Erdafitinib Research Articles

2020TiP SOGUG-NEOWIN: A phase II, open-label, multi-centre trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) and FGFR gene alterations

2020TiP SOGUG-NEOWIN: A phase II, open-label, multi-centre trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) and FGFR gene alterations

SOGUG-NEOWIN: A phase 2, open-label, multi-centre, multi-national interventional trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC) whose tumours express FGFR gene alterations.

TPS4623 Background: The standard treatment for nonmetastatic MIBC is neoadjuvant cisplatin-based therapy followed by radical cystectomy (RC). However, many patients are ineligible for cisplatin. Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for metastatic urothelial cancer (mUC), including for cisplatin-ineligible patients. Based on these results, ICIs are being explored as neoadjuvant treatment in resectable UC with preliminary data suggesting antitumour activity. ERDA is a Fibroblast Growth Factor Receptor (FGFR) inhibitor, which has shown efficacy in advanced UC with select FGFR2/3 mutations/fusions. ERDA plus cetrelimab demonstrated clinically meaningful activity in patients with newly diagnosed FGFR-altered mUC in the phase 2 NORSE trial. We hypothesize that ERDA plus cetrelimab will improve the pathological complete response (pCR) rate in patients with FGFR+ MIBC who are candidates for RC and are ineligible for or refuse neoadjuvant cisplatin-based therapy. Methods: SOGUG-NEOWIN is a prospective, non-comparative, open label, multicentre, international trial to assess the efficacy of 9 or 12 weeks of neoadjuvant ERDA (cohort 1) or the combination of cetrelimab and ERDA (cohort 2) in patients with MIBC (cT2-Ta N0/1 M0) and FGFR alterations. Key eligibility criteria include ECOG PS 0-1; pure or predominant UC histology; decline or ineligible for cisplatin-based chemotherapy as defined by one of the following criteria: impaired renal function (GFR < 60 mL/min), ≥ grade 2 hearing loss, or ≥ grade 2 peripheral neuropathy; patients are considered fit for cystectomy; no prior FGFR-targeted or anti-PD-(L)1 therapy; no prior systemic therapy, radiation or surgery (except TURBT or biopsies) for bladder cancer; prior BCG was allowed if completed ≥ 6 weeks before initiation of study treatment; no current retinopathy. A total of 45 patients will be allocated to each cohort by a centralized system. Co-primary endpoints are pCR rate and percentage of pathological downstaging response (<ypT2). Secondary endpoints include event-free survival, overall survival, overall response rate, safety, tolerability, and delay to surgery. Biomarkers of response and resistance will be assessed using baseline archival tissues, blood and urine. Quality of life (QoL) will be assessed using FACT-Bl and EQ-5D-5L. Tumour response assessment via PET-MRI will be performed in a subset of patients. The trial is approved in 4 countries. The first patient was included on 31-Jan-2024. This trial would be the first to systematically address whether ERDA ± cetrelimab improves pCR in patients with FGFR-positive MIBC. (EudraCT 2022-002586-15). Clinical trial information: 2022-002586-15.

In vitro biodistribution studies on clinically approved FGFR inhibitors ponatinib, nintedanib, erlotinib and the investigational inhibitor KP2692

Binding towards human serum albumin (HSA) and α1-acid glycoprotein (AGP) of three approved fibroblast growth factor receptor (FGFR) inhibitors ponatinib (PON), nintedanib (NIN) and erdafitinib (ERD), as well as the experimental drug KP2692 was studied by means of spectrofluorometric and UV–visible spectrophotometric methods. Additionally, proton dissociation processes, lipophilicity, and fluorescence properties of these four molecules were investigated in detail. The FGFR inhibitors were predominantly presented in their single protonated form (HL+) at pH 7.4 (at blood pH). At gastric pH (pH 1–2) the protonated forms (+1 – +3) are present, which provide relatively good aqueous solubility of the drugs. All of the four inhibitors are highly or extremely lipophilic at pH 7.4 (logD7.4 ≥ 2.7). At acidic pH 2.0 PON and ERD are rather lipophilic, NIN is amphiphilic, while KP2692 is highly hydrophilic. All four compounds bind to HSA and AGP. Moderate binding of PON, KP2692 and NIN was found towards albumin (logK’ = 4.5–4.7), while their affinity for AGP was about one order of magnitude higher (logK’ = 5.2–5.7). ERD shows a larger affinity for both proteins (logK’HSA ≈ 5.2, logK’AGP ≈ 7.0). The computed constants were used to model the distribution of the FGFR inhibitors in blood plasma under physiological and pathological (acute phase) conditions. The changing levels of the two proteins under pathological conditions compensate each other for PON and NIN, so that the free drug fractions do not change considerably. In the case of ERD the higher AGP levels distinctly reduce the free available fraction of the drug. Comparison with clinical pharmacokinetic data indicates that the here presented solution distribution studies can very well predict the conditions in cancer patients.

