Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Gene Aberrations

[Balsam01]

TAKE-HOME MESSAGE

•This phase 2 trial was designed to evaluate olaparib for patients with metastatic castrate-resistant prostate cancer with DNA damage response gene abnormalities. A high response rate was observed in this patient population, with a confirmed composite response achieved by 54.3% of those taking olaparib 400 mg and 39.1% of those taking 300 mg.

•The response seen to olaparib in this population supports the implementation of clinical genomic stratification of men with metastatic castration-resistant prostate cancer.

– Neil Majithia, MD

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.

The Lancet Oncology

Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Gene Aberrations (TOPARP-B): A Multicentre, Open-Label, Randomised, Phase 2 Trial

Lancet Oncol 2019 Dec 02;[EPub Ahead of Print], J Mateo, N Porta, D Bianchini, U McGovern, T Elliott, R Jones, I Syndikus, C Ralph, S Jain, M Varughese, O Parikh, S Crabb, A Robinson, D McLaren, A Birtle, J Tanguay, S Miranda, I Figueiredo, G Seed, C Bertan, P Flohr, B Ebbs, P Rescigno, G Fowler, A Ferreira, R Riisnaes, R Pereira, A Curcean, R Chandler, M Clarke, B Gurel, M Crespo, D Nava Rodrigues, S Sandhu, A Espinasse, P Chatfield, N Tunariu, W Yuan, E Hall, S Carreira, JS de Bono

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

[Jbooml]

Frustrating that our next course of diagnosis after unusual PSA numbers and assfingering ISNT a genetic workup. Cytological changes are somewhat beside the point in reviewing the provided trial efficacy evidence. As a stage 4 survivor I really don't have anything elucidating what's at the core of what's wrong with me....A liquid genetic biopsy would clear it up in short order....and point to what I should be prepared to face come castration resistance. I was pleased to note my past oncologist is on board....wish my next blood draw would headline just such a test.

prostatecancer.ca/Prostate-...

[HopingForTheBest1]

I was lucky enough to have been put on Olaparib, outside of any clinical trials, as a result of being granted off-label use from an application made by my Oncologist. Had genetic testing, after having failed six months of Zytiga/Prednisone treatment, and was found to be BRCA2+. Put on Olaparib 400 mg 2x daily. I have been on Olaparib for 11 months, and PSA has so far been undetectable for the past 10.