624P - Tolerability of olaparib (OLA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: PROfound

Background

PROfound (NCT02987543), the first positive phase III PARP inhibitor study in mCRPC, showed that OLA significantly prolonged radiographic progression-free survival vs a control of physician’s choice of hormonal agent (pcHA, enzalutamide or abiraterone) in pts with HRR gene alterations and who had progressed on a prior HA. Adverse events (AEs) were also reported and here we describe further details on the tolerability assessments from the study with a focus on the four most common AEs (anaemia, nausea, decreased appetite and fatigue/asthenia) along with pulmonary embolism (PE).

Methods

Pts were randomized to OLA (tablets; 300 mg bid) or control until disease progression or unacceptable toxicity. Safety was assessed through reporting of AEs (CTCAE v4.0) and blood sample analyses.

Results

386 pts received treatment in the overall population (OLA, n=256; control, n=130) and were included in safety analyses. AEs (in ≥10% of pts) in the OLA and control arms (Table) were predominantly Grades 1 or 2 with an onset in <3 months of treatment. Management of the four most common AEs included supportive treatment and/or dose modification (Table). For OLA, 18% of pts discontinued treatment due to AEs (most commonly anaemia, 7%; all other AEs, ≤2%); incidence of PE (all grades) was reported in 4% (11 pts), time to onset was 6–337 days, and in 8 of the 11 pts treatment was continued without interruption. One patient discontinued OLA due to PE, 4 pts had an alternative cause of PE. Table: 624P

Details on the four most common adverse events

Median total treatment duration; OLA (n=256) 7.4 m, control (n=130) 3.9 m. No ≥ grade 4 AEs were recorded for the four events shown.*Grouped term. m, months; †Patients with multiple AEs leading to dose interruption/reduction were counted once for each preferred term

Conclusions

OLA tolerability in mCRPC pts was consistent with other tumour types. Common AEs of anaemia, nausea, decreased appetite and fatigue/asthenia occurred early, gave no indication of cumulative toxicity, were manageable and led to few treatment discontinuations. There was insufficient evidence to confirm or refute a causal association between PE and OLA.

Clinical trial identification

NCT02987543.

Editorial acknowledgement

Medical writing assistance was provided by Martin Goulding, DPhil, from Mudskipper Business, Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).

Legal entity responsible for the study

AstraZeneca and Merck.

Funding

AstraZeneca & Merck.

Disclosure

M. Ozguroglu: Honoraria (self), Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Sanofi; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Astellas; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Roche; Travel/Accommodation/Expenses: Bristol-Myers Squibb; Travel/Accommodation/Expenses: AstraZeneca. N. Matsubara: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Speaker Bureau/Expert testimony: Chugai; Research grant/Funding (institution): Eisai. 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. M.P. Kolinsky: Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: AstraZeneca; Travel/Accommodation/Expenses: Novartis. G. Procopio: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Janssen; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer. S. Feyerabend: Honoraria (self), Advisory/Consultancy: Janssen; Advisory/Consultancy: Astellas; Advisory/Consultancy: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: Aventis. G. Gravis: Travel/Accommodation/Expenses: Janssen Oncology; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Roche. K. Nishimura: Honoraria (self), Advisory/Consultancy: Astellas Pharma; Honoraria (self): Novartis; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Janssen; Research grant/Funding (self): Bayer. C. Gedye: Honoraria (institution), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, I don't accept any funds ever, and use pharma travel to save our taxpayers as our contract allows international travel: Bristol-Myers Squibb; Honoraria (institution), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, I don't accept any funds ever, and use pharma travel to save our taxpayers as our contract allows international travel: MSD; Honoraria (institution), Speaker Bureau/Expert testimony, I don't accept any funds ever, and use pharma travel to save our taxpayers as our contract allows international travel: AstraZeneca; Honoraria (institution), Speaker Bureau/Expert testimony, I don't accept any funds ever, and use pharma travel to save our taxpayers as our contract allows international travel: Iosen; Honoraria (institution), Speaker Bureau/Expert testimony, I don't accept any funds ever, and use pharma travel to save our taxpayers as our contract allows international travel: Pfizer; Honoraria (institution), Speaker Bureau/Expert testimony, I don't accept any funds ever, and use pharma travel to save our taxpayers as our contract allows international travel: AbbVie; Honoraria (institution), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, I don't accept any funds ever, and use pharma travel to save our taxpayers as our contract allows international travel: Astellas; Honoraria (institution), Speaker Bureau/Expert testimony, Research grant/Funding (institution), I don't accept any funds ever, and use pharma travel to save our taxpayers as our contract allows international travel: Amgen. N. Shore: Advisory/Consultancy, Research grant/Funding (self): Amgen; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (self): Dendreon; Advisory/Consultancy, Research grant/Funding (self): Ferring; Advisory/Consultancy, Research grant/Funding (self): Janssen; Advisory/Consultancy, Research grant/Funding (self): Merck; Advisory/Consultancy, Research grant/Funding (self): MDxHealth; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Research grant/Funding (self): Sanofi; Advisory/Consultancy, Research grant/Funding (self): Tomar. 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), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche/Genentech; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy: Astellas Pharma. C. Gresty: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. N. Brickel: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. J. Burgents: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck. A. Allen: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. K. Fizazi: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Astellas Pharma; 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. All other authors have declared no conflicts of interest.