Background: Patients (pts) with HER2-expressing breast cancer (BC) are in need of novel therapies, including chemotherapy-free treatments and more options post-progression on available therapies, such as trastuzumab deruxtecan (T-DXd). Zanidatamab (zani) is a HER2-targeted bispecific antibody that binds two domains on HER2, leading to crosslinking of adjacent HER2 molecules and multiple mechanisms of action, including inhibition of growth signaling, complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP). Evorpacept (evo) is a high-affinity CD47-blocker with an inactive IgG Fc region designed to enhance ADCP. Here, we report results from a phase 1b/2 trial of zani + evo in advanced HER2-expressing cancers. Methods: This two-part, open-label, multicenter study (NCT05027139) included pts with previously treated, inoperable, locally advanced, or metastatic (m) HER2-expressing (by local or central assessment) cancers. Part 1 evaluated safety/tolerability and established the recommended dose (RD) for Part 2. The primary objective in Part 2 was to evaluate the antitumor activity by cORR per RECIST 1.1 in HER2-positive (HER2+) mBC (cohort 1), HER2-low mBC (IHC1+ or IHC2+/ISH negative; cohort 2), and other HER2-overexpressing advanced tumors (cohort 3). DCR, DOR, PFS, OS, and safety were secondary endpoints. Prophylactic treatment for infusion-related reactions (IRRs) was mandatory. Based on the IRR rate in the first 25 pts enrolled, the protocol was amended to reverse the dosing order to zani followed by evo. Results: As of March 27, 2024, enrollment was complete with a total of 52 pts; 44 at the RD (cohort 1, n=21; cohort 2, n=15; cohort 3, n=8). Median age (range) was 59 (34-81) yrs; 15 pts (29%) had a history of brain metastasis, and 15 pts (29%) had de novo metastatic disease. By central HER2 assessment, 9/21 (43%) pts in cohort 1 had HER2+ mBC and 14/15 (93%) pts in cohort 2 had HER2-low mBC. The median number of prior systemic regimens in the metastatic setting was 6 in cohort 1, 5 in cohort 2, and 3.5 in cohort 3. All pts in cohort 1 and 5 pts in cohort 2 had prior T-DXd. Median follow-up was 7 months, with 8 pts on treatment at data cutoff. In Part 1, there were two dose-limiting toxicities, both grade 3 IRRs that resolved following treatment discontinuation. The Part 2 RD was zani 1200 mg (pts <70 kg) or 1600 mg (pts ≥70 kg) + evo 30 mg/kg IV Q2W. Among all 52 pts, treatment-related (zani or evo) adverse events (TRAEs) of any grade occurring in ≥20% of pts were diarrhea (62%), fatigue (31%), nausea (27%), and IRRs (21%). Grade 3 TRAEs occurring in ≥2 pts were diarrhea (6%) and IRRs (4%). There were no grade 4 or 5 TRAEs. Three (6%) pts had serious TRAEs (dyspnea, GGT increase, and IRR; 1 pt each). TRAEs of special interest included 1 (2%) pt with a grade 2 LVEF decrease and 12 (23%) pts with IRRs, 11 of whom had the event before the dosing order was reversed. No non-infectious pulmonary toxicities occurred. TRAEs led to treatment discontinuation and dose reductions in 2 pts (4%) each. Among response-evaluable pts treated at the RD, in cohort 1 (n=19) the cORR (95% CI) was 37% (16, 62) and the DCR (95% CI) was 74% (49, 91). The median DOR (range) was not reached (2-22 months). In the 9/19 pts in cohort 1 with centrally confirmed HER2+ mBC, the cORR (95% CI) was 56% (21, 86) and the DCR (95% CI) was 78% (40, 97). For cohort 2 (n=15), the cORR (95% CI) was 20% (4, 48) and the DCR (95% CI) was 40% (16, 68). The median DOR (range) was 6 (4-7) months. Additional efficacy results (including PFS) will be presented at the congress. Conclusions: Zani + evo showed a manageable safety profile and promising antitumor activity, particularly in pts with heavily pretreated HER2+ mBC, including prior exposure to T-DXd. Further development of this novel chemotherapy-free regimen is warranted. Citation Format: Alberto Montero, Kari B. Wisinski, Bruno Fang, Kelly E. McCann, Sara Hurvitz, Kay T. Yeung, Ritesh Parajuli, Jorge Chaves, Adam Brufsky, Peter A. Kaufman, Manish R. Patel, Timothy Pluard, Bob Salim, Kavita V. Shah, Shanhong Guan, Athanasios C. Tsiatis, Sophia Randolph, Funda Meric-Bernstam. Zanidatamab in combination with evorpacept in HER2-positive and HER2-low metastatic breast cancer: Results from a phase 1b/2 study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS8-09.

