Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial

Accepted/In Press date: 1 January 2019

e-pub ahead of print date: 2 December 2019

Published date: January 2020

Additional Information: Funding Information: TOPARP-B is a multicentre, open-label, investigator-initiated, randomised phase 2 trial. Patients were recruited from 17 UK hospitals ( appendix p 2 ). Patients with prostate cancer that had developed metastasis and castration resistance were first registered on the trial for molecular preselection by targeted next-generation sequencing (NGS) of primary or metastatic prostate cancer biopsies. Eligible patients were men aged 18 years or older, with histologically confirmed prostate adenocarcinoma (metastatic and castration-resistant), and whose tumours had a putatively pathogenic mutation or homozygous deletion in a DDR gene that could be associated with sensitivity to PARP inhibition as identified by NGS. Patients were required to have previously received at least one but no more than two taxane-based chemotherapy regimens, regardless of prior exposure to novel hormonal drugs. Other inclusion criteria included: documented prostate cancer progression at trial entry, defined by either rising prostate-specific antigen (PSA) serum concentration (according to the Prostate Cancer Working Group 2 [PCWG2] criteria 13 ) or radiologically (according to modified Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 14 or by bone scan as per PCWG2 criteria); a castrate testosterone concentration of less than 50 ng/dL; an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; and adequate organ function (including haemoglobin ≥9 g/dL after a protocol amendment on March 15, 2018 [previously ≥10 g/dL], platelets ≥100 × 10 9 per L, serum creatinine ≤1·5 times the institutional upper limit of normal, and albumin >25 g/L). Patients previously treated with PARP inhibitors, platinum, cyclophosphamide, or mitoxantrone were not eligible, nor were patients with known symptomatic brain metastasis or untreated spinal cord compressions. The baseline count for circulating tumour cells (CellSearch system; Menarini Silicon Biosystems, Castel Maggiore, Italy) had to be five cells per 7·5 mL blood or higher except in patients with radiologically measurable target lesions of 2 cm or more in diameter on the baseline CT scan and a PSA concentration of 2 ng/mL or higher on screening. The full eligibility criteria are in the appendix (pp 3–4) . The complete study protocol is available in the appendix . The study was approved by the London–Surrey Borders Research Ethics Committee (REC reference 11/LO/2019), and co-sponsored by The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (ICR), London, UK. The trial was done in accordance with the principles of good clinical practice and overseen by independent data monitoring and trial steering committees. A trial management group was responsible for the day-to-day running of the trial. The Clinical Trials and Statistics Unit at ICR (ICR-CTSU) had overall responsibility for trial coordination, monitoring, and analysis. Patients provided written informed consent before enrolment, both for the NGS prescreening and treatment stages. Funding Information: The TOPARP-B trial has confirmed the antitumour activity of olaparib against metastatic castration-resistant prostate cancer with specific DDR gene aberrations. The number of composite responses observed in the cohort of patients who received 400 mg tablets of olaparib twice daily met the predefined criteria for success, validating the DDR biomarker identified in TOPARP-A as being predictive of response. 12 Overall, the data suggest that both drug dose and the specific type of DDR gene aberration might influence antitumour activity, given that the composite response at the 300 mg regimen was lower and did not reach the predefined criteria for success. The antitumour activity observed varied considerably for different DDR gene aberrations, with the greatest antitumour activity seen in the subgroup with BRCA1/2 alterations. Despite randomisation, CDK12 aberrations were imbalanced between the cohorts, with an enrichment in the 300 mg cohort. This imbalance might explain, at least in part, the inferior composite response in the 300 mg cohort. 4,24 The rationale to explore the two doses originated from prior clinical observations indicating a dose–response relationship for olaparib between 100 mg and 400 mg at twice daily dosing, although 400 mg has been associated with enhanced toxicity. 