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CCTG IND 232: A Phase II Study of Durvalumab With or Without Tremelimumab in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Date

29 Sep 2019

Session

Poster Discussion – Genitourinary tumours, prostate

Presenters

Sebastien Hotte

Citation

Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394

Authors

S.J. Hotte1, E. Winquist2, K.N. Chi3, S.L. Ellard4, S. Sridhar5, U. Emmenegger6, M. Salim7, N.N. Iqbal8, C. Canil9, C.K. Kollmannsberger10, A.R. Hansen11, A.A. Lalani1, J. Gingerich12, D. Finch4, M. Cabanero13, A.W. Wyatt14, D. Tu15, F. Vera-Badillo16, L.K. Seymour17, M. Smoragiewicz16

Author affiliations

  • 1 Oncology, Juravinski Cancer Centre, L8V 5C2 - Hamilton/CA
  • 2 Oncology, London Regional Cancer Program (LRCP) - London Health Science Center (LHSC), N6A 4L6 - London/CA
  • 3 Medical Oncology, BC Cancer Vancouver, V5Z 4E6 - Vancouver/CA
  • 4 Medical Oncology, BC Cancer Kelowna, V1Y 5L3 - Kelowna/CA
  • 5 Medical Oncology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 6 Medical Oncology, Sunnybrook Odette Cancer Center, Sunnybrook HSC, M4N 3M5 - Toronto/CA
  • 7 Oncology, Saskatchewan Cancer Agency-Allan Blair Cancer Centre at Pasqua Hosp, S4T 7T1 - Regina/CA
  • 8 Medical Oncology, Saskatoon Cancer Centre University of Saskatchewan, S7N 4H4 - Saskatoon/CA
  • 9 Oncology, The Ottawa Hospital Regional Cancer Centre, K1H 8L6 - Ottawa/CA
  • 10 Medical Oncology Department, BC Cancer Vancouver, V5Z 4E6 - Vancouver/CA
  • 11 Oncology, Princess Margaret Cancer Center, M5G 2M9 - Toronto/CA
  • 12 Hematology/oncology, CancerCare Manitoba, Winnipeg/CA
  • 13 Department Of Laboratory Medicine And Pathobiology, University Health Network - University of Toronto, Toronto/CA
  • 14 Urological Sciences, University of British Columbia, Vancouver/CA
  • 15 Cctg Trials Unit, Queen's University, K7L 3N6 - Kingston/CA
  • 16 Oncology, Queen's University, K7L 3N6 - Kingston/CA
  • 17 Ind Program, Canadian Cancer Trials Group, K7L 3N6 - Kingston/CA
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Resources

Abstract 1085

Background

PD-L1 is overexpressed by dendritic cells of mCRPC patients (pts) progressing on androgen receptor antagonist therapy. Anti-PD-1 agents lead to infrequent but durable responses. We tested the hypothesis that dual checkpoint blockade of CTLA-4 with tremelimumab (T) and PD-L1 with durvalumab (D) enhances immune mediated activity in mCRPC.

Methods

In this multicenter randomized phase II study, mCRPC pts (measurable disease, prior abiraterone and/or enzalutamide, no more than one taxane for mCRPC) were randomized to D 1500mg IV Q4 weeks +/- 4 doses of T 75mg IV. The primary endpoint was ORR (RECIST1.1 and iRECIST) using a Simon 2-stage design. Key secondary endpoints were PSA response rate (RR) and time to progression (TTP). A treatment arm would be considered of interest if ≥ 4 ORs (null 5% or less, alt 20% or more). Correlative testing was done for PD-L1/CD8 IHC on mandatory tumour biopsies and 74-gene panel (∼1Mb) sequencing of plasma cell-free DNA (cfDNA) both collected at baseline.

Results

52 pts were enrolled: median age 70 yrs (50-83), ECOG 0/1 (13/39 pts), taxane for CRPC (25 pts/48%). Table below shows details of responses. In stage 1, 13 pts were randomized to D with 0% ORR. D+T advanced to stage 2 with a total of 39 pts enrolled who received a median of 3 cycles (1-27). D+T related AEs were mainly grade 2 or less: fatigue (46%), anorexia (28%), rash (24%), diarrhea (23%), nausea/vomiting (21/18%) and thyroid dysfunction (15%). Most common grade 3/4 AEs: LFTs (8%) and diarrhea (8%). Six pts discontinued treatment due to AEs. There were no grade 5 AEs. There were six ORs (16% (95% CI: 6-32); OR median duration not reached, longest ongoing 25mos+ with PSA < 0.2 ng/ml); all six remain on D, and pain improved in three of four pts. Correlation with full cfDNA panel to be presented.Table:

LBA51

DurvalumabDurvalumab + Tremelimumab
ORR0% (95% CI, 0-25%) 0/1316% (95% CI, 6-32%) 6/37
PD-L1≥1%0/35/13 (38%)
<1%0/91/19 (5%)
TMB , 11 mts/Mb ctDNA0/11/2 (50%)
<0/84/30 (13%)
CD8 density median0/55/16 (31%)
<0/71/14 (7%)
PSA RR0% (0-25%) 0/1316% (6-32%) 6/37
TTP, median (95% CI), mos2.1 (1.4, 2.6)2.6 (1.8, 2.8)

Conclusions

Based on prespecified criteria, D did not show sufficient clinical activity, but further studies incorporating patient selection by biomarkers are warranted for D+T.

Clinical trial identification

NCT02788773.

Editorial acknowledgement

Legal entity responsible for the study

Canadian Cancer Trials Group (CCTG).

Funding

AstraZeneca.

Disclosure

S.J. Hotte: Research grant / Funding (institution): AstraZeneca. E. Winquist: Honoraria (self): AstraZeneca. K.N. Chi: Advisory / Consultancy: AstraZeneca. S. Sridhar: Advisory / Consultancy: AstraZeneca. U. Emmenegger: Research grant / Funding (institution): AstraZeneca. C. Canil: Advisory / Consultancy: AstraZeneca. A.R. Hansen: Research grant / Funding (institution): AstraZeneca. L.K. Seymour: Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

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