Initial systemic therapy for metastatic exocrine pancreatic cancer

INTRODUCTION — Exocrine pancreatic cancer includes all malignant tumors related to the pancreatic ductal and acinar cells. Most patients with exocrine pancreatic cancer are diagnosed with adenocarcinomas arising from the ductal epithelium of the pancreas. (See "Pathology of exocrine pancreatic neoplasms".)

Patients with exocrine pancreatic cancer typically present with advanced disease due to its aggressive natural history. Surgical resection offers the only chance of cure. However, only 15 to 20 percent of patients have resectable disease at initial diagnosis; the majority have either locoregionally advanced or metastatic pancreatic cancer.

The approach to initial systemic therapy for metastatic pancreatic exocrine cancer (adenocarcinoma and acinar cell carcinoma) will be reviewed here. Second-line and later lines of systemic therapy for pancreatic exocrine cancer are discussed separately. (See "Second-line systemic therapy for advanced exocrine pancreatic cancer".)

PRETREATMENT EVALUATION — In patients with an established diagnosis of metastatic exocrine pancreatic cancer, pretreatment evaluation includes imaging studies, laboratory testing, and supportive care. The clinical presentation, diagnosis, and staging of exocrine pancreatic cancer are discussed separately. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer".)

Imaging studies — A contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis is performed prior to initiating therapy to assess the extent of disease. This also serves as a baseline imaging study to assess subsequent treatment response. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Abdominal CT'.)

Laboratory testing — Prior to initiating therapy, we obtain a complete blood count (CBC) with differential, a comprehensive metabolic panel that includes liver function testing and serum total bilirubin, and serum levels of the tumor marker carbohydrate antigen 19-9 (CA 19-9; also called cancer antigen 19-9). If elevated, CA 19-19 may be used to follow treatment response during systemic therapy. (See 'Assessing treatment response' below.)

Some UpToDate contributors also test for dihydropyrimidine dehydrogenase (DPD) deficiency prior to administering a fluoropyrimidine as part of systemic therapy. (See "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation", section on 'Testing for DPYD and TYMS variants'.)

Supportive care — Patients with metastatic pancreatic cancer should be evaluated and treated for cancer-related symptoms (such as pain, jaundice, weight loss, and pancreatic exocrine insufficiency, among others) and psychosocial concerns. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

Patients should be offered a palliative care referral early in their treatment course, especially for those with a high symptom burden. The benefits of early initiation of palliative care services should be discussed with the patient, including improved clinical outcomes, prolonged survival, and better quality of life. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer" and "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)

Patients who are ineligible for systemic therapy (eg, due to poor performance status [PS], significant comorbidities) may be offered best supportive care. (See 'Poor PS and/or significant comorbidities' below.)

Genetic testing — For all patients with metastatic exocrine pancreatic cancer, we assess for both germline and somatic (tumor) molecular alterations. Selection of initial therapy is guided by the presence or absence of select, actionable molecular alterations [1]. (See 'Actionable molecular alterations' below.)

Germline testing — All patients with metastatic exocrine pancreatic cancer should receive universal germline testing to assess for associated genetic conditions, which is consistent with guidelines from the National Comprehensive Cancer Network (NCCN) [2]. Such germline testing is typically performed using comprehensive multigene panel assays. Prior to testing, the clinician should counsel the patient on the frequency of actionable germline pathogenic variants in pancreatic cancer and the need for genetic counseling. (See "Genetic testing" and "Genetic counseling: Family history interpretation and risk assessment", section on 'Content of genetic counseling'.)

●BRCA1/2 and PALB2 – We test all patients with metastatic pancreatic cancer for germline pathogenic variants in breast cancer susceptibility (BRCA1/2) or partner and localizer of BRCA2 (PALB2). Testing should be obtained soon after diagnosis to guide management [3,4], which is discussed separately. (See 'BRCA1/2 or PALB2 pathogenic variants' below and 'Patients awaiting genetic testing results' below.)

Germline alterations in BRCA1/2 or PALB2, also known as the core homologous repair deficiency (HRD) genes, are present in approximately 3 to 5 percent of patients with pancreatic cancer [5]. Pathogenic variants in BRCA1/2 or PALB2 cause deficient repair of deoxyribonucleic acid (DNA) double-stranded breaks, which results in increased tumor sensitivity to specific DNA-damaging drugs. (See "Molecular pathogenesis of exocrine pancreatic cancer", section on 'Familial pancreatic cancer genes'.)

●Other genes – In addition to germline alterations in BRCA and PALB2, patients should also be offered universal germline testing for other molecular alterations associated with pancreatic cancer. Genes of interest for pancreatic cancer include ATM (ataxia telangiectasia), CDK2NA (familial atypical multiple mole and melanoma [FAMMM] syndrome), Lynch syndrome genes (MLH-1, MSH-2, MSH6, EPCAM), STK11 (Peutz-Jeghers syndrome), and TP53 (Li-Fraumeni syndrome), among others.

Any patient who is diagnosed with (or suspected to have) a high-risk hereditary syndrome associated with pancreatic cancer (table 1) should be referred for genetic counseling and, if the diagnosis is confirmed, advice on screening for other associated primary cancers [6]. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients".)

Somatic (tumor) testing — Patients with metastatic pancreatic cancer should have somatic (tumor) tissue tested for actionable molecular alterations. This is typically performed using next-generation sequencing (NGS) on a tissue sample obtained either from the primary pancreatic tumor or a metastatic site [3,4].

For patients with insufficient tissue available for testing (eg, disease that is inaccessible to biopsy), actionable alterations can be identified using circulating tumor DNA (ctDNA). The accuracy of ctDNA for diagnosing pancreatic cancer varies based on tumor stage and the specific assay used; sensitivity generally ranges between 62 to 95 percent and specificity ranges between 92 and 100 percent [7-9].

The initial management of patients with pancreatic cancer based on these actionable somatic molecular alterations is discussed separately. (See 'Actionable molecular alterations' below.)

Somatic molecular alterations that can be used to guide management include:

●Somatic pathogenic variants in BRCA1/2 or PALB2 – Somatic pathogenic variants in BRCA1/2 and PALB2 are present in approximately 5 percent of patients with pancreatic cancer [5]. Of note, all patients should be evaluated for both somatic and germline pathogenic variants in BRCA1/2 and PALB2. (See 'Genetic testing' above.)