LBA102 THOR-2 cohort 1: Results of erdafitinib (ERDA) vs intravesical chemotherapy (chemo) in patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) with select fibroblast growth factor receptor alterations (FGFRALT) who received prior bacillus calmette-guérin (BCG) treatment

LBA102 THOR-2 cohort 1: Results of erdafitinib (ERDA) vs intravesical chemotherapy (chemo) in patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) with select fibroblast growth factor receptor alterations (FGFRALT) who received prior bacillus calmette-guérin (BCG) treatment

Abstract 1117: Acquired resistance to ATP-competitive and irreversible FGFR inhibitors (FGFRi's): A library-based approach

Abstract Background: The emergence of secondary FGFR kinase domain (KD) mutations with FGFRi's leads to drug resistance and disease progression. The frequency of resistance mutations with individual FGFRi's is unknown. Using an unbiased library-based approach, we examined the development of acquired resistance with the irreversible FGFRi futibatinib and the ATP-competitive FGFRi's erdafitinib (ERD) and pemigatinib (PEM). Methods: Mutant (mt) libraries were generated with random mutagenesis in two FGFR2 KD regions: #1 (amino acids [aa] 540-569), and #2 (aa 640-669). Library were transfected as TEL-fusions into Ba/F3 cells, resulting in FGFR2-dependent cell growth. Transfected cells were treated with FGFRi's at concentrations suppressing parental cell line growth. Surviving drug-resistant clones were counted, isolated, and sequenced to identify the KD mutation. The inhibitory activity of FGFRi's against resistant clones was assessed using phospho-FGFR2 ELISA. Results: Treatment of the library-transfected Ba/F3-TEL-FGFR2 KD cells with PEM, ERD, and futibatinib resulted in an average (n=2) of 93, 27, and 13 resistant clones in region #1 and 28, 21 and 1 resistant in region #2, respectively. Sequencing (table) identified, among others, the following aa mutations: N549, E565, and K641 (regulatory triad), V564 (gatekeeper region) and K659 (activation loop), also seen in patients who developed resistance to Debio1347, infigratinib, and PEM. Among FGFR mts shown (table), futibatinib inhibited 8/10, and ERD, 5/10 mts at IC50 values comparable to wild type (wt) FGFR; however, PEM activity against all FGFR mts was attenuated by ≥5-fold vs wt. Conclusions: Resistance mutations identified with this unbiased library-based in vitro approach were consistent with those observed in the clinic. Acquired drug resistance mutations were less frequent with futibatinib than with ATP-competitive FGFRi's. Futibatinib demonstrated the most robust inhibition of drug resistant mts. FGFR mutationKD regionFutibatinib IC50 (nM)Erdafitinib IC50 (nM)Pemigatinib IC50 (nM)Wild-type (parent)-2.12.51.5N549DRegulatory triad4.225.5153.2N549KRegulatory triad16.732.0246.2V562L-6.32.97.7V564IGatekeeper8.32.762.4V564LGatekeeper91.956.5502.3E565ARegulatory triad6.82.911.8E565GRegulatory triad3.93.09.0K641IRegulatory triad3.855.829.6K641RRegulatory triad4.73.210.3K659MActivation loop9.546.633.8 Citation Format: Hiroshi Sootome, Suzuko Kato, Masanori Kato, Hiroshi Hirai. Acquired resistance to ATP-competitive and irreversible FGFR inhibitors (FGFRi's): A library-based approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1117.

Mechanism-Based Inactivation of Cytochrome P450 3A4 and 3A5 by the Fibroblast Growth Factor Receptor Inhibitor Erdafitinib.