4575 Background: Maximizing antibody dependent cellular phagocytosis (ADCP) in the tumor microenvironment requires both the inhibition of the myeloid CD47/SIRPα checkpoint and activation of the macrophage’s FcyR by an anti-cancer specific antibody (Lakhani et al. Lancet Oncol 2021). Evorpacept (EVO) is a CD47 inhibitor with an inactivated Fc effector domain that blocks the CD47-SIRPα interaction. Enfortumab vedotin (EV) is a nectin-4-directed antibody drug conjugate (ADC) which engages the FcyR on the macrophage. We evaluated whether EVO plus EV would be safe, tolerable and active in pts with la/mUC. Methods: 20 pts with la/mUC who had received prior platinum-based chemotherapy and progressed during or after treatment with a PD-1/L1 inhibitor were administered study drug in this phase 1 study (NCT05524545). Dose escalation (DE) cohorts were administered intravenous (IV) EVO 20 mg/kg or 30 mg/kg Q2W plus standard EV 1.25 mg/kg IV on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was first cycle dose limiting toxicity (DLT) using a Bayesian Optimal Interval design. Additional pts were enrolled in both dose levels as backfill cohorts to further characterize safety, PK, PD, and preliminary antitumor activity. Investigator response was based on RECIST v1.1, and data cut off was 18Jan(safety)/24Jan(efficacy) 2024. Results: Fourteen pts were administered EVO 20 mg/kg Q2W (DE n= 3; backfill n=11) and 6 pts EVO 30 mg/kg Q2W (DE n=6) plus standard EV. No DLTs were observed, and the maximum tolerated dose (MTD) of the combination was not reached. The maximum administered dose (MAD) of EVO was 30 mg/kg Q2W combined with EV. There were no treatment-related deaths on study. Treatment emergent adverse events (TEAEs) occurring in > 25% of subjects included fatigue, diarrhea, abnormal loss of weight, dysgeusia, decrease appetite, hyperglycemia, constipation, hypomagnesemia, lacrimation increased, nausea, peripheral sensory neuropathy, rash maculo-papular and urinary tract infection (UTI). There were 3 serious adverse events that were related to EVO plus EV (G3 UTI [1 pt]; G4 neutrophil count decreased and G3 UTI [1 pt]). Sixteen patients were response evaluable. The overall response rate (ORR) was 63% (1CR, 9PR). Accrual is ongoing and updated data will be provided at the time of presentation. Conclusions: This is the first study, to our knowledge, reporting data on the combination of a CD47 blocking agent in combination with an ADC in la/mUC. EVO plus EV is well tolerated at doses evaluated with no MTD reached and a MAD of 30 mg/kg Q2W. The combination shows early promising clinical activity compared to an ORR of 41% with EV alone in pts with la/mUC who had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor (Powles et al. N Engl J Med 2021). Further investigation in this refractory population, including patients with prior EV exposure, is warranted. Clinical trial information: NCT05524545 .

Abstract Background:Evorpacept (EVO) is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of other anti-neoplastic therapies with minimal additional toxicity. Here, we present final phase 1 results from the ASPEN-02 study. Methods:ASPEN-02 is an open-label, multicenter phase 1/2 study designed to evaluate the safety and activity of EVO in combination with azacitidine (AZA) in subjects with newly diagnosed (ND) higher-risk (HR) or relapsed/refractory (R/R) MDS. Adult subjects with ND HR (IPSS-R > 3.5) or R/R MDS were enrolled into phase 1 cohorts receiving escalating doses of EVO (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with AZA (75 mg/m2 IV/SC x 7d) in a 28-day treatment cycle. A phase 1 dose expansion portion enrolled adults with ND HR MDS into two dosing cohorts determined to be safe at EVO 40 mg/kg Q4W and 60 mg/kg Q4W. This clinical trial is registered at clinicaltrials.gov: NCT04417517. Results: As of June 2, 2023, 65 subjects were treated in the phase 1 portion, including 13 subjects with R/R MDS [EVO doses of 20 mg/kg Q2W (n=1) or 60 mg/kg Q4W (n=12)], and 52 subjects with ND HR MDS [EVO doses of 40 mg/kg Q4W (n=23) and 60 mg/kg Q4W (n=29)]. Of 52 ND HRMDS subjects, 9 (17.3%) had therapy-related MDS. Multi-hit TP53 mutations were present at baseline in 2/13 (15.4%) R/R MDS and 3/52 (5.8%) ND HR MDS patients. 13/13 (100%) R/R MDS patients had received prior hypomethylating agents or cytotoxic chemotherapy. Median age was 70 (range 24 - 88) years, and baseline ECOG scores were 0 (n=27, 41.5%), 1 (n=31, 47.7%), or 2 (n=7, 10.8%). No dose-limiting toxicity was observed, and a maximum tolerated dose (MTD) was not reached. Treatment-emergent AEs and treatment-related AEs for EVO were reported in 65/65 (100%) and 35/65 (53.8%) subjects respectively; discontinuation, however, was infrequent. Seven (10.8%) subjects experienced a serious adverse event related to EVO. There were no EVO-related deaths on study. Preliminary PK indicated dose-proportional pharmacokinetics consistent with prior studies. Objective response [complete remission (CR), partial remission (PR), marrow CR (mCR), hematologic improvement (HI)], per modified International Working Group 2006 criteria, was observed in 19/52 (36.5%) ND HR [CR=8, mCR=9, HI=2] and 2/13 (15.4%) R/R [mCR=2] MDS subjects. Conclusion:The myeloid checkpoint inhibitor EVO was well tolerated in combination with AZA with an initial safety and activity profile comparable to that of historical AZA monotherapy. Additional updated data will be provided at the time of presentation. Citation Format: Guillermo Garcia-Manero, Bart L. Scott, Ashwin Kishtagari, Srinivasa R. Sanikommu, Aref Al-Kali, Je-Hwan Lee, Juan M. Bergua Burgues, Maria Diez-Campelo, Harry P. Erba, Carmen Garcia-Hernandez, Guillermo Sanz Santillana, Casey O'Connell, Jun-Ho Jang, Dong-Yeop Shin, Hamid Sayar, Mayank Rao, Richard S. Schwartz, Grace An, Feng Jin, Alison J. Forgie, Athanasios C. Tsiatis, Jessica K. Altman. Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT060.