Somatic (tumor) testing cannot substitute for germline testing in patients where a germline pathogenic variant in BRCA1/2 or PALB2 might influence treatment decisions. In principle, all patients with a germline BRCA or PALB2 pathogenic variant should have that same pathogenic variant detected in the tumor. For patients whose germline BRCA or PALB2 pathogenic variant carrier status is not known, targeted tumor testing that identifies one of these pathogenic variants might be interpreted as likely somatic or germline. However, most tests cannot reliably distinguish between the two, and this differentiation may not be reported uniformly across all tests. Furthermore, germline pathogenic variants may be missed by tumor testing alone for a variety of reasons, including the amount of available tumor tissue, technical limitations of tumor sequencing (especially small copy number deletions, and large or complex insertions or deletions), variant interpretation differences between tumor and germline tests, or differences in the genes evaluated using tumor tissue versus through germline testing [10].

●Molecular alterations in other HRD genes – These include somatic pathogenic variants in genes that are also classified as HRD genes, other than BRCA1/2 or PALB2. These include ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 [11]. The frequency of these pathogenic variants in patients with pancreatic cancer varies between 13 to 44 percent [5]. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Inherited cancer susceptibility syndromes'.)

●Less prevalent alterations – Molecular alterations that are clinically actionable for initial therapy but are less prevalent in pancreatic adenocarcinoma include mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H) (table 2), neurotrophic tyrosine receptor kinase (NTRK) fusions (algorithm 1), BRAF V600E mutations, and RET fusions. (See "Molecular pathogenesis of exocrine pancreatic cancer".)

Tumor tissue may also be evaluated for other molecular alterations including, but not limited to ALK, NRG1, ROS1, FGFR2, KRAS, HER2, and high tumor mutational burden (TMB-H). Such alterations either have clinical relevance in second- and later-line therapy for metastatic pancreatic cancer or are associated with clinically available targeted therapies for other cancers. (See "Second-line systemic therapy for advanced exocrine pancreatic cancer".)

ACTIONABLE MOLECULAR ALTERATIONS — In patients with metastatic exocrine pancreatic cancer, the goals of initial systemic therapy are palliative and not curative. However, systemic therapy reduces cancer-related symptoms and improves overall survival (OS) and quality of life in those who are eligible for treatment [12-21]. Clinical trials enrollment is encouraged, where available.

The approach to initial systemic therapy for metastatic exocrine pancreatic cancer (algorithm 2) is based on the presence or absence of specific germline pathogenic variants and/or actionable molecular alterations in the tumor. Other clinical factors that also influence selection of therapy include patient performance status (PS) and comorbidities, laboratory values (including serum total bilirubin levels), symptom burden, and goals of care.

Patients awaiting genetic testing results — Patients who are awaiting the results of genetic testing, such as germline or somatic (tumor) testing, or those whose results are unknown, are initially managed using the same approach as those without actionable molecular alterations. (See 'No actionable molecular alterations' below.)

We do not wait for genetic test results to initiate systemic therapy, given the aggressive nature of metastatic pancreatic cancer. Patients whose genetic testing results reveal an actionable molecular alteration may switch to the appropriate therapy, if necessary.

BRCA1/2 or PALB2 pathogenic variants — For patients with metastatic pancreatic cancer and a germline or somatic pathogenic variant in BRCA1/2 or PALB2, we suggest platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase (PARP) inhibitor rather than other systemic agents.

Platinum-based chemotherapy — Metastatic pancreatic cancer with a germline or somatic pathogenic variant in BRCA1/2 or PALB2 is sensitive to initial therapy with platinum-based chemotherapy. For patients with good Eastern Cooperative Oncology Group (ECOG) PS (0 to 1) and a good comorbidity profile, we typically use modified FOLFIRINOX (table 3). Gemcitabine plus cisplatin (table 4) is an appropriate alternative, especially for patients who are ineligible for or anticipated to not tolerate FOLFIRINOX (eg, ECOG PS of 2), or those who prefer a regimen without a continuous fluorouracil infusion pump. Patients who are ineligible for these regimens (eg, due to poor PS and/or significant comorbidities) should be offered alternate therapies or receive best supportive care. (See 'Poor PS and/or significant comorbidities' below.)

Homologous repair deficiency (HRD) genes, such as BRCA1/2 and PALB2, repair double-strand breaks generated during DNA interstrand crosslinking, which occurs during treatment with platinum agents (such as cisplatin or oxaliplatin). For this reason, tumors with pathogenic variants in HRD genes are sensitive to regimens that contain platinum, which further damages DNA and causes cancer cell death. (See "Molecular pathogenesis of exocrine pancreatic cancer", section on 'BRCA2 and BRCA1' and "Molecular pathogenesis of exocrine pancreatic cancer", section on 'PALB2'.)

Based on initial observational studies, platinum-based chemotherapy improved outcomes in patients with advanced and metastatic pancreatic cancer and germline pathogenic variants in BRCA1/2 and PALB2, particularly those with biallelic BRCA1/2 alterations [22-29]. Therefore, randomized trials evaluating maintenance PARP inhibitors were subsequently conducted in such patients who received initial platinum-based chemotherapy (most frequently FOLFIRINOX and gemcitabine plus cisplatin). Although these randomized trials were not designed to directly compare platinum-based regimens to other non-platinum-based regimens, both FOLFIRINOX and gemcitabine plus cisplatin (in combination with maintenance PARP inhibitor therapy) demonstrated high response rates and durable overall survival (OS). This approach is also extrapolated to patients with somatic pathogenic variants BRCA or PALB2 [2].

●FOLFIRINOX – There are limited data directly evaluating FOLFIRINOX in patients with metastatic pancreatic cancer and germline pathogenic variants in BRCA or PALB2. In a placebo-controlled phase III trial (POLO), maintenance olaparib improved progression-free survival (PFS) in patients with metastatic pancreatic cancer and germline pathogenic variants in BRCA1/2 who did not progress on initial platinum-based therapy (most of whom received FOLFIRINOX [84 percent]) [30]. Full details of this study are discussed below. (See 'Olaparib' below.)

●Gemcitabine plus cisplatin – In a randomized phase II trial, gemcitabine plus cisplatin (table 4) demonstrated a high objective response rate (ORR) (65 percent) and was well-tolerated. In this study, 50 patients with germline BRCA or PALB2-altered locally advanced or metastatic pancreatic cancer were randomly assigned to gemcitabine plus cisplatin either alone or with veliparib (80 mg orally on days 1 through 12 every 21 days) [31]. The addition of veliparib to gemcitabine plus cisplatin did not improve ORR (74 versus 65 percent), PFS (median 10 months each), or OS (median 16 months each) and increased grade 3 to 4 hematologic toxicity including neutropenia (40 versus 30 percent), anemia (52 versus 35 percent), and thrombocytopenia (55 versus 9 percent).

Maintenance therapy — For patients with metastatic pancreatic cancer and either a germline or somatic BRCA or PALB2 pathogenic variant who do not progress on at least four months of initial platinum-based therapy, we offer switch maintenance therapy with a PARP inhibitor. In randomized trials, maintenance therapy with PARP inhibitors improved PFS and was well-tolerated.

