Alexa Gillman

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

BACKGROUND Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconis anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

Abstract CT322: DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer

Introduction: Next generation sequencing (NGS) has identified genomic aberrations causing DNA repair defects in sporadic metastatic castration resistant prostate cancer (mCRPC). We hypothesized that single agent olaparib would have antitumor activity in a sub-population of mCRPC patients (pts) and that exome and transcriptome studies would identify this population. Methods: TOPARP is an open-label, investigator-initiated phase II trial with a novel multi-step adaptive design (CRUK/11/029). The first part of the study (TOPARP-A) has a two-stage design evaluating the antitumor activity of single agent olaparib in unselected mCRPC pts (p0 = 0.05; p1 = 0.20; α = 0.02; β = 0.10) with a preplanned analysis to identify a biomarker defined sensitive subgroup. Primary endpoint, response rate (RR), was defined as objective response by RECIST 1.1 and/or PSA fall ≥50% and/or confirmed circulating tumor cell (CTC) count falls from ≥5 to Results: Fifty pts were enrolled from 7 UK centers; all had had prior docetaxel, 48 (96%) prior abiraterone and 29 (58%) prior cabazitaxel. Overall, 16 of 49 evaluable pts experienced a response (RR 32.7%, 95% CI: 20.0 to 47.5), with 11 and 4 pts having been on treatment for >6 and >12 months respectively at data cut-off. NGS identified homozygous deletions and/or putatively deleterious mutations in DNA repair genes in 15/49 (30.6%) evaluable pts. While a majority of these genomic aberrations occurred in BRCA2 and ATM, biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2, were also observed. Among these fifteen pts, 13 (86.7%) responded to olaparib. All seven pts with BRCA2 loss (somatic [4/7] or germline [3/7]) and 4/5 pts with ATM truncating mutations responded to olaparib. The specificity of the biomarker suite was 94% in this population. Conversely, PTEN loss and ERG rearrangements were not associated with response. Finally, consistent with previous studies of olaparib, anemia (10/50, 20%) and fatigue (6/50, 12%) were the most common grade>3 adverse events, with 13 (26%) pts requiring a dose reduction. Conclusions: Olaparib has durable antitumor activity in heavily pre-treated pts with sporadic mCRPC with a 32.7% overall response rate. Genomic defects in DNA repair genes associate with olaparib sensitivity in sporadic mCRPC, offering a possibility for the very first molecular treatment stratification of advanced prostate cancer. Citation Format: Joaquin Mateo, Shahneen Sandhu, Susana Miranda, Suzanne Carreira, Suneil Jain, Christy Ralph, Andrew Protheroe, Syed Hussain, Robert Jones, Tony Elliot, Ursula McGovern, Alexa Gillman, Claire Paulding, Helen Mossop, Nuria Porta, Diletta Bianchini, Zafeiris Zafeiriou, Gunther Boysen, Daniel Nava Rodrigues, Penelope Flohr, George Seed, Jane Goodall, Ines Figueiredo, Raquel Perez-Lopez, Nina Tunariu, Aurelius Omlin, Roberta Ferraldeschi, Lakshmi P. Kunju, Rosalind Eeles, Gerhardt Attard, Dan Robinson, Arul Chinnaiyan, Emma Hall, Johann S. de Bono. DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT322. doi:10.1158/1538-7445.AM2015-CT322

Abstract P2-05-01: Clinico-pathological relationships with Ki67 in POETIC (CRUK/07/015) – Critical lessons for assessing Ki67 for prognosis and as a pharmacodynamic marker

Background Higher levels of the proliferation marker Ki67 at breast cancer (BC) diagnosis are increasingly recognised to indicate poorer prognosis. Change in ΔKi67 in response to endocrine treatment reflects response. The precise relationship between Ki67 and other clinico-path factors and how associations are affected by short exposure to aromatase inhibitor (AI) has been unclear. Methods POETIC was a UK-wide, phase III, randomised trial which tested perioperative use of AI (anastrozole (A), letrozole (L)) in postmenopausal women with early BC (Dowsett JNCI Monogr 2011). Ki67 was measured in a single central lab at diagnosis (B=baseline) and 2 weeks later at surgery (S) allowing in vivo assessment of AI sensitivity. POETIC recruited 4483 women from 130 UK centres. Paired biopsies were available for 96%. Relationship between Ki67 and clinico-path factors is described by summary statistics (median) and independent associations explored in multivariable linear regression models (MVM). Analyses of Ki67 at S and ΔKi67 (reduction) were adjusted for B Ki67 and surgical sample type. Results Absolute Ki67 (B) was associated with each classic prognostic factor. Factors affecting ΔKi67 in control pts were Ki67 (B), grade (B) and surgical sample type (core cut 4.1%; excision 17.7% p Summary POETIC provides the largest multi-centre series of women in whom centrally assessed Ki67 has been correlated with classic clinico-path factors and impact of short term AI exposure explored. Choice of AI and surgical sample type are both dictated by participating site and their inter-relationship requires further review. Whether the greater suppression of Ki67 following L, a drug associated with better E2 suppression and aromatisation than A has clinical consequences is beyond the scope of this work. Relationships found (e.g. sample type, grade) are critical for interpretation of studies using Ki67 for prognosis and ΔKi67 as a pharmacodynamic response marker. Citation Format: Bliss JM, Morden J, Evans A, Holcombe C, Horgan K, Mallon E, Raghavan V, Skene A, Dodson A, Hills M, Detre S, Zabaglo L, Graf M, Banerji J, Gillman A, Robertson J, Dowsett M, Smith I, On Behalf of the POETIC Trialists. Clinico-pathological relationships with Ki67 in POETIC (CRUK/07/015) – Critical lessons for assessing Ki67 for prognosis and as a pharmacodynamic marker [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-01.