Erdafitinib (ERD) is a first-in-class pan inhibitor of fibroblast growth factor receptor 1-4 that has garnered global regulatory approval for the treatment of advanced or metastatic urothelial carcinoma. Although it has been previously reported that ERD elicits time-dependent inhibition (TDI) of cytochrome P450 (P450) 3A4 (CYP3A4), the exact biochemical nature underpinning this observation remains obfuscated. Moreover, it is also uninterrogated if CYP3A5-its highly homologous counterpart-could be susceptible to such interactions. Mechanism-based inactivation (MBI) of P450 is a unique subset of TDI that hinges on prior bioactivation of the drug to a reactive intermediate and possesses profound clinical and toxicological implications due to its irreversible nature. Here, we investigated and confirmed that ERD inactivated both CYP3A isoforms in a time-, concentration-, and NADPH-dependent manner with KI, kinact, and partition ratio of 4.01 and 10.04 μM, 0.120 and 0.045 min-1, and 32 and 55 for both CYP3A4 and CYP3A5, respectively, when rivaroxaban was employed as the probe substrate. Co-incubation with an alternative substrate or direct inhibitor of CYP3A attenuated the rate of inactivation, whereas the addition of glutathione or catalase did not induce such protection. The lack of enzyme activity recovery following dialysis for 4 h and oxidation with potassium ferricyanide combined with the lack of a Soret peak in spectral scans collectively substantiated that ERD is an irreversible covalent MBI of CYP3A. Finally, glutathione trapping and high-resolution mass spectrometry experiments illuminated a plausible bioactivation mechanism of ERD by CYP3A arising from metabolic epoxidation of its quinoxaline ring.

Management of fibroblast growth factor receptor inhibitor (FGFRi) treatment-emergent adverse events (TEAEs) of interest in patients (Pts) with locally advanced or metastatic urothelial carcinoma (mUC).

426 Background: Erdafitinib (ERDA), a pan-FGFR kinase inhibitor, was US FDA approved for adults with mUC with susceptible FGFR3/2 alterations ( FGFRa) who progressed on ≥ 1 line of prior platinum-based chemotherapy based on primary results of the BLC2001 trial (NCT02365597). At final analysis (median 2-y follow-up), ERDA showed median OS of 11.3 mo and a manageable safety profile. Some FGFRi toxicities are distinct from those of other small-molecule TKIs. Proactive AE management can avoid treatment discontinuation, ensuring maximum benefit. We report the frequency and management of TEAEs of interest (central serous retinopathy [CSR], hyperphosphatemia [“on-target” FGFRi class effect], stomatitis, and skin and nail toxicities) for the optimal schedule of ERDA from the final analysis of BLC2001. Methods: The open-label, phase II BLC2001 study enrolled pts with measurable mUC, prespecified FGFRa, and progression during/after ≥ 1 line of prior chemotherapy or ≤ 12 mos of (neo)adjuvant chemotherapy or who were cisplatin ineligible, chemo naive. Optimal dose schedule in the study was 8 mg/d continuous ERDA in 28-d cycles with uptitration to 9 mg/d (ERDA 8 mg/d UpT) if prespecified serum phosphate level was not reached and no significant TEAEs occurred. ERDA 8 mg/d UpT safety results as of Aug 9, 2019 (final analysis) are summarized here. AEs were graded using NCI CTCAE v4.0. Results: Median follow-up for 101 pts treated with ERDA 8 mg/d UpT was 24.0 mos; median treatment duration was 5.4 mos. All pts had ≥ 1 TEAE. Hyperphosphatemia, stomatitis, nail disorders, skin disorders, and CSR TEAEs occurred in 78%, 59%, 59%, 55%, and 27% of pts, respectively (few were grade [gr] 3; none were gr ≥ 4; Table). TEAEs were mostly managed with concomitant treatment and dose modifications. As of data cutoff, hyperphosphatemia had resolved in 74/79 (94%) pts; stomatitis in 44/60 (73%); nail and skin TEAEs in 26/60 (43%) and 25/55 (45%), respectively; and CSR in 17/27 (63%). Most unresolved TEAEs were gr 1–2. No treatment-related deaths occurred. Conclusions: ERDA had measurable benefit in pts with advanced UC with FGFRa. As with other targeted therapies, exposure to ERDA is associated with a pattern of AEs. The most common and FGFRi class effect TEAEs were generally reversible and managed by supportive care and dose modification. Clinical trial information: NCT02365597 . Research Sponsor: Janssen Research & Development, LLC[Table: see text]

752P Updated data from the NORSE trial of erdafitinib (ERDA) plus cetrelimab (CET) in patients (pts) with metastatic or locally advanced urothelial carcinoma (mUC) and specific fibroblast growth factor receptor (FGFR) alterations

ERDA (an oral pan-FGFR inhibitor) plus CET (an immunoglobulin G4 monoclonal antibody specific for programmed death protein 1 [PD-1]) showed promising activity in the NORSE study (Moreno ASCO GU 2020, abst. 511). We present updated results from the phase 1b/2 NORSE study (NCT03473743).