●Olaparib is an option only for patients with a germline pathogenic variant in BRCA1/2. (See 'Olaparib' below.)

●Rucaparib is an option for patients with a germline or somatic pathogenic variant in BRCA1/2 or PALB2. (See 'Rucaparib' below.)

We do not administer a PARP inhibitor concurrently with platinum-based chemotherapy, as this approach does not improve OS and increases hematologic toxicity [31].

Olaparib — Olaparib, a PARP inhibitor, is an option for maintenance therapy in patients with metastatic pancreatic cancer and a germline pathogenic variant in BRCA1/2 who do not progress on at least four months of initial platinum-based therapy. In a phase III trial, maintenance olaparib improved PFS but failed to improve OS in this population. (See 'Platinum-based chemotherapy' above.)

PARP activity is essential for the repair of single-strand DNA breaks via the base excision repair pathway [32,33]. Because cancer cells with pathogenic variants in BRCA or PALB2 have deficient homologous recombination repair function, PARP inhibitors lead to unrepaired DNA breaks and, eventually, cancer cell death [34,35]. This process is known as "synthetic lethality," in which two conditions cause cell death when present in combination, but not independently [36,37].

Based on initial data from a phase II trial [38], maintenance therapy with olaparib was evaluated in a double-blind, placebo-controlled phase III trial (POLO) of 154 patients with metastatic pancreatic cancer and germline pathogenic variants in BRCA1/2 who did not progress during at least 16 weeks (four months) of initial platinum-based therapy [30]. Most patients received platinum-based therapy with a modified form of FOLFIRINOX (84 percent) while the remainder received gemcitabine plus cisplatin (3 percent) or another platinum-based regimen (12 percent). Patients were randomly assigned to maintenance therapy with either olaparib (300 mg twice a day) or placebo, which was initiated four to eight weeks after the last dose of first-line chemotherapy. Notably, crossover to olaparib was not allowed for patients in the placebo group who progressed.

At median follow-up of nine months, relative to placebo, maintenance olaparib improved PFS (median 7.4 versus 3.8 months; two-year PFS 22 versus 10 percent, hazard ratio [HR] for disease progression or death 0.53, 95% CI 0.35-0.82) but failed to improve OS (median 18.9 versus 18.1 months, HR 0.91, 95% CI 0.56-1.46) [30]. In a subsequent analysis, at extended median follow-up of 31 months, three-year OS was higher with olaparib than placebo, but the difference was not statistically significant (median OS 19 months each; three-year OS 34 versus 18 percent HR 0.83, 95% CI 0.56-1.22) [39].

Grade ≥3 toxicity was higher with olaparib (40 versus 23 percent with placebo), including anemia, fatigue, and anorexia [30]. Health-related quality of life (HRQOL) was preserved with maintenance olaparib, with no clinically meaningful differences compared with placebo [40].

Olaparib is approved by the US Food and Drug Administration (FDA) for first-line maintenance therapy in patients with germline BRCA gene pathogenic variants whose cancer has spread beyond the pancreas and whose tumors did not worsen after chemotherapy of at least 16 weeks [41].

Rucaparib — Rucaparib, a PARP inhibitor, is an option for maintenance therapy in patients with metastatic pancreatic cancer and a somatic or germline pathogenic variant in BRCA1/2 or PALB2 who do not progress on at least four months of initial platinum-based therapy.

In a single-arm phase II trial, 46 patients with advanced pancreatic cancer and a germline or somatic pathogenic variant in BRCA or PALB2 who did not progress after at least 16 weeks (four months) of platinum-based chemotherapy were treated with maintenance rucaparib (600 mg twice daily) until disease progression or unacceptable toxicity [42]. Most patients received platinum-based therapy with FOLFIRINOX (60 percent), followed by FOLFOX (21 percent), gemcitabine plus cisplatin (10 percent), and gemcitabine plus oxaliplatin (2 percent).

At median follow-up of 18 months, median PFS and OS were 13 and 23 months, respectively. The ORR for the entire cohort was 42 percent, with objective responses in 11 of 27 patients (41 percent) with a germline pathogenic variant in BRCA2, in three of six patients (50 percent) with germline pathogenic variant in PALB2, in one of two patients (50 percent) with a somatic pathogenic variant in BRCA2, and zero out of seven patients (0 percent) with germline pathogenic variant in BRCA1 [42]. Common grade 3 toxicities included anemia (22 percent), fatigue, increased alanine transaminase (ALT), thrombocytopenia (4 percent each), nausea, vomiting, and low white blood cell count (2 percent each).

In another phase II study (RUCAPANC), rucaparib also demonstrated an ORR and disease control rate of 16 and 32 percent in patients with previously treated pancreatic cancer and germline or somatic pathogenic variants in BRCA1/2 [43].

Non-core HRD pathogenic variants — For patients with metastatic pancreatic cancer and pathogenic variants (either somatic or germline) in HRD genes other than the core genes (BRCA1/2 or PALB2), such as ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1, we suggest initial platinum-based therapy, such as modified FOLFIRINOX (table 3), rather than a non-platinum-based regimen. FOLFOX is an appropriate alternative for patients who are ineligible for or not anticipated to tolerate FOLFIRINOX (eg, ECOG PS of 2). NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin) is also an option since this regimen includes oxaliplatin, although data are limited in this population. We do not offer gemcitabine plus cisplatin since this regimen has only demonstrated benefit in patients with pathogenic variants in the core HRD genes (BRCA1/2 or PALB2) [31], and it does not improve OS in unselected patients with pancreatic cancer [44].

Patients who are ineligible for these regimens (eg, due to poor PS and/or significant comorbidities) should be offered alternate therapies or receive best supportive care. (See 'Poor PS and/or significant comorbidities' below.)

Pathogenic variants in non-core HRD genes can result in defective DNA damage repair. All cells are equipped with DNA damage response mechanisms that guard the genome against mutational insults. Double-strand DNA breaks are repaired using two major pathways: error-free (high-fidelity) homologous recombination and nonhomologous (low fidelity) end-joining [45,46]. Although HRD was initially described in cancers that arose from germline pathogenic variants in BRCA1 and BRCA2, which are classified as core HRD genes, genetic and epigenetic inactivation of non-core HRD genes can also lead to sporadic cancers with HRD.

In patients with metastatic pancreatic cancer and pathogenic variants in non-core HRD genes, data suggest improved PFS with initial platinum-based chemotherapy, especially in those with biallelic alterations. In an observational study, 262 patients with advanced pancreatic adenocarcinoma who had germline and somatic targeted gene sequencing were treated with various initial therapies that were platinum-based (FOLFIRINOX [53 percent], FOLFOX [3 percent], gemcitabine plus cisplatin [2 percent]) and non-platinum-based (gemcitabine plus nabpaclitaxel [35 percent], gemcitabine [3 percent], and others [4 percent]) [11]. Pathogenic variants in HRD genes were found in 50 patients (19 percent; 15 percent somatic, 4 percent germline) including BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1.