Background: Evorpacept is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to promote phagocytosis of tumor cells in combination with other anti-neoplastic therapies, while adding minimal toxicity. Here, we present results from the phase 1a dose escalation part of the ASPEN-05 study evaluating the safety and tolerability of evorpacept administered in combination with standard venetoclax (VEN) and azacitidine (AZA) in subjects with acute myeloid leukemia (AML). Methods: ASPEN-05 (NCT04755244) is a phase 1/2 open-label, multicenter study. The phase 1a dose escalation part is designed to evaluate the safety and tolerability and establish the maximum tolerated dose (MTD) of intravenous (IV) evorpacept in combination with VEN and AZA. Adult subjects with relapsed/refractory (R/R) AML or newly diagnosed (ND) AML with adverse risk genetics and considered ineligible for intensive induction therapy were enrolled into cohorts of escalating doses of evorpacept (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with VEN (400 mg PO daily for up to 28 days) and AZA (75 mg/m2 IV/SC daily for 7 days) in a 28-day treatment cycle. The primary endpoint is the frequency of first cycle dose-limiting toxicities (DLTs). Key secondary endpoints are to characterize the pharmacokinetic (PK) profile of evorpacept in combination with VEN and AZA, and to assess anti-leukemic activity using the ELN 2017 response criteria. Results: As of July 8, 2022, 14 subjects including 10 males and 4 females with a median age of 71 years (range 50-82) were treated at evorpacept doses of 20 mg/kg Q2W (N=4), 30 mg/kg Q2W (N=4), and 60 mg/kg Q4W (N=6). There were 11 subjects with R/R AML with a median of 1 prior line of therapy (range 1-2), including 9 that were exposed to prior VEN, 2 that were VEN-naïve, and 5 that had received a prior hypomethylating agent. Of the 3 subjects with ND AML, 2 had therapy-related AML, and all had TP53 mutation. Patient characteristics included a median ECOG score of 1 (range 0-2) at the time of screening, and median baseline laboratory values of: creatinine 0.92 mg/L (range 0.54-3.31), total bilirubin 0.7 mg/L (0.3-1.7), platelet count 31.5 x 109/L (range 13-117), and WBC count 2 x 109/L (range 0.4-12.3). Bone marrow studies performed at screening demonstrated a median blast percentage of 27% (range 5-84), 11 subjects with adverse risk and 2 with intermediate risk cytogenetics, and mutations in TP53 (N=10), DNMT3A (N=3), ASXL1, RAS, and RUNX1 (N=2 each). An MTD of evorpacept was not reached. All subjects experienced an adverse event. Evorpacept-related AEs of nausea, vomiting (n=2 each; 14%), cytokine release syndrome, metabolic acidosis, muscular weakness, and pyrexia (n=1 each; 7%) were observed. Grade ≥3 AEs of any causality occurring in >2 subjects were febrile neutropenia, anemia (n=6 each; 43%), AST increased (n=5; 36%), platelet count decreased (n=4; 29%), and pneumonia (n=3; 21%). There was one reversible Grade 3 evorpacept-related AE of cytokine release syndrome that met criteria for DLT in the 60 mg/kg Q4W cohort. There were no on-study evorpacept-related deaths. Preliminary PK data indicated dose-proportional pharmacokinetics and PD data demonstrated full CD47 target occupancy in both peripheral blood and bone marrow across all dose levels at both evorpacept peak and trough concentrations. With limited follow up data, in 12 subjects that had a post-baseline disease assessment there was initial evidence of clinical activity observed, with a reduction in bone marrow blasts (Figure 1) across all cohorts and objective responses in 3 ND subjects, 2 R/R VEN-naïve subjects, and 2 R/R VEN-exposed subjects. Results will be updated at the time of presentation. Conclusions: The addition of evorpacept to standard dose VEN and AZA for AML was well tolerated with no MTD reached. The maximum administered evorpacept dose was 60 mg/kg Q4W, and preliminary dose-proportional pharmacokinetics was seen along with full CD47 target occupancy in both peripheral blood and bone marrow across all dose levels evaluated. Initial anti-leukemic activity was observed in subjects with both ND and R/R AML (including VEN-naïve and prior VEN-exposed disease). These results support further evaluation of evorpacept in myeloid malignancies, including AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Background: Relapsed and refractory myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a clinical challenge due to high morbidity and mortality as well as a paucity of effective therapeutic agents. PLX2853 is an orally available, non-benzodiazepine bromodomain and extraterminal domain (BET) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g., MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 has demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profiles in patients with AML or MDS revealed high peak plasma concentrations, a short terminal half-life (T1/2 < 3 hour), and nearly complete elimination from the plasma by 9 hour post dose. This PK profile is hypothesized to enable improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: This is an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily for 21 day cycles in adult patients with relapsed or refractory AML or high risk MDS. A modified continuous reassessment model with escalation with overdose control is employed to determine the recommended phase 2 dose (RP2D). Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments. Enrollment through Cohort 5 (140 mg QD) is ongoing as of July 2020. Results: 9 subjects with relapsed or refractory AML and 7 subjects with high risk MDS (median age 65.7 years, range 47-77 years old; median number of prior therapies 2.3, range 1-5 prior therapies) have received PLX2853 in escalating doses from 20 to 140 mg QD. Through the data cut-off of 19 Jul 2020 (n=16), the most common treatment emergent adverse events (AEs) regardless of causality occurring in ≥20% of patients (n≥4) are: decreased appetite (n=9), (n=8), fatigue (N=8), hyperbilirubinemia (N=8), nausea (n=7), constipation (n=6), hypokalemia (n=6), leukopenia (n=6), vomiting (n=5), international normalised ratio increased (n=5), proteinuria (n=5), and dyspnea (n=5). