotecan) chemotherapy.

The primary endpoint is OS, and secondary endpoints include safety, PFS, and response rate. Another randomized phase II trial is evaluating veliparib in combination with gemcitabine and cisplatin, in patients with PDAC who are positive for the

mutations, with a primary endpoint of response rate and secondary endpoints including PFS, OS, and safety.

Phase II trials investigating rucaparib have had promising results. In the RUCAPANC trial (NCT02042378), patients with advanced PDAC and a

mutation received rucaparib until disease progression. Among 19 patients who were treated, the confirmed objective response rate was 11%, and the drug had an acceptable safety profile.

Rucaparib is also being evaluated as maintenance therapy in patients with

mutations and platinum-sensitive, advanced pancreatic cancer.

Interim analysis of this single-arm, phase II trial demonstrated encouraging disease control with minimal toxicity.

Desmoplasia is a classic feature of PDAC, characterized by dense stromal tissue that can comprise up to 80% of the tumor mass.

The stroma is heterogeneous and includes fibroblasts, pancreatic stellate cells, immune cells, blood vessels, and extracellular matrix (ECM).

Hyaluronic acid (HA) is normally found in the ECM, but it is present in higher quantities in several solid tumors. As much as 90% of PDAC tissue has high HA content, and it is associated with poor prognosis, as well as with chemoresistance and tumor proliferation.

Targeting components that promote depletion of the tumor stroma represent potential strategies to improve drug delivery and PDAC treatment. However, the cellular and biochemical interactions between the stroma and tumor cells are highly complex, and studies targeting the stroma have produced surprising discrepancies between preclinical and clinical trials.

Clinical trials investigating HA as a potential target to improve drug delivery have shown conflicting results. Preclinical studies demonstrated that human recombinant PEGylated hyaluronidase (PEGPH20) degrades HA and promotes stromal degradation.

PEGPH20 demonstrated a benefit in patients with HA-high tumors when given in combination with GEM plus nab-paclitaxel in a randomized phase II trial.

The efficacy and safety of PEGPH20 are currently being evaluated in a phase III trial in which patients with HA-high tumors were randomized to receive GEM plus nab-paclitaxel alone or in combination with PEGPH20 (NCT02715804).

In contrast, administration of PEGPH20 with FOLFIRINOX resulted in decreased OS for patients with metastatic PDAC in a phase Ib/II trial that was halted following interim analysis.

&ldquo;PEGPH20 had very mixed results in earlier studies, but a phase III study assessing the role of PEGPH20 in combination with standard chemotherapy in HA-high patients with PDAC is underway. Once complete, this study will provide us with a better understanding about the potential role of PEGPH20 in PDAC,&rdquo; said Bekaii-Saab.

O&rsquo;Reilly added that in this phase III study, &ldquo;selection included individuals who have elevated HA in their tumor, which is more common than the genetic mutations.&rdquo; She went on to say that &ldquo;the data will be important and potentially could define a new approach to treating pancreas cancer.&rdquo;

Reprograming the Immunosuppressive Tumor Microenvironment

Although immunotherapy has shown marked success in treating other malignancies, these advancements have not translated to the treatment of PDAC; it has been associated with disappointing results in early clinical trials.

In PDAC, the TME suppresses the antitumor immunogenic response, rendering agents that inhibit T-cell immune checkpoints, such as antiPD-1, ineffective.8 Current strategies to identify distinct immune targets and reprogram the TME are aimed to harness the potential benefits of immunotherapy.

One promising therapeutic target in the TME is the costimulatory protein CD40.

Preclinical studies demonstrated that in combination with chemotherapy, an agonistic CD40 antibody promoted effector T-cell expansion in the TME of a mouse model of pancreatic cancer.

Additionally, a CD40 agonistic antibody (CP-870,893) administered in combination with gemcitabine in a phase I trial demonstrated a partial response in several patients with advanced PDAC.

Currently, a phase I/II study is evaluating treatment of a CD40 agonistic monoclonal antibody (APX005M) with gemcitabine plus nab-paclitaxel chemotherapy, as well as with an antiPD-1 monoclonal antibody, nivolumab (Opdivo; NCT03214250).