Design considerations when transitioning from paper case report forms (CRFS) to electronic data capture (EDC)

Background ICR-CTSU introduced EDC in 2012; this necessitated a revision of the systems and processes implemented for paper CRFs. Traditionally sites manually completed, signed and posted CRFs to ICR-CTSU. Once received, CRFs were tracked and transcribed onto the study database by a member of the ICR-CTSU trial team. Databases contained multiple complex validations to aid central data management. Data queries were raised by ICR-CTSU and sent to the sites by post. These processes had to be revised when EDC was introduced and alteration of CRF and database design was integral to this.

What are the main inefficiencies in trial conduct : a survey of UKCRC registered clinical trials units in the UK

BackgroundThe UK Clinical Research Collaboration (UKCRC) registered Clinical Trials Units (CTUs) Network aims to support high-quality, efficient and sustainable clinical trials research in the UK. To better understand the challenges in efficient trial conduct, and to help prioritise tackling these challenges, we surveyed CTU staff. The aim was to identify important inefficiencies during two key stages of the trial conduct life cycle: (i) from grant award to first participant, (ii) from first participant to reporting of final results.MethodsRespondents were asked to list their top three inefficiencies from grant award to recruitment of the first participant, and from recruitment of the first participant to publication of results. Free text space allowed respondents to explain why they thought these were important. The survey was constructed using SurveyMonkey and circulated to the 45 registered CTUs in May 2013. Respondents were asked to name their unit and job title, but were otherwise anonymous. Free-text responses were coded into broad categories.ResultsThere were 43 respondents from 25 CTUs. The top inefficiency between grant award and recruitment of first participant was reported as obtaining research and development (R&D) approvals by 23 respondents (53%), contracts by 22 (51%), and other approvals by 13 (30%). The top inefficiency from recruitment of first participant to publication of results was failure to meet recruitment targets, reported by 19 (44%) respondents. A common comment was that this reflected overoptimistic or inaccurate estimates of recruitment at site. Data management, including case report form design and delays in resolving data queries with sites, was reported as an important inefficiency by 11 (26%) respondents, and preparation and submission for publication by 9 (21%).ConclusionsRecommendations for improving the efficiency of trial conduct within the CTUs network include: further reducing unnecessary bureaucracy in approvals and contracting; improving training for site staff; realistic recruitment targets and appropriate feasibility; developing training across the network; improving the working relationships between chief investigators and units; encouraging funders to release sufficient funding to allow prompt recruitment of trial staff; and encouraging more research into how to improve the efficiency and quality of trial conduct.

What are the main inefficiencies in trial conduct? A survey of staff at registered clinical trials units

Results There were 43 respondents from 25 registered CTUs; one third were trial managers. From grant award to first participant R&D approvals were reported as a top inefficiency by 23 respondents, contracts by 22 and other approvals by 13. Site selection, feasibility, piloting at site, and site training were also issues. From recruitment of first patient to publication the top inefficiency was recruitment targets not met, with data collection (including CRF design) the next most common, followed by writing up. Delays in approvals for new sites and poor planning were also issues.

A poetic story: lessons learnt from the world's largest breast cancer window of opportunity study

Hormone sensitive breast cancer (BC) is a common disease in postmenopausal women. Generally seen as less aggressive than other BC subtypes patients have a continued risk of relapse for 15+ years (EBCTCG, 2011) thus the cumulative risk is not insubstantial. Efforts continue to identify patients who are at continued residual risk of relapse in order to develop new treatment strategies. Previous trials (IMPACT, 2007) suggested that aromatase inhibitor (AI) treatment for 2 weeks in the peri-surgical window-of-opportunity results in detectable biomarker changes (Ki67) and predicts long term outcome. Gene expression profiling offers opportunities to identify patients demonstrating early resistance to endocrine therapy. POETIC was a UK-wide RCT devised to provide definitive results on the role of perioperative (AI) treatment. Biopsies were taken at diagnosis and 2 weeks later at surgery thus allowing an in vivo assessment of AI sensitivity. To succeed, POETIC needed to overcome substantial barriers in relation to compliance with cancer wait times, recruitment of women at diagnosis, varied clinical practice and to ensure receipt of sufficient quality tissue samples for analysis of biomarker endpoints. Patient advocates were involved from inception. POETIC succeeded in recruiting 4486 women from 130 UK centres. Paired tissue samples were received for 96% patients. Lessons learnt in rolling out the worlds largest window-of-opportunity BC trial illustrate the viability and potential of this experimental model as a vehicle for testing early biological effects of novel agents and to identify women most likely to be at long term residual risk of relapse.

Benefits and challenges of electronic data capture (EDC) systems versus paper case report forms

Challenges EDC does not allow central data cleaning at point of entry or traditional manual CRF tracking upon receipt so alternative approaches are required. EDC specific site training is required and site staff need to be encouraged to submit data immediately following participant visits, instead of batching data entry. Database user access and internet browser compatibility monitoring systems are required to ensure only current site staff have access and are using a supported browser. Conventions for CRF design and submission require revision to facilitate EDC use at sites.