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patients are: anemia (n=7), leukopenia (n=5) hyperbilirubinemia (n=4), febrile neutropenia (n=4), sepsis (n=3), thrombocytopenia (n=3), hypertension (n=2), lymphocyte count decreased (n=3), and neutrophil count decreased (n=3). No dose limiting toxicity (DLT) has been observed. Following a daily dose of PLX2853 the median time to reach maximal plasma concentration (Tmax) is 1 hour, and no accumulation observed at steady state, which is consistent with the short T1/2 (< 3 hours). Dose-dependent increases in exposures were observed across the dose range tested (20-80 mg daily). Fifteen of 16 subjects have completed at least 1 cycle of treatment. The following best overall responses have been observed: 1 subject with a confirmed marrow complete remission, 1 subject with a partial remission (myeloid sarcoma), 10 subjects with stable disease, 1 subject with progressive disease, and 3 subjects not evaluable. Conclusions: In an ongoing Ph1b study of PLX2853, four cohorts have been completed with continuous, once daily dosing in patients with relapsed or refractory AML or high risk MDS, and no DLTs have been observed yet. As dose escalation continues, PK, PD, preliminary safety, and efficacy data will be reviewed further to determine the clinical significance of this BET inhibitor and identify the RP2D. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Mims: Agios: Consultancy; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Novartis: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board. Borate:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Blueprint Medicines: Honoraria; MustangBio: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria. Borthakur:BioTherix: Consultancy; BioLine Rx: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; BMS: Research Funding; Jannsen: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Consultancy; AstraZeneca: Research Funding. Roboz:Agios: Consultancy; Amphivena: Consultancy; MEI Pharma: Consultancy; Helsinn: Consultancy; Epizyme: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Trovagene: Consultancy; Takeda: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; AstraZeneca: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Argenx: Consultancy; Actinium: Consultancy; Sandoz: Consultancy; Astex: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy. Powell:Plexxikon Inc.: Current Employment. Severson:Plexxikon Inc.: Current Employment. Matusow:Plexxikon Inc.: Current Employment. Halladay:Plexxikon Inc.: Current Employment. Hsu:Daiichi Sankyo Inc.: Current Employment. Watkins:Plexxikon Inc.: Current Employment. Zhang:Plexxikon Inc.: Current Employment. Walling:Plexxikon Inc.: Consultancy; Aduro Biotech: Consultancy; Arch Oncology: Consultancy; CytomX Therapeutics: Consultancy; Harpoon Therapeutics: Consultancy; ImmuNext: Consultancy; Myovant Sciences: Consultancy; Nurix Therapeutics: Consultancy; Que Oncology: Consultancy; Sesen Bio: Consultancy; Amgen: Consultancy; Aminex: Consultancy; Crown Bio: Consultancy; Leap Therapeutics: Consultancy; Prothena Corporation: Consultancy; Puma Biotechnology: Consultancy; Rhizen Pharmaceuticals: Consultancy; Shanghai Pharmaceuticals: Consultancy; Stealth Biotherapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Upsher-Smith Laboratories: Consultancy; Flag Therapeutics: Consultancy; January Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Current Employment. DeZern:Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy; MEI: Consultancy.

3018 Background: PLX2853 is a potent, orally active small molecule BET inhibitor. Its unique pharmacokinetic (PK) profile is associated with less thrombocytopenia and improved tolerability by allowing transient target engagement with a prolonged pharmacodynamic (PD) response and time for recovery after dosing. Methods: We conducted a first-in-human 3+3 Ph1b/2a study of PLX2853 in adults with relapsed or refractory solid tumors and lymphoma to determine the safety, PK and recommended phase II dose (RP2D) (NCT03297424). Secondary endpoints included efficacy and PD. Results: As of 2 February 2021, 44 subjects (median age 65, range 39 - 84) received PLX2853 in escalating doses from 5mg to 120mg QD and 40mg to 60mg BID. Ovarian cancer (n = 11), uveal melanoma, colorectal, and prostate (n = 5 each) were the most represented tumor types. Adverse events (AE) occurring in ≥15% of subjects included nausea (41%), decrease appetite (39%), fatigue (27%), vomiting (25%), diarrhea (25%), dysgeusia (25%), dehydration (23%), anemia (20%), dry mouth (18%), dizziness (16%), abdominal pain (16%), and pyrexia (16%). Thrombocytopenia occurred in 11% of subjects. Most AEs ( > 85%) were grades (G) 1-2. Of all AEs, 40% were related. There were 5 treatment-related serious AEs in 2 subjects (n = 1 G4 thrombocytopenia, G4 ischemic stroke, G3 subarachnoid hemorrhage [SAH], and G3 thromboembolic event; n = 1 G3 vomiting). Dose-limiting toxicities were observed at 120mg QD (G4 thrombocytopenia, G4 ischemic stroke, G3 thromboembolic event, and G3 SAH; asymptomatic G4 thrombocytopenia), 60mg BID (G3 thrombocytopenia with recovery > 7 days), and 40mg BID (dose reduction for transient G3 fatigue). PLX2853 systemic exposure was dose-proportional up to 120mg with a short terminal half-life ( < 3.5 hr). Plasma concentrations were above the IC 90 in the MYC-responsive reporter assay for 9 hr at 80mg or higher doses. RNA-seq analyses of peripheral blood mononuclear cells showed a dose-dependent modulation of BET target gene expression. One complete response (ongoing 9+ months) was seen in a patient with DLBCL, two patients had partial responses (1 uveal melanoma, 1 primary peritoneal cancer), and 14 patients had stable disease. The median PFS was 82.5 days (range: 51 – 209 days). Conclusions: PLX2853 shows encouraging signs of clinical activity and is well tolerated at the anticipated RP2D of 80 mg/day. PLX2853 is being evaluated as monotherapy and in combination. Clinical trial information: NCT03297424.