750P Erdafitinib (ERDA) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC): Subgroup analyses of long-term efficacy outcomes of a pivotal phase II trial (BLC2001)

750P Erdafitinib (ERDA) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC): Subgroup analyses of long-term efficacy outcomes of a pivotal phase II trial (BLC2001)

Evolving development of PD-1 therapy: Cetrelimab (JNJ-63723283) from monotherapy to combination with erdafitinib.

3055 Background: Cetrelimab (CET) is an investigational checkpoint inhibitor (CI). In part 1 of a first-in-human (FIH) trial (LUC1001; NCT02908906), pts with advanced solid tumors with ≥1 prior treatment received CET 80–800 mg Q2W or 480 mg Q4W. Response rates and safety profiles were similar to other CIs. Based on preclinical and clinical data, a phase 1/2 study (NORSE; NCT03473743) of CET + erdafitinib (ERD) in metastatic urothelial carcinoma (mUC) + FGFR alterations (alt) was initiated and is ongoing. Methods: In LUC1001 Part 2, pts with nonsmall cell lung cancer (NSCLC), melanoma (MEL), or MSI-H/dMMR colorectal cancer (CRC) received CET IV 240 q2w. Overall response rates (ORR = % complete response + partial response [PR] confirmed) were assessed as per RECIST v1.1. Adverse events (AEs) were assessed for all patients receiving CET IV 240 q2w in parts 1 and 2. Results: As of July 1, 2019, 122 pts with NSCLC (n=30); MEL (n=50); or CRC (n= 42) had been treated in Part 2. Median age ranged from 58 to 64 yrs (overall range, 23–86 yrs). Duration of treatment was 8.1 mos (range, 0.0-24.7) for NSCLC; 5.5 mos (range, 0.0-25.0) for MEL; and for 3.0 mos (0.0-16.1) for CRC. ORR was 37% in NSCLC; 53% in PD-L1+ NSCLC (≥50% by IHC), 28% in MEL; 32% in non-uveal MEL, 14% in CRC and 24% in centrally confirmed MSI-high CRC. In all CET IV 240 q2w treated pts in the FIH study (N= 162), treatment-related grade ≥3 and serious AEs were reported in 15% and 12% of pts, respectively. All grade and grade ≥3 immune-related (ir) AEs were reported in 41% and 8% of pts, respectively Most common ir AE: hypothyroidism (8%), asthenia (6%), diarrhea (4%), rash (4%), hyperthyroidism (4%), dyspnea (3%), pruritis (3%) and pneumonitis (3%). There was 1 treatment-related death due to myasthenia gravis. In the phase 1 combination study (NORSE), pts with mUC + FGFR alt (n=17) received fixed-dose CET IV 240 q2w + ERD 6mg, 8 mg or 8mg + up titration (UpT) to 9 mg to establish the RP2D for the combination as CET + ERD 8mg + UpT. In the RP2D group (n=10), 60% had treatment-related grade ≥3 AEs. ORR (all confirmed PR) was 50% in the all treated response-evaluable group (n=16). Conclusions: CET is a CI with efficacy and safety profiles in advanced solid tumors similar to approved CIs. In NORSE phase 1, CET+ ERD demonstrated antitumor activity in mUC with an acceptable safety profile. NORSE phase 2 is evaluating this combination as first-line therapy in pts with mUC with FGFR alt.

Erdafitinib exerts the anticancer effect on urothelial carcinoma via induction of authophagy.

