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[109]
in advanced PDAC . Recent experimental data suggest that MTKIs may remodel the PDAC
microenvironment, enhancing the efficacy of immunotherapy, which may lead to trials combining MTKIs
[110]
with immune checkpoint inhibitors . In the neoadjuvant setting, the NCT00557492 trial examining the
combination of RT with bevacizumab and gemcitabine before surgery has been completed; there are no
available results yet.

Targeting the intense desmoplastic activity of PDAC is another interesting area of research. Saridegib
(IPI-926), an inhibitor of the Sonic Hedgehog pathway involved in fibroblastic proliferation, has been tested
[111]
in a phase I trial together with FFX in advanced PDAC . Hyaluronan depletion through the
administration of pegylated hyaluronidase (PEGPH20) is also of therapeutic relevance in PDAC. A
randomized trial combining PEGPH20 with GnP did not, however, improve the survival of patients with
[112]
metastatic PDAC . In fact, the SWOG S1313 trial showed detrimental effects .
[113]
In patients with BRCA mutations, DNA repair is compromised. In this subgroup of patients, poly(ADP-
ribose) polymerase (PARP) compensates for the missing repair activity of BRCA. PARP inhibitors, such as
olaparib, improve the survival of PDAC patients with BRCA mutations, administrated either as
monotherapy or in combination with gemcitabine . The POLO trial randomized patients whose disease
[114]
had not progressed after platinum-based chemotherapy to maintenance olaparib or placebo; the results,
although not statistically significant, displayed a trend towards longer time to subsequent chemotherapy and
overall survival with olaparib treatment . The ongoing APOLLO trial (NCT04858334), sponsored by the
[115]
NCI, is investigating olaparib’s role as a postoperative monotherapy regimen in R-PDAC, but there are no
trials at the neoadjuvant level. Niraparib is also under investigation in the treatment of PDAC
(NCT03553004).

Losartan is an angiotensin II receptor blocker, mostly used to treat hypertension. It was also utilized in the
neoadjuvant setting as a targeting agent for LA-PDAC treatment in a single-arm phase II study by
[116]
Murphy et al. ; neoadjuvant FFX combined with losartan followed by either short or long course chemo-
RT was prescribed in patients with unresectable PDAC. Surgery was performed in 86% of patients, while R0
resection was achieved in 69% of them. In the subgroup of patients who underwent surgery, median PFS
and OS were longer when compared to the overall median PFS and OS (21.3 and 33 months vs. 17.5 and
31.4 months, respectively). Losartan, together with FFX, SBRT, and nivolumab, is also under investigation
in a phase II trial for LA-PDAC (NCT03563248).

ONGOING TRIALS ON NEOADJUVANT CHEMOTHERAPY AND CHEMO-RT
There are several ongoing phase II and III trials for PDAC, examining both chemotherapy [Table 3] and
chemo-RT [Table 4] in the neoadjuvant setting. Selected trials are presented in this section.

LA-PDAC
Connective tissue growth factor (CTGF) promotes the growth of fibroblasts and angiogenesis . The
[117]
NCT03941093 phase III trial is examining the addition of an anti-CTGF MoAb to the standard FFX or GnP
neoadjuvant chemotherapy, aiming at OS. Alternating electric fields have a direct inhibitory effect on tumor
growth . In this context, the PANOVA-3 (NCT03377491) phase III trial is actively recruiting patients to
[118]
assess the effects of GnP plus alternated electric tumor treating field (TTFields), provided by an externally
applied device, on OS. The Y2018-ZD-001 (NCT03673137) phase II/III trial incorporates irreversible
electroporation to chemotherapy with gemcitabine, which could potentially enhance the bioavailability of
drugs. Gene therapy is also being explored in the THERGAP-02 (NCT02806687) phase II trial, which
randomizes patients to gemcitabine alone or gemcitabine plus intratumoral injection of CYL-02 (plasmid