Importance Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors. Objective To assess whether combining a type II KIT inhibitor with a conformation-complementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control. Design, Setting, and Participants A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020. Interventions Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal. Main Outcomes and Measures Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA. Results A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively. Conclusions and Relevance In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile. Trial Registration ClinicalTrials.gov Identifier: NCT02401815.

PURPOSE The 17-gene Onco type DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort. MATERIALS AND METHODS Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models. RESULTS GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; P = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; P = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade ( P = .48). CONCLUSION In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.

Background: PLX2853 is an orally available, non-benzodiazepine BET (bromodomain and extraterminal domain) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g. MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profile in solid tumor patients revealed a short half-life (< 3 hour) enabling high peak plasma concentrations and nearly complete elimination from the plasma 9 hour post dose. Since strong and prolonged suppression of BET proteins have often untoward effects in normal tissues, the PLX2853 PK profile is hypothesized to be associated with improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: We are conducting an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily in adult patients with relapsed or refractory acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) using a modified continuous reassessment model (mCRM) with escalation with overdose control (EWOC) to determine the recommended phase 2 dose (RP2D). Up to 36 patients are expected to enroll. The dosing cycle and dose limiting toxicity window (DLT) is 21 days. Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments in various tissues. Enrollment through Cohort 2 (40 mg QD) is ongoing as of July 2019. Results: Five subjects with relapsed or refractory AML (median age 65 years) have received PLX2853 in escalating doses from 20 to 40 mg QD. Among these first 5 patients treated, the most common treatment emergent adverse events (AEs) regardless of causality in > 1 patient: decreased appetite (n=3), nausea (n=2), diarrhea (n=2), peripheral edema (n=2), cough (n=2), oropharyngeal pain (n=2), blood bilirubin increase (n=2), anemia (n=2), febrile neutropenia (n=2), fatigue (n=2), bacteremia (n=2), headache (n=2), dyspnea (n=2), and hypertension (n=2). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patient included: anemia (n=2), febrile neutropenia (n=2) and hypertension (n=2). No treatment-related serious AEs or DLTs have been observed. Following a 20 mg daily dose of PLX2853, median time to reach maximal plasma concentrations (Tmax) is 1 hour and the absorption half-life (T1/2) is < 3 hours. Conclusions: In an ongoing Ph1b study, PLX2853 has now completed its first dosing cohort for patients with relapsed or refractory AML or high risk MDS, and no DLT has been observed yet. As dose escalation continues, PK, PD, preliminary safety and efficacy data will be assessed further to determine the clinical significance of target engagement. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Pemmaraju: mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Borthakur:Polaris: Research Funding; Arvinas: Research Funding; Agensys: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; NKarta: Consultancy; Incyte: Research Funding; Janssen: Research Funding; GSK: Research Funding; PTC Therapeutics: Consultancy. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Zhang:Plexxikon Inc.: Employment. Powell:Plexxikon Inc.: Employment. Severson:Plexxikon Inc.: Employment. Inokuchi:Plexxikon Inc.: Employment. Matusow:Plexxikon Inc.: Employment. Halladay:Plexxikon Inc.: Employment. Hsu:Daiichi Sankyo, Inc.: Employment. Watkins:Plexxikon Inc.: Employment. Walling:Myovant Sciences: Consultancy; Nurix: Consultancy; Aduro Biotech: Consultancy; Plexxikon: Consultancy; CytomyX: Consultancy; Flag Therapeutics: Consultancy; Aminex: Consultancy; Immunext: Consultancy; SensenBio: Consultancy; Harpoon Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Employment. Mims:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

262 Background: The 17-gene Genomic Prostate Score (GPS) test (scale 0-100) predicts adverse surgical pathology (AP) and recurrence in newly diagnosed low- and intermediate-risk PCa. Studies of the predictive value of the GPS test in men initially managed with AS are limited. Methods: Diagnostic biopsy tissue was obtained from 634 men enrolled at 8 sites in PASS. Time to AP (Gleason Grade Group (GG) ≥3, ≥pT3a, or N1) in men who underwent radical prostatectomy (RP) was the primary endpoint. All diagnostic biopsies and RP specimens were centrally reviewed. Multivariate regression models for interval censored data were used to evaluate the association between time to AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Association between GPS and time to Gleason score upgrade on surveillance biopsy was also evaluated using a Cox Proportional Hazards model. Results: GPS results were obtained for 432 men (median follow-up 4.6 [IQR: 2.9-6.2] years); 374 and 58 with GG 1 or 2 cancer, respectively; median PSA density (PSAD) was 0.11 [IQR: 0.08-0.15]; 101 men underwent RP with central pathology after a median of 2.1 [IQR: 1.3-4.3] years surveillance, and 52 (52%) men undergoing RP had AP. 167 men upgraded at a subsequent biopsy. No clinico-pathologic covariates were significantly associated with AP other than PSAD. GPS was significantly associated with time to AP (hazards ratio [HR]/20 GPS units: 1.96 [95% CI = 1.17-4.28]; p = 0.030), when adjusted for diagnostic GG, or for dichotomous PSAD ( < vs ≥ 0.15; HR: 1.83, 95% CI = 1.04-3.62; p = 0.046). GPS was not significantly associated with AP (HR: 1.61, 95% CI = 0.87-2.98; p = 0.12) when adjusted for continuous PSAD. No association, either univariable or multivariable, was observed between GPS and subsequent biopsy upgrade. Conclusions: In a cohort of men on AS, GPS was associated with time to AP when adjusted for diagnostic GG or dichotomous PSAD. GPS was not associated with surveillance biopsy GG upgrading or AP at surgery after adjustment for continuous PSAD, although a trend was seen for AP, suggesting an association may be seen in a larger study.