Erdafitinib has recently been approved for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC). The current study aimed to evaluate whether erdafitinib inhibits the proliferation in UC via inducing authophagy. Our data showed that erdafitinib demonstrated strong toxicity for the T24 and UMUC6 cell lines. Flow cytometry analysis showed that erdafitinib increased the proportion of G0/G1 phase in both T24 and UMUC6 cells. Additionally, Annexin V staining indicated that erdafitinib enhanced the apoptosis of UC cells. Meanwhile, the expression of apoptosis-related proteins was significantly elevated after treatment with erdafitinib. Transwell assay showed that erdafitinib significantly reduced T24 and UMUC6 cell migration and invasion. More importantly, western blot assay showed that erdafitinib induced the expression of autophagy-related proteins. Besides, GFP-LC3 transfection assay and electron microscopy examination showed that erdafitinib could partially diminish 3-methyladenine (3-MA) induced impairment of autophagy in UC cells. In summary, for the first time we showed novel data that erdafitinib inhibited UC cell malignant proliferation via inducing cell autophagy.

Does escalation results from phase Ib/II Norse study of erdafitinib (ERDA) + PD-1 inhibitor JNJ-63723283 (Cetrelimab [CET]) in patients (pts) with metastatic or locally advanced urothelial carcinoma (mUC) and selected fibroblast growth factor receptor (FGFR) gene alterations.

511 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for pts with metastatic urothelial carcinoma (mUC) with susceptible FGFR3/2 gene alterations and progressed after ≥1 line of prior platinum-containing chemotherapy (PCC).1 CET, an IgG4, binds to anti-programmed cell death proteins (PD-1) and has shown activity in solid tumors.2 ERDA+CET may demonstrate complementary mechanisms as neoantigen release by ERDA may prime the tumor microenvironment for response. NORSE is a phase 1b/2 study to evaluate ERDA+CET in pts with mUC. Methods: Adult mUC pts with specific FGFR alterations who have progressed after ≥1 prior systemic therapy and no prior FGFR or PD-1/PD(L)-1 inhibitors enrolled in 3 dose levels (DL) of ERDA (DL1: 6 mg, DL2A: 8 mg, DL2: 8 mg with uptitration [UPT] to 9 mg) + CET (IV, 240 mg). Cohorts enrolled until dose limiting toxicity (DLT) or RP2D was identified. Primary endpoints: DLT and adverse events (AEs). Results: Of 15 pts (DL1: 4, DL2A: 3, DL2: 8), 11 continued on treatment at the time of the data cut. 14/15 pts experienced AEs; 3 experienced serious unrelated AEs (urinary tract infection, urosepsis, and large intestinal obstruction) all in DL1, 2 led to death; 10 experienced Grade >3 AEs and 2 experienced AEs of special interest, considered related to ERDA (Table). No DLTs were observed in any cohorts, 8 mg with UPT + CET was established as the RP2D. At data cut-off, investigator-assessed best overall response rate (CR+PR+uCR+uPR) in pts treated with the RP2D was 71% and disease control rate was 100% for RECIST 1.1 evaluable pts (n=7). Conclusions: 8 mg ERDA with UPT+240 mg CET was well tolerated and established as the RP2D. The combination of ERDA+CET is being further explored in the ongoing randomized phase 2 study in first-line cisplatin-ineligible mUC pts (NCT03473743). Clinical trial information: 2017-001980-19. [Table: see text]

A randomized phase II study of erdafitinib (ERDA) versus intravesical chemotherapy (IC) in patients with high-risk nonmuscle invasive bladder cancer (HR-NMIBC) with FGFR mutations or fusions, who recurred after Bacillus Calmette-Guérin (BCG) therapy.