25,26 In keeping with this finding, 37% patients at 400 mg had to reduce their dose to 300 mg, most commonly because of anaemia. All of these data would need to be considered when assessing the optimal dose of olaparib for prostate cancer treatment. Our results support the implementation of routine genomic testing of metastatic prostate cancer, to detect DNA repair defects for targeting by PARP inhibition. In a previous study, we reported an enrichment of germline inherited mutations in DDR genes in metastatic prostate cancer, 27 which has led to the recommendation of broad germline NGS testing in all men with metastatic prostate cancer per National Comprehensive Cancer Network guidelines. The antitumour activity of olaparib indicated in this trial, in patients with metastatic castration-resistant prostate cancer with both germline and somatic aberrations of BRCA2 , now supports the implementation of NGS testing of tumour samples. Antitumour activity was also observed in other DDR gene aberration subgroups. Responses in tumours with PALB2 mutations were frequent, although the low prevalence of these mutations means that further data are required to confirm these findings. Clinical qualification of low-prevalence biomarkers is challenging in the pursuit of precision medicine approaches; the validation of genomic signatures 24,28 or functional biomarkers 29 that identify tumours with defective homologous-recombination, regardless of the mutated gene of origin, could help move the field forward, but such assays have not yet been validated in prostate cancer. Conversely, germline and somatic ATM aberrations are common in metastatic prostate cancer; ATM functions as a cell cycle checkpoint, preventing cell cycle progression in the presence of DNA damage rather than directly mediating repair, unlike BRCA2 and PALB2 . In the TOPARP-A trial, five patients had ATM aberrations in tumour biopsies: two of these had a PSA response, and two more had circulating tumour cell conversion. Preliminary results suggest that rucaparib, another PARP inhibitor, results in few PSA decreases in patients with ATM aberrations. 30 In TOPARP-B, we treated 21 patients with suspected deleterious ATM aberrations: two achieved a RECIST or PSA response, and several others had circulating tumour cell count conversions following therapy. Circulating tumour cell count decreases seen in this subgroup were associated with increased duration on the trial, tumour shrinkage per RECIST, and a PSA decrease, as was the case for the overall TOPARP-B population, with circulating tumour cell conversions robustly associating with increased radiographic progression-free survival and overall survival. Overall, the data suggest that the antitumour activity of olaparib in metastatic castration-resistant prostate cancer with ATM loss is less than that for BRCA -altered tumours; nevertheless, a subset of patients with ATM -altered metastatic castration-resistant prostate cancer appear to derive benefit. However, detection of ATM alterations alone might be insufficient to identify these sensitive tumours. Further studies, as well as the study of rational drug combinations, are now needed to elucidate how to best evaluate and treat metastatic castration-resistant prostate cancer with ATM alterations. Ongoing exploratory analyses from this trial will look to further characterise exceptional responses within each gene-defined subgroup to optimise patient stratification. We do acknowledge limitations to this study. Although the use of targeted NGS facilitates the clinical implementation of patient stratification, this method might be insufficient to capture complex aberrations resulting in PARP inhibitor sensitivity. Furthermore, because all patients in our study had DDR gene aberrations and received olaparib, we are not able to fully differentiate the predictive value versus the prognostic effect of the gene aberrations in terms of survival. Randomised trials including patients with and without the biomarkers will be more able to clinically qualify putative predictive biomarkers. Nonetheless, the results from TOPARP-B have overall driven the design and conduct of several registration trials of PARP inhibitors in metastatic castration-resistant prostate cancer ( NCT02987543 , NCT02975934 , and NCT03148795 ), which are likely to guide the clinical use of PARP inhibitors in metastatic prostate cancer in the future. Most of these studies aim to validate PARP inhibition as a precision medicine strategy for prostate cancers with DDR gene aberrations. Other studies, in parallel, are exploring the addition of PARP inhibitors to the standard-of-care drugs targeting the androgen receptor ( NCT03732820 and NCT03395197 ), on the basis of results from a phase 2 clinical trial indicating that a broader target population than just patients with gene aberrations might benefit from these drugs. 