OBJECTIVE:To compare the ability of loss of phosphatase and tensin homolog (PTEN) and Genomic prostate score assay (GPS) in predicting the biochemical-recurrence (BCR) and clinical-recurrence (CR) after radical prostatectomy (RP) for clinically localized prostate cancer (PCa). METHODS:Three hundred seventy seven patients with and without CR were retrospectively selected by stratified cohort sampling design from RP database. PTEN status (by immunohistochemistry [IHC] and fluorescence in situ hybridization [FISH]) and GPS results were determined for RP specimens. BCR was defined as Prostate Specific Antigen (PSA) ≥ 0.2 ng/mL or initiation of salvage therapy for a rising PSA. CR was defined as local recurrence and/or distant metastases. RESULTS:Baseline mean age, PSA, and GPS score for the cohort were 61.1 years, 8 ng/dL, and 32.8. PTEN loss was noted in 38% patients by FISH and 25% by IHC. The concordance between FISH and IHC for PTEN loss was 66% (Kappa coefficient 0.278; P < .001). On univariable analysis, loss of PTEN by FISH or IHC was associated with BCR and CR (P < .05). However, after adjusting for GPS results, PTEN loss was not a significant predictor for CR or BCR (P > .1). The GPS result remained strongly associated with CR and BCR after adjusting for PTEN status (P < .001). PTEN status and GPS results only weakly correlated. GPS was widely distributed regardless of PTEN status indicating the biological heterogeneity of PCa even in PTEN-deficient cases. CONCLUSION:GPS is a significant predictor of aggressive PCa, independent of PTEN status. After adjustment for GPS results, PTEN was not independently associated with recurrence for PCa.

BACKGROUND:A 17-gene biopsy-based reverse transcription polymerase chain reaction assay, which provides a Genomic Prostate Score (GPS-scale 0-100), has been validated as an independent predictor of adverse pathology and biochemical recurrence after radical prostatectomy (RP) in men with low- and intermediate-risk prostate cancer (PCa). OBJECTIVE:To evaluate GPS as a predictor of PCa metastasis and PCa-specific death (PCD) in a large cohort of men with localized PCa and long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS:A retrospective study using a stratified cohort sampling design was performed in a cohort of men treated with RP within Kaiser Permanente Northern California. RNA from archival diagnostic biopsies was assayed to generate GPS results. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:We assessed the association between GPS and time to metastasis and PCD in prespecified uni- and multivariable statistical analyses, based on Cox proportional hazard models accounting for sampling weights. RESULTS AND LIMITATIONS:The final study population consisted of 279 men with low-, intermediate-, and high-risk PCa between 1995 and 2010 (median follow-up 9.8 yr), and included 64 PCD and 79 metastases. Valid GPS results were obtained for 259 (93%). In univariable analysis, GPS was strongly associated with time to PCD, hazard ratio (HR)/20 GPS units=3.23 (95% confidence interval [CI] 1.84-5.65; p<0.001), and time to metastasis, HR/20 units=2.75 (95% CI 1.63-4.63; p<0.001). The association between GPS and both end points remained significant after adjusting for National Comprehensive Cancer Network, American Urological Association, and Cancer of the Prostate Risk Assessment (CAPRA) risks (p<0.001). No patient with low- or intermediate-risk disease and a GPS of<20 developed metastases or PCD (n=31). In receiver operating characteristic analysis of PCD at 10 yr, GPS improved the c-statistic from 0.78 (CAPRA alone) to 0.84 (GPS+CAPRA; p<0.001). A limitation of the study was that patients were treated during an era when definitive treatment was standard of care with little adoption of active surveillance. CONCLUSIONS:GPS is a strong independent predictor of long-term outcomes in clinically localized PCa in men treated with RP and may improve risk stratification for men with newly diagnosed disease. PATIENT SUMMARY:Many prostate cancers are slow growing and unlikely to spread or threaten a man's life, while others are more aggressive and require treatment. Increasingly, doctors are using new molecular tests, such as the17-gene Genomic Prostate Score (GPS), which can be performed at the time of initial diagnosis to help determine how aggressive a given patient's cancer may be. In this study, performed in a large community-based healthcare network, GPS was shown to be a strong predictor as to whether a man's prostate cancer will spread and threaten his life after surgery, providing information that may help patients and their doctors decide on the best course of management of their disease.

