LBA20 - Antitumour activity of the PARP inhibitor olaparib in unselected sporadic castration-resistant prostate cancer (CRPC) in the TOPARP trial

Date 29 September 2014
Event ESMO 2014
Session Genitourinary tumours, prostate 2
Topics Anti-Cancer Agents & Biologic Therapy
Prostate Cancer
Presenter Joaquin Mateo
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors J. Mateo1, E. Hall2, S. Sandhu1, A.G. Omlin1, S. Miranda3, S. Carreira3, J. Goodall3, A. Gillman2, H. Mossop2, C. Ralph4, Z. Zafeiriou1, R. Perez Lopez1, N. Tunariu1, R. Ferraldeschi3, D. Nava Rodrigues3, L.P. Kunju5, D. Robinson5, G. Attard1, A. Chinnaiyan5, J.S. De Bono1
  • 1Prostate Targeted Therapy Group, The Institute of Cancer Research and The Royal Marsden NHS Trust, SM2 5NG - London/GB
  • 2Clinical Trials And Statistics Unit, The Institute of Cancer Research, SM2 5NG - London/GB
  • 3Cancer Biomarkers Group, The Institute of Cancer Research, SM2 5NG - London/GB
  • 4Medical Oncology, St James’s Institute of Oncology-Leeds University, Leeds/GB
  • 5Michigan Center For Translational Pathology, University of Michigan, Ann Arbor/US

Abstract

Aim

Next generation sequencing studies have identified defects in DNA repair machinery in 20-40% of sporadic castration resistant prostate cancer (CRPC) patients (pt). We hypothesized that single agent PARP inhibition would have antitumour activity based on synthetic lethality in CRPC.

Methods

An investigator initiated adaptive multi-part Phase II trial (TOPARP; CR-UK/11/029) was pursued to assess olaparib antitumour activity and identify predictive biomarkers for response in CRPC. Part A is a 2-stage open labeled multi-centre study [po = 0.05; p1= 0.20; α = 0.02; ß = 0.10; 30/45 pt]. Olaparib dosing was with 400mg tablets BID continuously. The primary endpoint was response, defined as a confirmed radiological response (RECIST 1.1), confirmed PSA decline ≥50% and/or confirmed circulating tumour cells (CTC) count fall from ≥5 to <5/7.5ml blood. Paired tumour biopsies at screening and day 8-28 of treatment were mandated for biomarker studies, including exome, transcriptome and functional DNA repair studies.

Results

Preliminary results are available for the first stage after 30 pt have been evaluated for the primary endpoint. Prior lines of treatment include docetaxel (n = 30, 100%), cabazitaxel (17, 57%), abiraterone (29, 97%) and enzalutamide (5, 17%). CRPC biopsies for biomarker studies were acquired from bone marrow (17), nodal/soft tissue disease (10) or visceral metastasis (3). The most common grade > 3 adverse events (AE) were anaemia (6, 20%) and fatigue (3, 10%). Olaparib was well tolerated; 6 (20%) pt required a dose reduction, with no permanent discontinuations due to drug-related AEs. Response rate was 33% (10/30 pt, Table 1). Median time on treatment for responding pt was 6.9 months (range 2.8m-14.4m). Somatic cell exome and transcriptome analyses have identified loss of function of genes involved in DNA repair including BRCA2 and ATM among the responding patients.

Response assessment (PSA, CTC count and radiological response) for the patients who achieved a response per protocol definition (10 out of 30, response rate 33%)

Responder patient ID Maximum PSA decline from baseline Measurable disease at baseline Best RECIST response (if measurable disease) Confirmed CTC conversion Baseline CTC count (cells/7.5ml blood) Maximum CTC decline from baseline Time on treatment (weeks) (+: on-going)
1 No decline Yes PD Yes 6 83.3% 12
2 47.3% No Yes 38 94.7% 62
3 94.6% Yes PR Yes 8 100% 24
4 58.7% Yes SD Yes 22 100% 36 +
5 80.1% No Unconfirmed 87 100% 42 +
6 79.9% Yes PR Yes 18 100% 36
7 29.3% Yes SD Yes 105 97.1% 17
8 82.6% No Yes 102 100% 39
9 51.2% No Yes 24 100% 32 +
10 No decline Yes SD Yes 38 100% 12 +

Conclusions

Olaparib has antitumour activity in sporadic mCRPC with DNA repair defects; multiple durable responses have led to continuation to the next stage of this trial, which is nearing completion.

Disclosure

A.G. Omlin: has served as advisor for Astra-Zeneca; J.S. de Bono: has served as paid advisor for Astra-Zeneca. All other authors have declared no conflicts of interest.