5059 - PROfound: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations

Background

Loss-of-function alterations in HRR genes are associated with response to PARP inhibition. PROfound (NCT02987543) is a randomized, open-label, phase III trial evaluating efficacy and safety of olaparib (ola) vs enzalutamide (enza) or abiraterone (abi) in patients (pts) with mCRPC with alterations in any of 15 predefined genes with a direct or indirect role in HRR whose disease had progressed on prior new hormonal agent (NHA) therapy.

Methods

Qualifying tumour tissue HRR alterations were centrally and prospectively identified using an investigational next-generation sequencing test (Foundation Medicine, Inc). Cohort A included pts with alterations in BRCA1, BRCA2 or ATM; Cohort B pts with any 1 of 12 other HRR alterations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L). Pts were randomized (2:1) to ola (300 mg bid) or physician’s choice (pcNHA) of enza (160 mg/d) or abi (1000 mg/d + prednisone 5 mg bid). Primary endpoint was radiographic progression-free survival (rPFS) in Cohort A, assessed by blinded independent central review (BICR) and analysed via stratified log-rank test. Crossover to ola was allowed after BICR progression.

Results

4425 men were screened; 245 randomized to Cohort A, 142 to Cohort B (65.6% had prior taxane). Efficacy is shown in Table. Most common adverse events (AEs) were anaemia (46.1 v 15.4%), nausea (41.4 v 19.2%), decreased appetite (30.1 v 17.7%) and fatigue (26.2 v 20.8%) for ola vs pcNHA; 16.4 and 8.5% of pts, respectively, discontinued due to AE.Table: LBA12_PR

Efficacy summary*

NR, not reached; ORR, objective response rate; OS, overall survival

Key secondary endpoints were confirmed ORR in Cohort A, rPFS in Cohort A+B, time to pain progression in Cohort A and OS in Cohort A;

In patients with measurable disease;

Interim analysis at 38% (Cohort A) and 41% (Cohort A+B) data maturity; Of the pcNHA patients whose disease progressed by BICR and were eligible, 80.6% in Cohort A and 84.6% in Cohort B crossed over to olaparib treatment;

Alpha spend at interim was 0.01; statistical significance not reached

Conclusions

In pts with mCRPC and HRR alterations with prior NHA treatment, ola improved rPFS and ORR vs pcNHA, with a favourable trend for OS despite crossover. Safety was generally consistent with the known profile of ola. PROfound is the first positive phase III biomarker-selected study evaluating a targeted treatment in pts with mCRPC.

Clinical trial identification

NCT02987543.

Editorial acknowledgement

Medical writing assistance was provided by Debbi Gorman, PhD, from Mudskipper Business, Ltd and funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Legal entity responsible for the study

AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Funding

AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Disclosure

M. Hussain: Honoraria (self), Women in Pca (lectures): Sanofi/Genzyme; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Lectures: Genentech; Honoraria (self), Lectures: Research to Practice; Honoraria (self), Lectures: Aptitude Health; Honoraria (self), Covering 2019 GU ASCO (lectures): Epics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: Pfizer; Honoraria (self), Lectures: PER; Honoraria (self), Travel / Accommodation / Expenses, Lectures: Astellas. J. Mateo: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Sanofi. K. Fizazi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AAA; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Curevac; Honoraria (self), Advisory / Consultancy: Essa; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Orion; Honoraria (self), Advisory / Consultancy: Sanofi. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas. N.D. Shore: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Dendreon; Advisory / Consultancy: Ferring; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: MDx Health; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Tolmar. S. Sandhu: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Serono; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (institution), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche Genentech; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck. K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. O. Sartor: Shareholder / Stockholder / Stock options: Eli Lilly, GlaxoSmithKline, Noria; Advisory / Consultancy: Bayer HealthCare Pharmaceuticals, Bellicum Pharmaceuticals, Johnson & Johnson, Sanofi, AstraZeneca, Dendreon, Endocyte, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Celgene, Bavarian Nordic, Oncogenex, EM; Research grant / Funding (institution): Bayer HealthCare Pharmaceuticals, Johnson & Johnson, Sanofi, Endocyte, Innocrin Pharma, Merck, InVitae; Speaker Bureau / Expert testimony: Sanofi; Travel / Accommodation / Expenses: Bayer HealthCare Pharmaceuticals, Johnson & Johnson, Sanofi, AstraZeneca, Progenics. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Ely Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Pharmacyclics; Research grant / Funding (institution): Bavarian Nordic, Calithera, Celldex, GSK, Immunomedics, New Link Genetics, Prometheus, Rexahn, Sanofi, Takeda, Tracon. D. Olmos: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony: Sanofi-Aventis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Tokai; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Roche; Officer / Board of Directors, Directors Board Committee, Member: EORTC; Non-remunerated activity/ies: BioOncoTech & Tokai. A. Thiery-Vuillemin: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. P. Twardowski: Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: BMS. N. Mehra: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Sanofi. C. Goessl: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Kang: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Burgents: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck and Co, Inc.. W. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C.A. Adelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. de Bono: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: GSK; Licensing / Royalties, Abiraterone rewards to inventors with royalties paid to institution, no personal income: Janssen Oncology; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Genmab, Orion Pharma, Taiho Pharma, Vertex; Licensing / Royalties, A patent PARP inhibitors and DNA repair defects with royalties paid to institution, no personal income: N/A.