You have accessJournal of UrologyProstate Cancer: Staging I1 Apr 2017MP20-05 A DIAGNOSTIC BIOPSY-BASED GENOMIC PROSTATE SCORE AS AN INDEPENDENT PREDICTOR OF PROSTATE CANCER DEATH AND METASTASIS IN MEN WITH LOCALIZED PROSTATE CANCER Stephen Van Den Eeden, Nan Zhang, Jun Shan, Charles Quesenberry, Jeong Han, Athanasios Tsiatis, Ruixiao Lu, Jeffrey Lawrence, Phillip Febbo, and Joseph Presti Stephen Van Den EedenStephen Van Den Eeden More articles by this author , Nan ZhangNan Zhang More articles by this author , Jun ShanJun Shan More articles by this author , Charles QuesenberryCharles Quesenberry More articles by this author , Jeong HanJeong Han More articles by this author , Athanasios TsiatisAthanasios Tsiatis More articles by this author , Ruixiao LuRuixiao Lu More articles by this author , Jeffrey LawrenceJeffrey Lawrence More articles by this author , Phillip FebboPhillip Febbo More articles by this author , and Joseph PrestiJoseph Presti More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.637AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer (PCa) aggressiveness can be gauged by both short- and long-term outcomes including adverse surgical pathology, biochemical recurrence, development of metastases, and PCD. A 17-gene biopsy-based RT-PCR assay, which provides a Genomic Prostate Score (GPS) result (scale 0-100), is validated as an independent predictor of adverse pathology and biochemical recurrence after radical prostatectomy (RP). We sought to validate GPS further as a predictor of prostate cancer death (PCD) and metastasis in a large cohort of men with long term follow-up. METHODS A retrospective cohort study using a stratified sampling design was performed within Kaiser Permanente Northern California (KPNC). Of 6,184 men in the full cohort, all men with PCD and available tissue were included along with men sampled from the non-PCD men at a ratio of approximately 1:3. PCD was determined by review of Cancer Registry and KPNC mortality files; metastases were confirmed by review of imaging, biopsy or clinical data. Central review of diagnostic biopsies was performed by one uropathologist (JSH). RNA from archival diagnostic biopsies was assayed to generate GPS results. We assessed the association between GPS and metastasis and PCD as co-primary endpoints in pre-specified univariable and multivariable statistical analyses, based on Cox proportional hazards models accounting for sampling weights. RESULTS The final study population consisted of 279 men treated with RP for clinically low, intermediate and high-risk PCa between 1995 and 2010 (median follow-up 9.8 years). This cohort included 64 PCD, 79 metastases, and 195 non-PCD cases. Valid GPS results were obtained for 259 men (93%). In univariable analysis GPS was strongly associated with PCD - HR/20 GPS units = 3.23 (p <0.001), and metastasis - HR/20 units = 2.75 (p <0.001). The association between GPS and both endpoints remained significant in multivariable analysis after adjusting for NCCN: 1) PCD: HR/20 units = 2.69; 2) metastasis: HR/20 units = 2.34 (p<0.001 for each). GPS was also significantly associated with both endpoints adjusting for AUA and CAPRA with similar HR (p<0.001 for each). No patient with low or intermediate risk disease and a GPS result < 20 developed metastases or PCD. CONCLUSIONS GPS is a strong independent predictor of late outcomes – PCD and metastases - in RP-treated men with clinically localized PCa, and may provide improved risk stratification for men with low, intermediate and high-risk disease. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e240-e241 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Stephen Van Den Eeden More articles by this author Nan Zhang More articles by this author Jun Shan More articles by this author Charles Quesenberry More articles by this author Jeong Han More articles by this author Athanasios Tsiatis More articles by this author Ruixiao Lu More articles by this author Jeffrey Lawrence More articles by this author Phillip Febbo More articles by this author Joseph Presti More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

e16570 Background: The overtreatment of prostate cancer and underutilization of active surveillance in men with Gleason 6 (GS6) cancer stems from uncertainty with current risk instruments such as volume of GS6 tumor and PSA > 10 ng/ml. The 17-gene biopsy-based RT-PCR assay has been analytically and clinically validated as an independent predictor of adverse pathology at prostatectomy. We report on the impact of volume of GS6 disease and PSA at biopsy on the biologic aggressiveness of the disease as measured by the assay (GPS). Methods: 1,055 pathology reports received at Genomic Health, Inc. were reviewed to record GS, number of cores positive, and PSA. GPS was calculated from a single block for each case with an associated path report using the validated algorithm of 12 cancer and 5 reference genes; median GPS was calculated for each sub-group ( ≤ 2 cores positive, > 4 cores positive, PSA < 4 ng/ml, PSA 4-10 ng/ml, PSA > 10 ng/ml). Results: 803 cases (76%) were submitted as GS6. 66% of cases contained 12 cores, 4% of cases had < 12 cores and 30% of cases had > 12 cores. The median GPS for GS6 cases with ≤ 2 cores positive was 24 (IQR 16.5 to 30.5) compared to a median GPS of 26 (IQR 20 to 34) for 4 or more cores positive. After incorporating the GPS, risk refinement, a change in categorical risk assessment was seen in 24% of cases with ≤ 2 cores positive and 26% of cases with > 4 cores positive. 294 of cases with GS6 also reported a PSA value. 25% of GS6 cases had a PSA < 4, 67% were 4-10, and 8% were > 10 ng/ml. No significant correlation was seen between PSA and GPS. The median GPS values for cases with a PSA < 4, 4-10, and > 10 were 25(IQR 16-31), 24(IQR 17-32), and 25(IQR 17-39), respectively. Risk refinement following GPS occurred in 48% of cases with a PSA < 10 and 23% with a PSA > 10. Conclusions: The GPS results highlight the broad spectrum of tumor aggressiveness in a series of 803 biopsies containing GS6 independent of % cores positive and PSA. The degree of risk refinement among all GS6 cases independent of tumor volume or PSA highlight the utility of the GPS to provide predictive information beyond traditional clinical variables used for risk stratification in the management of men with GS 6 disease at the time of diagnosis.