31 In conclusion, the data from TOPARP-B have confirmed the antitumour activity of olaparib against metastatic prostate cancer with particular DDR gene aberrations. The high response observed in patients with metastatic castration-resistant prostate cancer with germline or somatic BRCA1/2 aberrations, and the durability of many of these responses, support the use of olaparib in this subpopulation. The antitumour activity observed against tumours with ATM, PALB2, FANCA , or CHEK2 aberrations suggest that PARP inhibitors might have a role as single drug therapies or in rational combinations against these other subtypes of metastatic prostate cancer, although further data are needed to precisely assess the clinical relevance of each of these different DDR gene aberrations in prostate cancer. Contributors JM, NP, SS, EH, and JSdB designed the trial. AE and PC centrally managed the trial and trial data. JM, NP, RJ, PF, SS, EH, SuC, and JSdB developed the protocol. JM, DB, UMcG, TE, RJ, IS, CR, SJ, MV, OP, SiC, AR, DMcL, AB, JT, PR, RC, and JSdB recruited participants. SM, IF, CB, BE, GF, AF, RR, and RP processed samples. JM, DB, UMcG, TE, RJ, IS, CR, SJ, MV, OP, SiC, AR, DMcL, AB, JT, SM, IF, CB, PF, BE, PR, GF, AF, RP, AC, RC, NT, SuC, and JSdB collected data. JM, SM, IF, GS, CB, BE, GF, AF, RR, RP, MCl, BG, MCr, DNR, WY, SuC, and JSdB did the translational experiments. NP and EH did the statistical analyses. SM, IF, GS, PF, MCl, BG, DNR, WY, and SuC analysed the translational data. JM, NP, GS, PF, AC, MCl, BG, MCr, DNR, NT, WY, EH, SuC, and JSdB interpreted the data. JM, NP, EH, SuC, and JSdB wrote the manuscript. JM, NP, UMcG, TE, RJ, IS, CR, SJ, MV, OP, SiC, AR, DMcL, AB, SM, AE, PC, EH, and JSdB are members of the Trial Management Group of TOPARP. JSdB was the chief investigator. All authors reviewed the manuscript prior to submission. Declaration of interests JM reports a grant from AstraZeneca during the conduct of the study. He also reports personal fees and non-financial support from AstraZeneca, and personal fees from Janssen Pharmaceutica, Amgen, and Roche, outside of the submitted work. TE reports Janssen Educational Grants, outside of the submitted work. RJ reports grants and personal fees from Astellas, AstraZeneca, Exelixis, and Roche; personal fees and non-financial support from Bristol-Myers Squibb, Janssen Pharmaceutica, Ipsen, and Merck Sharp & Dohme; grants, personal fees, and non-financial support from Bayer; and personal fees from Merck Serono, Novartis, Pfizer, Sanofi Genzyme, and EUSA, outside of the submitted work. CR reports non-financial support from Pfizer and Ipsen, and personal fees and non-financial support from Bristol-Myers Squibb and Eisai, outside of the submitted work. SJ reports personal fees from Astellas, Janssen Pharmaceutica, Bayer, Boston Scientific, Movember, and Almac Diagnostics, outside of the submitted work. MV reports non-financial support from Janssen Pharmaceutica and Merck Sharp & Dohme, outside of the submitted work. SiC reports personal fees from Bayer and Janssen Pharmaceutica, and grants from AstraZeneca, Clovis Oncology, Roche, and Astex Pharmaceuticals, outside of the submitted work. AB reports advisory board fees and speaker fees from Sanofi and Bayer, advisory board fees from Astellas, speaker fees from Janssen Pharmaceutica, Merck Sharp & Dohme, and Roche, and provision of educational support to Janssen Pharmaceutica, outside of the submitted work. PC reports grants from AstraZeneca during the conduct of the study. SS reports grants and consultancy honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche, and grants from Endocyte and AstraZeneca, outside of the submitted work. EH reports grants from Cancer Research UK and grants and non-financial support from AstraZeneca, during the conduct of the study. She also reports grants and non-financial support from Merck Sharp & Dohme, AstraZeneca, and Bayer; and grants from Janssen Pharmaceutica, Kyowa Kirin, Alliance Pharma, Sanofi, and Accuray, outside of the submitted work. JSdB reports grants from AstraZeneca during the conduct of the study. He also reports personal fees and non-financial support from Astellas Pharma, Sanofi, and Menarini