●Among patients treated with initial platinum-based chemotherapy, HRD alterations were associated with improved PFS relative to no HRD alterations (HR 0.44, 95% CI 0.28-0.66). This associated PFS benefit was observed regardless of whether the HRD alterations were in core or non-core genes.

●Among patients with pathogenic variants in an HRD gene, platinum-based chemotherapy was associated with a higher PFS relative to non-platinum-based therapy (median 12.6 versus 4.4 months).

●Among the patients with biallelic HRD alterations, initial platinum-based chemotherapy was also associated with improved PFS relative to initial non-platinum-based therapy (median 13.3 versus 3.8 months). However, this associated PFS benefit was not observed among those with monoallelic alterations.

MSI-H/dMMR tumors — For patients with metastatic pancreatic cancer that is mismatch repair deficient (dMMR)/microsatellite-instability high (MSI-H), we suggest initial therapy with pembrolizumab rather than chemotherapy, extrapolating from data in treatment-refractory pancreatic cancer that suggest durable treatment responses with immune checkpoint inhibitors (ICIs). Combination immunotherapy with nivolumab plus ipilimumab is a reasonable alternative for medically fit patients, although high-quality data are limited.

Pembrolizumab — In a phase II trial (KEYNOTE-158), pembrolizumab demonstrated durable responses in patients with MSI-H/dMMR metastatic pancreatic cancer who progressed on prior standard treatments, such as chemotherapy [47,48]. Further details of this study are discussed separately. (See "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'Deficient mismatch repair or high tumor mutational burden'.)

Nivolumab plus ipilimumab — Nivolumab plus ipilimumab is an option for initial therapy in patients with dMMR/MSI-H metastatic pancreatic cancer, good ECOG PS (0 to 1) (table 5), and minimal comorbidities. Although data in metastatic pancreatic cancer are limited to case reports [49-52], this combination has been successfully used as initial therapy for other types of metastatic dMMR/MSI-H gastrointestinal cancers, such as colorectal cancer. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Nivolumab plus ipilimumab'.)

TRK fusion-positive tumors — For patients with metastatic pancreatic cancer whose tumors test positive for a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, we suggest initial therapy with larotrectinib or entrectinib rather than other systemic agents, as these targeted agents have durable treatment responses and are well tolerated. Patients who are ineligible for these agents may be treated using the same initial therapy as those without an actionable molecular alteration. (See 'No actionable molecular alterations' below.)

Larotrectinib and entrectinib are selective tropomyosin receptor kinase (TRK) inhibitors that are highly effective in NTRK gene fusion-positive cancers. Among patients with metastatic pancreatic cancer, although NTRK gene fusions occur at a low frequency (<1 percent), both agents demonstrate high ORRs (50 and 75 percent for larotrectinib [53] and entrectinib [54,55], respectively) that are durable (median duration of response of 4 and 13 months for larotrectinib and entrectinib, respectively), regardless of prior therapy. These agents can also be administered orally for patient convenience. The toxicities of larotrectinib and entrectinib are discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Side effects'.)

Larotrectinib and entrectinib are both approved by the FDA for the treatment of patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, who are metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or that have progressed following treatment [41]. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Treatment with TRK inhibitors'.)

Second- and later-line therapy for metastatic NTRK-fusion positive pancreatic cancer is discussed separately. (See "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'TRK fusion-positive cancers'.)

RET fusion-positive tumors — For patients with metastatic pancreatic cancer whose tumors test positive for a rearranged during transfection (RET) gene fusion, we suggest initial therapy with selpercatinib rather than other systemic agents, as this agent has durable treatment responses and is well-tolerated. Patients who are ineligible for selpercatinib may be treated using the same approach as those without an actionable molecular alteration. (See 'No actionable molecular alterations' below.)

The use of selpercatinib is extrapolated from a phase I/II basket trial (LIBRETTO-001) of various treatment-refractory cancer histologies. Among those with metastatic pancreatic cancer, at a median follow-up of 15 months, selpercatinib demonstrated ORRs over 50 percent that were also durable (median duration of response not reached) [56]. Further details are discussed separately. (See "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'RET fusion-positive tumors'.)

Selpercatinib has accelerated approval from the FDA for the treatment of adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options [41].

BRAF V600E positive-tumors — For patients with metastatic pancreatic cancer whose tumors test positive for a BRAF V600E mutation, we offer chemotherapy using the same approach to initial therapy as those without an actionable molecular alteration. (See 'No actionable molecular alterations' below.)

Dabrafenib plus trametinib is an alternative for those who are ineligible for or decline chemotherapy. This BRAF plus MEK inhibitor combination has an acceptable toxicity profile and can be administered orally for patient convenience. However, efficacy is modest in BRAF V600E mutant pancreatic cancer (stable disease as best response in one patient in the NCI-MATCH Trial) [57]. This approach is also mainly extrapolated from a phase II trial (ROAR) of BRAF V600E mutant metastatic biliary tract cancers [58]. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'BRAF V600E-mutated cancers' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

Dabrafenib plus trametinib has accelerated approval from the FDA for patients with any unresectable or metastatic solid tumor with a BRAF V600E mutation who have progressed on prior therapy and have no satisfactory alternative treatment options [41].

KRAS G12C positive-tumors — For patients with metastatic pancreatic cancer whose tumors test positive for a molecular alteration in KRAS G12C, we offer chemotherapy using the same approach to initial therapy as those without an actionable molecular alteration. (See 'No actionable molecular alterations' below.)

Sotorasib or adagrasib, which are molecularly targeted agents that specifically inhibit KRAS G12C, are acceptable alternatives for those who are ineligible for or decline chemotherapy. Their use is extrapolated from studies in treatment-refractory metastatic pancreatic cancer which demonstrate ORRs for sotorasib and adagrasib of 21 and 42 percent, respectively [59,60]. Further details are discussed separately. (See "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'RAS G12C-mutated tumors'.)

NO ACTIONABLE MOLECULAR ALTERATIONS — Most patients with metastatic pancreatic adenocarcinoma will not have an actionable molecular alteration. For such patients, selection of initial therapy (algorithm 2) is based upon patient performance status (PS), laboratory values (including total bilirubin), comorbidities (table 6), and goals of care. Clinical trial enrollment is encouraged, where available.

