BACKGROUND: Metastatic castration-resistant prostate cancer is enriched in DNA 
damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively 
validate the association between DDR gene aberrations and response to olaparib 
in metastatic castration-resistant prostate cancer.
METHODS: In this open-label, investigator-initiated, randomised phase 2 trial 
following a selection (or pick-the-winner) design, we recruited participants 
from 17 UK hospitals. Men aged 18 years or older with progressing metastatic 
castration-resistant prostate cancer previously treated with one or two taxane 
chemotherapy regimens and with an Eastern Cooperative Oncology Group performance 
status of 2 or less had tumour biopsies tested with targeted sequencing. 
Patients with DDR gene aberrations were randomly assigned (1:1) by a 
computer-generated minimisation method, with balancing for circulating tumour 
cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given 
continuously in 4-week cycles until disease progression or unacceptable 
toxicity. Neither participants nor investigators were masked to dose allocation. 
The primary endpoint of confirmed response was defined as a composite of all 
patients presenting with any of the following outcomes: radiological objective 
response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a 
decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from 
baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 
mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a 
consecutive assessment after at least 4 weeks was required for each component. 
The primary analysis was done in the evaluable population. If at least 19 (43%) 
of 44 evaluable patients in a dose cohort responded, then the dose cohort would 
be considered successful. Safety was assessed in all patients who received at 
least one dose of olaparib. This trial is registered at ClinicalTrials.gov, 
NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.
FINDINGS: 711 patients consented for targeted screening between April 1, 2015, 
and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were 
randomly assigned and treated (49 patients for each olaparib dose), with 92 
evaluable for the primary endpoint (46 patients for each olaparib dose). Median 
follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was 
achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg 
cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. 
Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable 
patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg 
cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 
(30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was 
achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The 
most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 
patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 
serious adverse reactions were reported in 13 patients. One death possibly 
related to treatment (myocardial infarction) occurred after 11 days of treatment 
in the 300 mg cohort.
INTERPRETATION: Olaparib has antitumour activity against metastatic 
castration-resistant prostate cancer with DDR gene aberrations, supporting the 
implementation of genomic stratification of metastatic castration-resistant 
prostate cancer in clinical practice.
FUNDING: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate 
Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the 
National Institute for Health Research Biomedical Research Centres.