TPS603 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for metastatic urothelial carcinoma (mUC) with susceptible FGFR3 or FGFR2 gene alterations and progressed on/ or after at least 1 line of prior platinum-containing chemotherapy (PCC) including within 12 months of neoadjuvant/adjuvant PCC.1 Around 40% of patients with bladder cancer present with HR-NMIBC. First-line BCG therapy fails in 30-40% of patients and subsequent treatment options are limited. This study is designed to evaluate recurrence-free survival (RFS) following treatment with ERDA vs IC in patients with FGFR positive HR-NMIBC who recurred after BCG therapy. Methods: This is an open-label, multicenter, randomized, phase 2, safety and efficacy study of ERDA in adults with histologically confirmed HR-NMIBC and FGFR mutations or fusions. Inclusion criteria: ECOG status ≤1, adequate bone marrow, liver, renal function, and ineligibility for or declining cystectomy, with no history of prior FGFR inhibitors. Patients will be enrolled into 1 of 3 cohorts. Cohort 1 (n=240): high-grade disease Ta/T1 lesion (papillary only) with disease recurrence after BCG therapy will be randomized to ERDA or IC (investigator choice: gemcitabine or mitomycin C); Cohort 2 (n=20): carcinoma in situ (CIS) with/without papillary disease to receive ERDA monotherapy; Cohort 3 (n=20): marker lesion study in patients with intermediate-risk papillary disease only to receive ERDA monotherapy. Dose will be maintained at 8 mg, up-titrated to 9 mg, or withheld based on phosphate levels. Primary endpoint: Cohort 1- RFS; Secondary endpoints: Cohort 1 - time to progression and disease worsening, disease-specific survival (invasive bladder cancer), overall survival, RFS rate at 6, 12, 24 months, and RFS on subsequent anticancer therapy (RFS2). An IDMC will be commissioned for Cohort 1. Exploratory endpoints: Cohort 2- complete response (CR) rate at 6 months; Cohort 3- CR in marker lesion. Patients will be enrolled at sites in ~14 countries. EudraCT: 2019-002449-39. Loriot Y et al. N Engl J Med. 2019;381:338-48. Clinical trial information: 2019-002449-39.

Abstract 2870: A specific pan-FGFR inhibitor has antitumor activity against prostate cancer patient derived xenografts, PDX, expressing high FGFR1

Abstract Prostate Cancer (PCa) is one of the most commonly diagnosed malignancies in men. Patients with advanced metastatic PCa have effective treatment options, but none of them are curative. Androgen deprivation is the most effective therapy, but growth of the cancer resumes over time in most cases, and the disease progresses to castration-resistant PCa (CRPC). Bone is the main site of CRPC progression. Acquired (or inherent) resistance mechanisms to second line therapy options for CRPC eventually lead to disease recurrence and, ultimately, death. The underlying mechanisms of PCa progression to first or second line therapy options are diverse and include fibroblast growth factor (FGF) axis activation. Indeed, we previously reported that blockade of FGFRs with dovitinib (TKI258) (Novartis Pharmaceuticals), a receptor tyrosine kinase inhibitor (TKI) with potent activity against FGFR1-3 and vascular endothelial growth factor receptor (VEGFR) has clinical activity in men with CRPC and bone metastases (PMID: 25186177), thus providing direction for therapy development of FGFR blockade in PCa. Because dovitinib was withdrawn from the clinic by Novartis, we seek to identify an alternative agent with activity against FGFR1 as a candidate for therapy development. With that goal, we tested the antitumor activity of a specific pan-FGFR TKI, JNJ-42756493 (JNJ) (Janssen Pharmaceutical Companies of Johnson&Johnson) against PCa patients derived xenografts (PDXs) expressing high (MDA PCa 118b) and low (MDA PCa 183) endogenous levels of FGFR1. Because bone is the primary site of CRPC progression we tested the antitumor activity of JNJ against these PDXs growing in the bone of mice. By assessing tumor volume by MRI, we found that JNJ has antitumor activity against MDA PCa 118b but not MDA PCa 183. Immunohistochemical analysis of FGFR1 expression exhibited reduction of FGFR1 in tumors of the treated group compared with vehicle treated group in MDA PCa 118b samples. Both these evidences suggest that FGFR1 is the main driver of PCa progression in this PDX and that JNJ is a potent agent against PCas with high FGFR1 expression.Due to the important role that FGF axis has in bone biology, we assessed the effect of JNJ in the bones of mice without tumors by micro-CT analysis. Interestingly, we observed a reduction in bone parameters including bone volume/ total volume (BV/TV) and trabecular thickness (Tb.Th) in the treated group compared with the vehicle treated group, suggesting FGF axis blockade reduces bone mass. However, we identified an increase in the bone surrounding the tumors in the MDA PCa 118b tumor-bearing bones of mice treated with JNJ. These results highlight the complex role of FGF axis in the PCa-bone interaction and warrant further studies to identify candidate patients for this therapy and markers of response in men treated with FGFR inhibition. Citation Format: Estefania Labanca, Jun Yang, Peter Shepherd, Xinhai Wan, Justin M. Roberts, Michael W. Starbuck, Nora M. Navone. A specific pan-FGFR inhibitor has antitumor activity against prostate cancer patient derived xenografts, PDX, expressing high FGFR1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2870.