Good PS, no hyperbilirubinemia — For patients with metastatic exocrine pancreatic cancer, a good comorbidity profile (table 6), good Eastern Cooperative Oncology Group (ECOG) PS (0 or 1 (table 5)), and total bilirubin less than 1.5 times the upper limit of normal (ULN), we suggest initial therapy with dose-modified FOLFIRINOX (table 3) rather than other systemic agents. Appropriate alternatives include gemcitabine plus nabpaclitaxel (table 7) and liposomal irinotecan in combination with fluorouracil, leucovorin, and oxaliplatin (NALIRIFOX).

FOLFIRINOX — FOLFIRINOX is the preferred initial systemic therapy for medically fit patients with metastatic pancreatic cancer. In a phase III trial with long-term follow-up, FOLFIRINOX improved overall survival (OS) and progression-free survival (PFS) as well as quality of life compared with single-agent gemcitabine, despite increasing toxicity [61].

Dosing and supportive care — We prefer a modified dosing of FOLFIRINOX (table 3) over standard dosing of FOLFIRINOX (table 8), which is better tolerated and similarly effective [62,63]. In a single-arm phase II trial of patients with treatment-naïve metastatic pancreatic cancer who received a modified dosing of FOLFIRINOX (table 3), the objective response rate (ORR) was 38 percent and median OS was 11 months [62]. Modified FOLFIRINOX demonstrated outcomes similar to those seen with standard dosing of FOLFIRINOX in a separate phase III trial [61] but with similar or lower grade 3 or 4 toxicity rates for neutropenia (48 percent), febrile neutropenia (9 percent), diarrhea (10 percent), fatigue, and sensory neuropathy (6 percent each) [62].

Patients receiving FOLFIRINOX should receive close supportive care during therapy including prophylactic G-CSF support, frequent clinical visits for laboratory testing, intravenous fluids, and surveillance for/management of common treatment-related toxicities such as fatigue, nausea/vomiting, diarrhea, and neuropathy. (See "Cancer-related fatigue: Treatment" and "Prevention of chemotherapy-induced nausea and vomiting in adults" and "Management of acute chemotherapy-related diarrhea" and "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)

Efficacy and toxicity — Based on data from initial studies [62,64], FOLFIRINOX was evaluated in an open-label, phase III trial (PRODIGE 4/ACCORD 11) of 342 patients with chemotherapy-naïve metastatic pancreatic cancer, an ECOG PS of 0 or 1 (table 5), and a serum total bilirubin <1.5 times ULN. Patients were randomly assigned to either standard dose FOLFIRINOX (table 8) or single-agent gemcitabine alone until disease progression or unacceptable toxicity [61].

At a median follow-up of 27 months, FOLFIRINOX improved OS (median 11.1 versus 6.8 months, hazard ratio [HR] 0.57, 95% CI 0.45-0.73), PFS (median 6.4 versus 3.3 months, HR 0.47, 95% CI 0.37-0.59), and ORRs (32 versus 9 percent). The trial was stopped early due to OS benefit with FOLFIRINOX [61].

Most grade 3 or 4 toxicity rates were higher with FOLFIRINOX than gemcitabine, including neutropenia (46 versus 21 percent), febrile neutropenia (5 versus 1 percent), thrombocytopenia (9 versus 4 percent), fatigue (23 versus 18 percent), sensory neuropathy (9 versus 0 percent), vomiting (15 versus 8 percent), and diarrhea (13 versus 2 percent). However, despite greater toxicity, FOLFIRINOX improved global health status and quality of life compared with gemcitabine alone [65].

Options for maintenance therapy — For patients who do not progress on FOLFIRINOX, various maintenance therapies that are free of oxaliplatin have been investigated in clinical trials [66]. The optimal maintenance regimen is not established, and further data are necessary.

The main toxicities of FOLFIRINOX are hematologic and cumulative sensory peripheral neuropathy due to oxaliplatin, which can be dose limiting. For most patients who do not progress (ie, have an objective response or stable disease) on at least four months of FOLFIRINOX, we offer maintenance therapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI). For patients who progress on maintenance FOLFIRI, particularly those with persistent neuropathy, we typically switch to a different regimen rather than reintroducing oxaliplatin (ie, restarting FOLFIRINOX). For patients without persistent neuropathy, restarting FOLFIRINOX is also a reasonable option.

Maintenance therapy with fluorouracil plus leucovorin is also an option, but it is less preferred as the likelihood of long-term meaningful disease control with single-agent chemotherapy is low [66].

Gemcitabine plus nabpaclitaxel — Gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel) (table 7) is an appropriate initial treatment option for medically fit patients with metastatic pancreatic cancer. In a phase III trial, the addition of nabpaclitaxel to gemcitabine improved OS and was well-tolerated [67]. Gemcitabine plus nabpaclitaxel has not been directly compared with FOLFIRINOX in randomized trials.

Dosing — Gemcitabine is administered at 1000 mg/m² and nabpaclitaxel is administered at 125 mg/m² on days 1,8, and 15 of a 28-day cycle (table 7). Alternatively, modified administration on an every two-week schedule (gemcitabine 1000 mg/m² and nabpaclitaxel 125 mg/m² on days 1 and 15 of a 28-day cycle) is also available [68,69]. (See 'Gemcitabine plus nabpaclitaxel (ECOG PS 2)' below.)

Efficacy and toxicity — Activity for gemcitabine plus nabpaclitaxel was initially demonstrated in a phase I/II trial [70]. Based on these results, an open-label phase III trial (MPACT) was conducted to evaluate this regimen in 861 patients with previously untreated metastatic pancreatic adenocarcinoma, a Karnofsky PS of 70 or more (table 9), and a serum total bilirubin at or below the ULN. Patients were randomly assigned to either gemcitabine (1000 mg/2) and nabpaclitaxel (125 mg/m²) given on days 1, 8, and 15 every 28 days or gemcitabine alone (1000 mg/m² weekly for seven weeks, then on days 1, 8, and 15 every four weeks) [67].

At a median follow-up of 9 months, the addition of nabpaclitaxel to gemcitabine improved OS (median 8.5 versus 6.7 months, HR 0.72, 95% CI 0.62-0.83), PFS (median 5.5 versus 3.7 months, HR 0.69, 95% CI 0.58-0.82), and ORR (23 versus 7 percent) [67]. This OS benefit was confirmed with extended follow-up (median OS 8.7 versus 6.6 months, HR 0.72, 95% CI 0.62-0.83), with long-term (greater than three-year) survivors identified only in the combination arm (4 percent) [71].

Compared with single-agent gemcitabine, gemcitabine plus nabpaclitaxel resulted in higher rates of grade 3 or 4 neutropenia (38 versus 27 percent), febrile neutropenia (3 versus 1 percent), fatigue (17 versus 7 percent), diarrhea (6 versus 1 percent), and neuropathy (17 versus 1 percent) [67].

Gemcitabine in combination with nabpaclitaxel is approved by the US Food and Drug Administration (FDA) for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas [41].