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 2016MP02-19 BIOMARKERS OF BIOCHEMICAL (BCR) AND CLINICAL RECURRENCE (CR) IN PROSTATE CANCER (PCA) FOLLOWING RADICAL PROSTATECTOMY (RP) – PERFORMANCE OF A 17-GENE GENOMIC PROSTATE SCORE (GPS) AND TESTS FOR PTEN LOSS. Cristina Magi-Galluzzi, Michael Bonham, Athanasios Tsiatis, Sara Falzarano, Anne Dee, Tara Maddala, Dejan Knezevic, Phillip Febbo, H. Jeffrey Lawrence, and Eric Klein Cristina Magi-GalluzziCristina Magi-Galluzzi More articles by this author , Michael BonhamMichael Bonham More articles by this author , Athanasios TsiatisAthanasios Tsiatis More articles by this author , Sara FalzaranoSara Falzarano More articles by this author , Anne DeeAnne Dee More articles by this author , Tara MaddalaTara Maddala More articles by this author , Dejan KnezevicDejan Knezevic More articles by this author , Phillip FebboPhillip Febbo More articles by this author , H. Jeffrey LawrenceH. Jeffrey Lawrence More articles by this author , and Eric KleinEric Klein More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1891AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES PTEN loss by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) has been reported in 20-60% of localized PCa and is viewed as an adverse prognostic factor. The GPS (scale 0-100) is an analytically and clinically validated RT-PCR assay that measures tumor aggressiveness in biopsies of men with early stage PCa. Gene selection for GPS was based on the strength of association between their expression and clinical outcomes and PTEN RNA expression was evaluated but not included in the GPS signature. The prognostic value of GPS and PTEN loss as determined by IHC and FISH in predicting cR and BCR after RP for clinically localized PCa was assessed. METHODS RPs from 441 AUA low, intermediate and high risk disease patients were used to develop GPS. PTEN status was assessed by FISH and IHC in 287 and 369 of these patients, respectively, using tissue microarrays. PTEN FISH loss was defined as hemizygous or homozygous deletion; PTEN IHC loss was defined as homogeneous loss of staining. GPS was generated using tumor RNA from microdissected RPs. Multivariable Cox models were used to analyze BCR and cR (defined as distant or local recurrence), and regression to the mean correction was used for GPS. RESULTS 38% of patients had PTEN loss by FISH and 25% by IHC, and evaluable patients were representative of the full cohort. While PTEN status by FISH or IHC was associated with BCR (p< 0.001) and cR (p<0.05) in univariate analysis, after adjusting for GPS, neither FISH nor IHC PTEN was a significant predictor of either BCR (p>0.05) or cR (p>0.1). Concordance between the 2 PTEN methodologies was 66% (p<0.001), whereas PTEN status and GPS were only weakly correlated (Spearman corr = 0.2 - FISH, 0.3 - IHC) and a broad range of overlapping GPS was observed in each PTEN category. GPS remained very strongly associated with cR and BCR after adjusting for PTEN [HR/20 units=CR 4.0 (95% CI 2.1, 7.6), BCR 2.1 (95% CI 1.3-3.3) by FISH; HR/20 units =CR 4.0 (2.3, 6.7), BCR 1.6 (95% CI 1.1-2.3) by IHC]. Of PTEN deleted cases (by FISH), 31% with the lowest GPS had <2% 10-year rate of cR. Of PTEN intact cases (by FISH), 29% with the highest GPS had a 14% 10-year rate of cR. CONCLUSIONS GPS is a significant predictor of BCR and cR following RP after adjustment for PTEN status assessed by FISH or IHC. PTEN is not a significant predictor of BCR or cR after adjustment for GPS. GPS can identify a group of PTEN loss patients with a very favorable prognosis and a group of PTEN intact patients with unfavorable prognosis. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e18 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Cristina Magi-Galluzzi More articles by this author Michael Bonham More articles by this author Athanasios Tsiatis More articles by this author Sara Falzarano More articles by this author Anne Dee More articles by this author Tara Maddala More articles by this author Dejan Knezevic More articles by this author Phillip Febbo More articles by this author H. Jeffrey Lawrence More articles by this author Eric Klein More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...