Silicon Biosystems; grants, personal fees, and non-financial support from AstraZeneca, Daiichi, Sierra Oncology, and CellCentric; personal fees from Genentech, Pfizer, Bayer, Boehringer Ingelheim, Merck Serono, and Merck Sharp & Dohme; and non-financial support from Genmab, GlaxoSmithKline, Orion Pharma, Qiagen, Taiho Pharmaceutical, and Vertex, outside of the submitted work. JSdB has an Abiraterone Rewards to Inventors patent with royalties paid to The Institute of Cancer Research (ICR; London, UK), and a PARP inhibitors and DNA repair defects patent with royalties paid to ICR. The authors affiliated to ICR disclose that the institution is a joint applicant for the patent entitled DNA damage repair inhibitors for treatment of cancer, which includes the granted application US8143241. All other authors declare no competing interests. Funding Information: The Institute of Cancer Research Clinical Trials and Statistics Unit (ICR-CTSU), London, UK, supports the wider dissemination of information from the research it does, and increased cooperation between investigators. Trial data is collected, managed, stored, shared, and archived according to ICR-CTSU standard operating procedures to ensure the enduring quality, integrity, and use of the data. Formal requests for data sharing are considered in line with ICR-CTSU procedures with due regard given to funder and sponsor guidelines. Requests are via a standard pro forma describing the nature of the proposed research and extent of data requirements. Data recipients are required to enter a formal data sharing agreement that describes the conditions for release and requirements for data transfer, storage, archiving, publication, and intellectual property. Requests are reviewed by the TOPARP Trial Management Group in terms of scientific merit and ethical considerations including patient consent. Data sharing is permitted if proposed projects have a sound scientific or patient benefit rationale as agreed by the Trial Management Group and approved by the ICR-CTSU independent data monitoring and steering committee as required. Restrictions relating to patient confidentiality and consent will be limited by aggregating and anonymising identifiable patient data. Additionally, all indirect identifiers that might lead to deductive disclosures will be removed in line with Cancer Research UK Data Sharing Guidelines. Acknowledgments We are grateful for the support and funding from AstraZeneca, and for the study grants from Cancer Research UK ( CRUK/11/029 , C12540/A12829 , C12540/A13230 , and C12540/A20447 ), Prostate Cancer UK and the Movember Foundation through the London Movember Centre of Excellence ( CEO13_2-002 ), and the Prostate Cancer Foundation ( 20131017 ). JM was supported by a Prostate Cancer Foundation Young Investigator Award ( PCF-16YOUN11 ) and a Prostate Cancer UK Movember Foundation Fellowship (MRC-CRTF13-001). The Institute of Cancer Research (ICR) Clinical Trials and Statistics Unit (ICR-CTSU), London, UK, also receives programme grant funding from Cancer Research UK ( C1491/A15955 and C1491/A25351 ). We also acknowledge support from the UK National Institute for Health Research (NIHR) Cancer Research Network and the UK National Health Service (NHS) funding to the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and ICR (London, UK), and support from the UK Experimental Cancer Medicine Centres Network. JdB is a senior investigator at the National Institute for Health Research (NIHR; London, UK). The views expressed in this article are those of the author(s) and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. We thank all patients and their families for participating in this study, all staff involved at the 17 participating hospitals, and the staff involved in the trial at the Cancer Biomarkers Group at ICR, at the Prostate Cancer Targeted Therapy Group at the Royal Marsden Hospital (London, UK), and at ICR-CTSU. Finally, we thank the past and present colleagues of the TOPARP trial management group, the TOPARP-B independent data monitoring committee, and the ICR-CTSU steering committee for trials in metastatic castration-resistant prostate cancer. Publisher Copyright: © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Local EPrints ID: 437345

URI: http://eprints.soton.ac.uk/id/eprint/437345

DOI: doi:10.1016/S1470-2045(19)30684-9

ISSN: 1470-2045

PURE UUID: cf79c1dd-9d60-45b4-a1fc-14b193c6fba9

ORCID for Simon Crabb: orcid.org/0000-0003-3521-9064

Date deposited: 24 Jan 2020 17:31

Last modified: 17 Mar 2024 02:57