Maintenance therapy — For patients who do not progress on (ie, have an objective response or stable disease) at least four months of gemcitabine plus nabpaclitaxel, the optimal regimen for maintenance chemotherapy is unclear. For most patients who do not progress on gemcitabine plus nabpaclitaxel, options include:

●Continuing standard dosing with dose modifications as indicated.

●Alternating standard dosing of gemcitabine plus nabpaclitaxel with single-agent gemcitabine after three induction cycles of gemcitabine plus nabpaclitaxel [72].

●Switching to a modified regimen where treatment is administered every two weeks (gemcitabine 1000 mg/m² and nabpaclitaxel 125 mg/m² on days 1 and 15 of a 28-day cycle) [68,69].

●Using single-agent gemcitabine.

NALIRIFOX — In patients with systemic-therapy naïve metastatic pancreatic cancer, NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin) improved OS with similar toxicity when compared with gemcitabine plus nabpaclitaxel in a phase III trial. NALIRIFOX and FOLFIRINOX have not been directly compared in randomized trials. One drawback for NALIRIFOX is increased cost due to the incorporation of liposomal irinotecan.

NALIRIFOX is administered as liposomal irinotecan at 50 mg/m², oxaliplatin 60 mg/m², leucovorin 400 mg/m², and fluorouracil 2400 mg/m² as a continuous intravenous infusion over 46 hours on days 1 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. We do not administer primary prophylaxis with granulocyte colony stimulating factors for chemotherapy-induced neutropenia due to low rates of neutropenia and other hematologic toxicity with this regimen.

NALIRIFOX initially demonstrated clinical benefit based on data from a phase I/II trial [73]. In a subsequent open-label phase III trial (NAPOLI-3), 770 patients with metastatic pancreatic ductal adenocarcinoma were randomly assigned to initial therapy with either NALIRIFOX or gemcitabine plus nabpaclitaxel [74]. Patients either had no prior systemic therapy in the metastatic setting or received their last dose of adjuvant chemotherapy more than 12 months prior with no persistent treatment-related toxicity.

At a median follow-up of 16 months, relative to gemcitabine plus nabpaclitaxel, NALIRIFOX improved OS (median 11.1 versus 9.2 months; one-year OS 46 versus 40 percent; HR 0.83, 95% CI 0.70-0.99) and PFS (median 7.4 versus 5.6 months, HR 0.69, 95% CI 0.58-0.83). OS benefits were seen across all clinically relevant subgroups, including presence or absence of liver metastases, site of the primary pancreatic tumor (head versus other location), and age. ORRs were similar between the two treatment arms (42 versus 36 percent).

Grade ≥3 toxicity rates were similar between the treatment arms (87 versus 86 percent). Compared with gemcitabine plus nabpaclitaxel, NALIRIFOX resulted in less grade ≥3 neutropenia (14 versus 25 percent) but more diarrhea (20 versus 5 percent), nausea (12 versus 3 percent), and vomiting (7 versus 2 percent).

Based on the results of the NAPOLI-3 trial, liposomal irinotecan is approved in combination with oxaliplatin, fluorouracil, and leucovorin for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma [41].

Less-preferred regimens — Gemcitabine plus erlotinib is a less preferred regimen for the initial management of metastatic pancreatic cancer. In a placebo-controlled phase III trial, the addition of erlotinib to gemcitabine plus erlotinib conferred only a modest OS benefit over gemcitabine plus placebo (median 6.2 versus 5.9 months; one-year OS 23 versus 17 percent; HR 0.82, 95% CI 0.69-0.99) and had higher incidence of certain toxicities such as rash, diarrhea, infection, and stomatitis [75].

We do not use gemcitabine plus FU [76,77], gemcitabine plus capecitabine [78-80], or gemcitabine plus S-1 [81-85] in the metastatic setting. In randomized trials, these combination regimens failed to improve OS and increased toxicity relative to single-gemcitabine.

ECOG PS of 2, no hyperbilirubinemia — For patients with metastatic pancreatic cancer, a good comorbidity profile (table 6), an ECOG PS of 2, and a total serum bilirubin less than 1.5 times ULN, we suggest initial therapy with gemcitabine plus nabpaclitaxel (table 7) rather than other systemic agents. Alternative options include fluoropyrimidine-based combination therapy (FOLFOX (table 10) [86], CAPOX [87], or FOLFIRI [88,89]) or single-agent chemotherapy (gemcitabine (table 11) or capecitabine).

Gemcitabine plus nabpaclitaxel (ECOG PS 2) — In patients with metastatic pancreatic cancer with less optimal ECOG PS (2), standard dosing of gemcitabine plus nabpaclitaxel (table 7) is an effective and well-tolerated option for initial therapy. In a randomized phase II trial (FRAGRANCE) of 221 patients with previously untreated metastatic pancreatic cancer and an ECOG PS of 2, the administration of two different doses of nabpaclitaxel (at either 100 or 125 mg/m²) in combination with gemcitabine (1000 mg/m²) on days 1, 8, and 15 of a 28-day cycle demonstrated similar response rates (24 versus 28 percent), PFS (median 5.7 and 6.7 months) and OS (six-month OS 63 and 69 percent) [68].

Alternatively, gemcitabine plus nabpaclitaxel may be administered on a modified every two-week schedule (gemcitabine 1000 mg/m² and nabpaclitaxel 125 mg/m² on days 1 and 15 of a 28-day cycle), which is also effective and well-tolerated in this population [68,69]. In a retrospective study of 57 patients with metastatic pancreatic cancer treated with this modified schedule as first-line therapy, median OS was 10 months with grade 3 to 4 rates for neutropenia and peripheral neuropathy of 19 and 2 percent, respectively [69]. These results compare favorably with the outcomes for standard dose gemcitabine plus nabpaclitaxel in a separate phase III trial (MPACT) [67]. Additionally, in the phase I dose finding portion of the FRAGRANCE trial, the differences in toxicity were subtle between modified and standard dosing of gemcitabine plus nabpaclitaxel [68].

Fluoropyrimidine-based combination therapy — In patients with metastatic pancreatic cancer with ECOG PS of 2, fluoropyrimidine-based doublet regimens such as FOLFOX, CAPOX, and FOLFIRI, are reasonable alternatives to gemcitabine-based therapy.

●FOLFOX – In a single-arm phase II trial of 30 patients with previously untreated advanced or metastatic pancreatic cancer who received FOLFOX, partial responses were seen in eight patients (27 percent) [86]. Median PFS and OS were four and eight months, respectively.

●CAPOX – In a single-arm phase II trial of 40 patients with advanced pancreatic cancer and ECOG PS ≥2, capecitabine plus oxaliplatin demonstrated an ORR of 13 percent [87]. Median PFS and OS were four and seven months, respectively.

