1648P - Final clinical and liquid biopsy (LBx) results of phase II trial of sacituzumab govitecan (SG) in patients (Pts) with metastatic castration resistant prostate cancer (mCRPC) progressing on androgen receptor signaling inhibitors (ARSI)

Background

There is a critical need for new therapies for pts with mCRPC progressing on ARSIs. SG is an antibody-drug conjugate targeting Trop-2, currently in use for breast and bladder cancer. Trop-2 is expressed in >80% of pts with mCRPC, though is downregulated in the neuroendocrine phenotype.

Methods

An open label, phase 2 trial was conducted testing SG in pts with mCRPC progressing on ARSIs, stratified by prior chemo. Radiographic/PSA progression on ARSIs was required. Primary endpoints were 6-month radiographic progression-free survival (rPFS) rate and PSA50. Blood and tissue samples were collected at baseline, on treatment, and at progression to identify biomarkers of response and resistance. An additional pilot cohort of pts treated with combined SG and ARSI was also studied.

Results

27 pts were treated with SG at 10 mg/kg and 3 received SG at the same starting dose in combination with ARSI. Pts had a median baseline PSA of 30 ng/mL (range: 3-3,852) with 90% bone only metastases and 22% with prior docetaxel for castrate-sensitive prostate cancer. Neutropenia was common (all grades: 80%, grade ≥ 3: 5%) and managed with G-CSF and dose reduction. The 6-month rPFS rate was 52% (14/27) in all and 68% (14/21) of chemo-naïve pts, with the longest treated pt on trial for 62 weeks. No PSA50 responses were observed with single agent SG. Single CTC analysis identified loss of Trop-2 as a negative biomarker of SG as well as neuroendocrine differentiation by CTC RNA and ctDNA fragmentation. 40% of pts were positive for AR-Variants in CTC RNA at baseline and all converted to negative within 9 weeks of treatment that correlated with 6-month rPFS. As a second arm, 3 pts received combination SG and ARSI; 2/3 pts had a PSA50 response by week 9 and continued on treatment past 6 months.

Conclusions

SG has clinical activity in pts with mCRPC progressing on prior ARSI(s) based on 6-month rPFS rates. Combination treatment with a Trop-2 ADC and ARSIs holds potential to restore sensitivity to ARSIs.

Clinical trial identification

NCT03725761.

Editorial acknowledgement

Legal entity responsible for the study

Joshua M Lang.

Funding

Gilead Sciences, Inc; Prostate Cancer Foundation; NCI; DoD.

Disclosure

J.M. Lang: Financial Interests, Personal, Advisory Board: Pfizer, Janssen, Gilead, 4D Pharma, Arvinas, Astellas, Myovant, AstraZeneca, Seagen, Macrogenics; Financial Interests, Institutional, Coordinating PI: Gilead; Financial Interests, Institutional, Local PI: Pfizer, Arvinas, Seagen. S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: Ambrx, Telix Pharma, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity, Merck, EMD Serono, Regeneron, Daiichi Sankyo; Financial Interests, Personal, Other, DSMB: Boston Scientific; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Advisory Board, Patent: Convergent Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Convergent Therapeutics; Financial Interests, Institutional, Local PI: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen; Financial Interests, Institutional, Steering Committee Member: Gilead, Novartis, POINT Biopharma, Clarity, Ambrx, Promontory, Telix. S. Slovin: Financial Interests, Personal, Invited Speaker: Physician Education Resource, Pfizer; Financial Interests, Personal, Other, Grant Reviewer: NCI; Financial Interests, Personal, Advisory Board: Clovis, Labcorp. H. Emamekhoo: Financial Interests, Personal, Advisory Board: Janssen, Aveo, Cardinal Health, Eisai, BMS. D. Rathkopf: Financial Interests, Trial Chair: Janssen; Financial Interests, Steering Committee Member: Janssen; Financial Interests, Institutional, Research Grant, Clinical Trial Grant: Genentech; Non-Financial Interests, Advisory Role: Janssen, Genentech, AstraZeneca, Myovant, Bayer, BMS; Non-Financial Interests, Principal Investigator: Janssen, Genentech, Promontory, BMS, BMS. W. Abida: Financial Interests, Personal, Invited Speaker: Roche, Medscape, Aptitude Health, Onclive, Clinical Education Alliance, TouchIME, Pfizer, theMedNet; Financial Interests, Personal, Advisory Board: Clovis Oncology, Janssen, ORIC Pharmaceuticals, Daiichi Sankyo, AstraZeneca UK, Pfizer, Laekna, MOMA therapeutics; Financial Interests, Personal, Royalties: UptoDate; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Zenith Epigenetics, ORIC Pharmaceuticals, Epizyme, Nuvation Bio, Merus; Financial Interests, Institutional, Steering Committee Member: Clovis Oncology; Financial Interests, Institutional, Funding: Transthera; Non-Financial Interests, Advisory Role: Nuvation Bio, Endeavor Bio; Non-Financial Interests, Member: ASCO, AACR. K. Autio: Financial Interests, Institutional, Local PI, Funding to institution for trial conduct: Amgen, Parker Institute for Cancer Immunotherapy, AstraZeneca, Johnson and Johnson, Janux; Financial Interests, Institutional, Coordinating PI, Lead PI - Funding to institution for trial conduct: Pfizer. A.M. Molina: Financial Interests, Personal, Advisory Board: Janssen,Eisa, Exelixis. S.G. Zhao: Financial Interests, Personal, Full or part-time Employment, Spouse is an Employee of Artera AI: Artera AI; Financial Interests, Personal, Stocks/Shares, Spouse has RSUs from Exact Sciences, where she was previously employed: Exact Sciences; Financial Interests, Institutional, Other, Patents licensed to Veracyte, no royalties yet: Veracyte; Non-Financial Interests, Institutional, Proprietary Information, Research collaboration with Tempus where they have shared data: Tempus. J. Eickhoff: Financial Interests, Personal, Other, Consultant: AbbVie, Amgen, Syneos Health; Financial Interests, Personal, Other, Consulting: Bluebird Bio, AIQ. S. Dehm: Financial Interests, Personal, Other, Scientific Consultant: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Oncternal Therapeutics. D.M. Nanus: Financial Interests, Personal, Advisory Board: tELIX; Financial Interests, Personal, Invited Speaker: Janssen Oncology; Financial Interests, Personal, Other, DSMB Member: Genentech Roche; Financial Interests, Institutional, Coordinating PI, PI clinical trial: Exelixis; Financial Interests, Institutional, Local PI, Site lead clinical trial: Zenith Epigenetics. C. Kyriakopoulos: Financial Interests, Personal, Advisory Board: Exelixis, AVEO, Sanofi-Aventis, EMD Serono, Janssen Pharmaceuticals, Pfizer; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Stocks/Shares: Biogen, Epic Systems; Financial Interests, Institutional, Local PI: Gilead Sciences, Incyte Corporation, Sanofi-Aventis, AstraZeneca, BMS, Madison Vaccines, Merck KGaA, ESSA Pharma, Pionyr Immunotherapeutics, Merck. All other authors have declared no conflicts of interest.