Reply to N. Fazio

We thank Fazio¹ for his letter, and we appreciate the thoughtful questions he raised. We have addressed each of them here. First, he pointed out that there are no random assignment trials comparing platinum-based therapy to non-platinum–based therapy in this specific patient population (BRCA/PALB2-mutated pancreatic ductal adenocarcinoma [PDAC]) to definitively test the role of platinum-based therapy as the superior treatment approach. Nonetheless, the concept that synthetic lethality for BRCA-deficient cells renders these cells highly vulnerable to DNA cross-linking agents is well characterized across multiple tumor types (including breast cancer).² Preclinical data support the use of platinum-based therapy over non-platinum–based therapy in mutated versus wild-type BRCA1/2 xenografts.³ Furthermore, Pishvaian et al⁴ have reported that specifically in PDAC (in both early- and late-stage disease), platinum-based therapy is superior to non-platinum–based therapy in patients with homologous repair deficiency (HRD). In addition, the authors have a manuscript in review that underscores that platinum therapy over non-platinum therapy early in the disease course for patients with HRD and advanced-stage PDAC maximizes outcome.⁵

Second, Fazio questions whether cisplatin-gemcitabine represents the standard of care over modified fluorouracil, oxaliplatin, irinotecan, and leucovorin (mFOLFIRINOX) or nab-paclitaxel-gemcitabine. Although we agree that there has not been a head-to-head comparison of cisplatin-gemcitabine versus mFOLFIRINOX, mFOLFIRINOX has not been prospectively tested in this specific patient population. There are only anecdotal data regarding mFOLFIRINOX in BRCA-mutated PDAC. We do not believe the outcome differences for this patient population are solely a result of the prognostic effect of BRCA/PALB2 mutations; there are relatively limited data to support this observation in PDAC, and data from the author addresses this point.⁵ We believe the major improvement in outcome is primarily related to the efficacy of platinum-based therapy in BRCA-mutated PDAC as in other germline BRCA-mutated cancers and is not solely the prognostic effect of these mutations.

Third, regarding the choice of which platinum agent to use, we agree that there is no clinical comparative data to suggest that one platinum agent may be better than another, specifically cisplatin versus oxaliplatin. However, we note the following points: (1) low-dose cisplatin as used by O’Reilly et al,⁶ is well-tolerated and can typically be administered on an indefinite basis, (2) oxaliplatin dosing is often limited by cumulative neuropathy and hypersensitivity or infusion reactions, and (3) preclinical data support that cisplatin may be more potent in view of its underlying mechanism of activity over oxaliplatin.^7,8 As noted above, there are no randomized data comparing cisplatin-gemcitabine to FOLFIRINOX or to leucovorin, fluorouracil, and oxaliplatin (FOLFOX). With respect to FOLFIRINOX compared with FOLFOX, again there are no randomized data in PDAC, nor in this specific patient population. However, phase II data for treatment with FOLFOX⁹ seem significantly inferior to that for FOLFIRINOX¹⁰ in unselected patients with PDAC.

Fourth, the response rate of cisplatin-gemcitabine with or without veliparib was high (65% to 74%), and we concur that this regimen is of interest in a neoadjuvant setting. As Fazio points out, small numbers of patients preclude any definitive statement regarding locally advanced PDAC. Most of the patients in our study had locally advanced, unresectable disease with vascular encasement with a low baseline potential for future surgery.

Fifth, the National Comprehensive Cancer Network endorsement for universal germline testing in pancreas cancer represents an important step and will allow more patients to be identified who may benefit from enhanced treatment selection at baseline as a consequence of this information. For an individual in whom the germline status is confirmed for mutated BRCA/PALB2 in PDAC, we believe treatment with cisplatin-gemcitabine should be the first choice. mFOLFIRINOX represents an option, especially if there is impaired renal or auditory function or performance status. For an individual in whom the germline status is not available before therapy is initiated, we favor FOLFIRINOX as the initial therapeutic step.

Sixth, we believe that a platinum-based regimen (we favor cisplatin-gemcitabine for the reasons noted above) as opposed to a non-platinum–based regimen (eg, nab-paclitaxel-gemcitabine) is the appropriate treatment choice for an individual with germline mutated BRCA/PALB2 PDAC. We believe an induction period of platinum therapy could be followed in responding patients using the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. We further note that the POLO (ClinicalTrials.gov identifier: NCT02184195) trial¹¹ was not in any way designed to evaluate which initial platinum therapy is optimal in the setting of BRCA-mutated PDAC.

Major unmet needs moving forward will include the ability to delay and overcome development of resistance to platinum agents and PARP inhibitors and will focus on expanding the signal observed with these agents in the HRD PDAC setting to a greater number of patients.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Reply to N. Fazio

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Eileen M. O'Reilly

Consulting or Advisory Role: Merck, Agios (I), AstraZeneca (I), Bayer (I), BeiGene (I), Berry Genomics (I), Celgene (I), CytomX Therapeutics, Debiopharm Group (I), Eisai (I), Exelixis/Ipsen (I), Flatiron Health (I), Genoscience Pharma (I), Incyte (I), Jansen, LAM Therapeutics (I), Eli Lilly (I), Genentech (I), QED Therapeutics (I), RedHill Biopharma (I), SillaJen (I), Sobi, Targovax, Yiviva (I), Rafael (I)

Research Funding: AstraZeneca/MedImmune (Inst), Acta Biologica, Celgene, MabVax Therapeutics

Wungki Park

Honoraria: Ipsen

Research Funding: Astellas Pharma (Inst), Merck (Inst), Gossamer Bio (Inst)

David P. Kelsen

Consulting or Advisory Role: Steba biotech, Novo Nordisk, Kitov Pharma

Patents, Royalties, Other Intellectual Property: Use of iron-containing particles in magnetic resonance imaging

No other potential conflicts of interest were reported.