●FOLFIRI – In a phase II trial of 40 patients with previously untreated advanced pancreatic cancer, FOLFIRI demonstrated an ORR of 38 percent. Median PFS and OS were 6 and 12 months, respectively [89]. Similar results were seen in another study, including an ORR of 25 percent [88].

ECOG PS 0 to 2 with hyperbilirubinemia — Some patients may have mild to moderate elevations in serum total bilirubin that are greater than 1.5 times ULN, despite appropriate endoscopic or surgical interventions to decompress the biliary tract. For such patients with an ECOG PS of 0 to 2 who otherwise have a good comorbidity profile (table 6), we suggest a fluorouracil-based regimen (FOLFOX or infusional fluorouracil plus leucovorin) rather than a dose-adjusted gemcitabine-containing regimen, since these regimens are less impacted by hepatic metabolization. Regimens that contain irinotecan are generally not used in these patients since irinotecan is mainly eliminated by the liver. (See 'Fluoropyrimidine-based combination therapy' above and 'Fluorouracil plus leucovorin' below and "Hepatotoxicity of chemotherapy and other cytotoxic agents", section on 'Irinotecan and liposomal irinotecan'.)

Poor PS and/or significant comorbidities — For patients with an ECOG PS of 3 who are still candidates for systemic therapy (table 6), we have an extensive discussion of patient values and preferences in determining the best initial therapeutic option. Well-tolerated single-agent chemotherapy is appropriate for patients willing to undergo the risks of adverse effects, despite low ORRs. Options include gemcitabine, infusional fluorouracil plus leucovorin, or capecitabine. Patients who select this approach should be counseled that single-agent chemotherapy has minimal activity, with ORRs of less than 10 percent and a median OS of less than six months.

Patients who are not candidates for any form of systemic therapy (eg, ECOG PS of 4, severe cytopenias, significant or poorly controlled comorbidities, severe hyperbilirubinemia, poor hepatic function) should be offered best supportive care alone. (See 'Supportive care' above.)

Gemcitabine — Gemcitabine monotherapy (table 11) is a well-tolerated regimen in metastatic pancreatic cancer that improved OS in a randomized trial.

Based on initial studies, including a phase II trial [90-92], gemcitabine was evaluated in a randomized controlled clinical trial of 126 patients with previously untreated advanced pancreatic cancer [93]. Relative to FU, gemcitabine improved OS (median 5.6 versus 4.4 months, one-year OS 18 versus 2 percent) and the clinical benefit response rate (24 versus 5 percent). There were no confirmed objective responses for either treatment arm. Grade 3 or 4 neutropenia was more frequent with gemcitabine than FU (23 versus 5 percent). In a separate study, responses to gemcitabine were not associated with an appreciable improvement in health-related quality of life (HRQOL) [94]. Small improvements were seen in pain, mood, and slowing of functional deterioration.

Gemcitabine monotherapy is approved by the FDA for the first-line treatment of metastatic pancreatic cancer.

Fluorouracil plus leucovorin — Contemporary studies of fluorouracil plus leucovorin in patients with advanced disease suggest a very low response rate (0 to 9 percent) using infusional as well as bolus administration schedules [95-97]. Median OS ranges from three to six months [95-97].

Capecitabine — The efficacy of capecitabine, an oral fluoropyrimidine, was demonstrated in a phase II trial of 42 patients with chemotherapy-naïve advanced pancreatic cancer [98]. Although objective responses were seen in only three patients (7 percent), the clinical benefit response rate was 24 percent.

SPECIAL POPULATIONS

Acinar cell carcinoma — For patients with metastatic acinar cell carcinoma (ACC), we suggest initial therapy with a fluorouracil and oxaliplatin-based regimen rather than other systemic agents, based on limited data. Preferred options include FOLFIRINOX for patients with good Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 to1) or FOLFOX for patients with less optimal PS (ECOG PS of 2) or are anticipated to not tolerate the potential toxicities of FOLFIRINOX.

ACC is a rare malignant exocrine pancreatic neoplasm with a better prognosis than that of pancreatic ductal adenocarcinoma, but limited data are available to guide initial therapy in the metastatic setting. In case reports and observational studies of patients with advanced or metastatic ACC, compared with gemcitabine-based regimens, fluoropyrimidines in combination with oxaliplatin resulted in higher objective responses or stable disease (ranging from 15 to 86 percent), many of which were durable [99-108]. ACCs may also be associated with BRCA2 pathogenic variants, which could explain the sensitivity of such tumors to oxaliplatin-based therapy. Further details on the histopathology and molecular alterations associated with ACC are discussed separately. (See "Pathology of exocrine pancreatic neoplasms", section on 'Acinar cell carcinoma' and "Molecular pathogenesis of exocrine pancreatic cancer", section on 'BRCA2 and BRCA1'.)

ASSESSING TREATMENT RESPONSE

●Imaging studies – For patients actively receiving treatment for metastatic pancreatic cancer, periodic imaging studies are used to assess tumor response to therapy. We obtain either a contrast-enhanced CT or gadolinium-enhanced magnetic resonance imaging (MRI) of the abdomen and pelvis every two to three months while on therapy [3,109]. For patients whose initial staging imaging studies confirm or suggest metastatic disease above the diaphragm (eg, new suspicious lung nodules), we also obtain interval chest imaging (eg, a contrast-enhanced CT of the chest) to assess for a potential treatment response in these lesions.

●Serum tumor markers – If initially elevated, we measure serum levels of the tumor marker carbohydrate antigen 19-9 (CA 19-9) at the start of treatment and then every one to three months during therapy. Of note, CA 19-9 requires expression of the Lewis blood group antigen (a glycosyl transferase). Among individuals with a Lewis blood group antigen-negative phenotype (an estimated 5 to 10 percent of the population), CA 19-9 levels are not a useful tumor marker. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Role of tumor markers'.)

•For patients who respond to therapy, decreases in CA 19-19 are a gradual process since this tumor marker has an estimated half-life of 15 to 33 days [110].

•However, for those with rising CA 19-9 levels while on therapy, disease progression should be confirmed on imaging studies. CA 19-9 alone is not an optimal substitute for radiographic imaging to assess treatment response [3].

INVESTIGATIONAL APPROACHES

●Gemcitabine plus nimotuzumab – In a placebo-controlled phase III trial conducted in China of 82 patients with KRAS wild-type metastatic pancreatic cancer, the addition of nimotuzumab, an epidermal growth factor receptor (EGFR) inhibitor, to gemcitabine improved progression-free survival (PFS; median 4.2 versus 3.6 months) and overall survival (OS; 10.9 versus 8.5 months) [111]. The use of this combination remains investigational. Additionally, the use of nimotuzumab is limited to pancreatic cancers that are KRAS wild-type, which occurs in less than 10 percent of all pancreatic cancers. (See "Molecular pathogenesis of exocrine pancreatic cancer", section on 'KRAS'.)