O&rsquo;Reilly noted that although &ldquo;single-agent checkpoints and combination checkpoint inhibitors haven&rsquo;t shown the successes observed in other solid tumors, a strategy of chemotherapy, checkpoint inhibitors, and other immune-modulating agents, like CD40, may be a way to get activated T cells into the tumor and facilitate an immune response.&rdquo;

In another attempt to reprogram the immune environment, mast cells have been targeted because these TME components induce cancer cell growth and invasion in vitro.

In human PDAC samples, mast cell infiltration correlated with higher tumor grade and worse survival.

Ibrutinib (Imbruvica) prevents mast cell degranulation and has been approved for treatment of other malignancies.

A randomized, placebo-controlled, phase III clinical trial (RESOLVE; NCT02436668) investigated the safety and efficacy of ibrutinib (Imbruvica) in combination with GEM plus nab-paclitaxel for the treatment of stage IV PDAC.

Unfortunately, RESOLVE failed to show a statistically significant PFS or OS benefit.

No significant difference in OS was observed between the ibrutinib and placebo arms (median, 9.7 vs 10.8 months; HR, 1.109;

= .3225), and PFS was shorter for the ibrutinib arm (median, 5.3 vs 6.0 months; HR, 1.525; P <.0001).

CSCs develop chemoresistance through activation of antiapoptotic pathways and increased DNA repair mechanisms. Furthermore, CSCs can convert non-CSCs to CSC-like cells upon exposure to cytotoxic therapies; the latter cells develop an attribute known as &ldquo;stemness.&rdquo;

Strategies have been developed to target signaling pathways that drive cancer stemness, such as the STAT3 pathway. Preclinical studies demonstrated that STAT3 inhibition resulted in PDAC tumor volume reduction and decreased cancer cell proliferation.

Cancer stemness inhibitor napabucasin is a first-in-class drug that blocks STAT3-driven gene transcription and cancer stemness properties.

A phase Ib/ II multicenter study investigating napabucasin in combination with GEM plus nab-paclitaxel for the treatment of metastatic PDAC reported disease control in 92% of patients.

These encouraging results led to CanStem111P (NCT02993731), a phase III trial investigating the efficacy and safety of napabucasin in combination with gemcitabine plus nab-paclitaxel for the treatment of metastatic PDAC.

The primary outcome was OS, and secondary outcomes included PFS, disease control rate, response rate, and adverse events.

The data and analyses from this study are awaiting publication; however, Bekaii-Saab, who led both clinical trials, told TTO that napabucasin &ldquo;failed to show an improved benefit over standard of care.&rdquo; He went on to say that &ldquo;the results from CanStem111P with napabucasin were particularly disappointing given the promising preliminary results from earlier studies.&rdquo; This study was discontinued due to futility following an interim analysis.

Looking Ahead: Achieving Better Outcomes for Patients With PDAC

Pancreatic cancer is notoriously difficult to treat, but a new generation of cancer therapeutics is bringing much encouragement to the field. Active research that is harnessing novel strategies to combat pancreatic cancer is underway. Promising results from the phase III POLO study, as well as pending results from other trials, may lead to the approval of new drugs to improve outcomes for patients with PDAC.

O&rsquo;Reilly commented that &ldquo;the next goal is to increase the population of people eligible for these treatments. A wider subset may include other DNA damage repair gene mutations; there is a list of 15 to 20 genes that are of significant interest.&rdquo; Speaking of the POLO trial result, O&rsquo;Reilly concluded, &ldquo;It&rsquo;s encouraging; it&rsquo;s exciting; it hopefully means a new drug in this disease, but I think it is just the start of more that needs to be done.&rdquo;

&ldquo;Unfortunately, these maintenance studies are unlikely to change practice as designed, but they do pave the way for continuous development of PARPi as promising agents in PDAC,&rdquo; said Bekaii-Saab. &ldquo;While monotherapy with PARPi, other than veliparib, has shown evidence of preliminary efficacy in metastatic PDAC, it is clear that more rational combinations targeting tumors with HRD mutations need to be tested to significantly improve therapeutic response and patient outcome.&rdquo;

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Articles

Outcomes in pancreatic cancer may be improving for the first time in decades. With pancreatic cancer projected to be the second leading cause of cancer-related deaths in the United States by the year 2030,1 this projection brings welcome optimism to the field.

Brigid Stadinski, PhD | Authors

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