●Alternating gemcitabine plus nabpaclitaxel with FOLFOX – In a randomized phase II trial (SEQUENCE) of 157 patients with previously untreated metastatic pancreatic cancer, alternating gemcitabine plus nabpaclitaxel with FOLFOX improved OS over gemcitabine plus nabpaclitaxel alone but increased toxicity [112,113]. This approach remains investigational, as it is not clear that alternating these regimens during initial therapy is better than sequential administration of these regimens at the time of disease progression.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pancreatic cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Pancreatic cancer (The Basics)")

●Beyond the Basics topic (see "Patient education: Pancreatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – Although the goals of therapy for metastatic exocrine pancreatic cancer (malignant tumors arising from ductal or acinar cells) are palliative and not curative, systemic therapy reduces cancer-related symptoms and improves overall survival (OS) and quality of life.

●Pretreatment evaluation – Pretreatment evaluation includes a contrast-enhanced CT scan of the chest, abdomen, and pelvis, laboratory testing including a carbohydrate antigen 19-9 (CA 19-9), management of cancer-related symptoms and psychosocial concerns, and early palliative care referral. (See 'Pretreatment evaluation' above.)

●Genetic testing – We assess all patients with metastatic exocrine pancreatic cancer for both germline and somatic (tissue) molecular alterations, which guides selection of initial therapy (algorithm 2). (See 'Genetic testing' above.)

●Initial therapy for tumors with actionable molecular alterations

•BRCA1/2 or PALB2 pathogenic variants – For patients with a germline or somatic pathogenic variant in BRCA1/2 or PALB2, we recommend platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase (PARP) inhibitor rather than other systemic agents (Grade 1B). For those with a good performance status (PS), we typically use modified FOLFIRINOX (table 3). Gemcitabine plus cisplatin (table 4) is an appropriate alternative. (See 'BRCA1/2 or PALB2 pathogenic variants' above.)

•Other homologous recombination deficiency (HRD) pathogenic variants – For patients with pathogenic variants (either somatic or germline) in HRD genes other than the core genes (BRCA1/2 or PALB2), such as ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1, we suggest platinum-based therapy, such as modified FOLFIRINOX (table 3), rather than a non-platinum-based regimen (Grade 2C). We do not offer gemcitabine plus cisplatin to this population due to lack of data. (See 'Non-core HRD pathogenic variants' above.)

•Mismatch repair deficient (dMMR)/microsatellite-instability high (MSI-H tumors) – For patients with dMMR/MSI-H tumors, we suggest pembrolizumab rather than chemotherapy (Grade 2C). Nivolumab plus ipilimumab is a reasonable alternative for medically fit patients, although high-quality data are limited. (See 'MSI-H/dMMR tumors' above.)

•Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors – For patients with NTRK gene fusion-positive tumors, we suggest larotrectinib or entrectinib rather than other systemic agents (Grade 2B). (See 'TRK fusion-positive tumors' above and "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'TRK fusion-positive cancers'.)

•Rearranged during transfection (RET) fusion-positive tumors – For patients with a RET gene fusion-positive tumor, we suggest selpercatinib rather than other systemic agents (Grade 2B). (See 'RET fusion-positive tumors' above and "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'RET fusion-positive tumors'.)

•BRAF V600E mutation-positive tumors – For patients with BRAF V600E mutation-positive tumors, we offer chemotherapy using the same approach to initial therapy as those without an actionable molecular alteration. Dabrafenib plus trametinib is an alternative for those who are ineligible for or decline chemotherapy. (See 'BRAF V600E positive-tumors' above.)

•KRAS G12C mutation-positive tumors – For patients with a KRAS G12C mutation-positive tumor, we offer chemotherapy using the same approach to initial therapy as those without an actionable molecular alteration. Sotorasib or adagrasib are alternatives for those who are ineligible for or decline chemotherapy. (See 'KRAS G12C positive-tumors' above.)

●Initial therapy for tumors with no actionable molecular alterations – For patients without an actionable molecular alteration, or while awaiting the results of genetic testing, selection of initial therapy (algorithm 2) is based upon patient PS, laboratory values (including total bilirubin), comorbidities (table 6), and goals of care. Patients whose genetic test results reveal an actionable molecular alteration may switch to the appropriate therapy, if necessary. (See 'No actionable molecular alterations' above and 'Patients awaiting genetic testing results' above.)

•Good PS, no hyperbilirubinemia – For patients with a good comorbidity profile (table 6), good Eastern Cooperative Oncology Group (ECOG) PS (0 or 1 (table 5)), and total bilirubin less than 1.5 times the upper limit of normal (ULN), we suggest dose-modified FOLFIRINOX (table 3) rather than other systemic agents (Grade 2C). (See 'FOLFIRINOX' above.)

Appropriate alternatives include gemcitabine plus nabpaclitaxel (table 7) and NALIRIFOX. (See 'Gemcitabine plus nabpaclitaxel' above and 'NALIRIFOX' above.)

•ECOG PS of 2, no hyperbilirubinemia – For patients with a good comorbidity profile (table 6), ECOG PS of 2 (table 5), and a total serum bilirubin less than 1.5 times ULN, we suggest gemcitabine plus nabpaclitaxel (table 7) rather than other systemic agents (Grade 2C). (See 'ECOG PS of 2, no hyperbilirubinemia' above.)

•ECOG PS of 0 to 2 with hyperbilirubinemia – For patients with mild to moderate elevations in serum total bilirubin greater than 1.5 times ULN who otherwise have a good comorbidity profile (table 6), we suggest a fluorouracil-based regimen (FOLFOX or infusional fluorouracil plus leucovorin) rather than a dose-adjusted gemcitabine-containing regimen (Grade 2C), since these regimens are less impacted by hepatic metabolization. Regimens that contain irinotecan are generally not used in these patients since irinotecan is mainly eliminated by the liver. (See 'ECOG PS 0 to 2 with hyperbilirubinemia' above.)

•Poor PS and/or significant comorbidities – For patients with an ECOG PS of 3 who otherwise have a good comorbidity profile (table 6), we have an extensive discussion of patient values and preferences in determining the best initial therapeutic option. Well-tolerated single agent chemotherapy (eg, gemcitabine, infusional fluorouracil plus leucovorin, or capecitabine) is appropriate for some patients willing to undergo the risks of adverse effects, despite low objective response rates (ORRs). (See 'Poor PS and/or significant comorbidities' above.)

Patients who are not candidates for any form of systemic therapy should be offered best supportive care alone. (See 'Supportive care' above.)