Background

In SOLO1 (NCT01844986; GOG-3004), maintenance olaparib significantly improved PFS vs placebo (HR 0.30; 95% CI 0.23–0.41; Moore et al. NEJM 2018) in patients with newly diagnosed advanced OC, a BRCA mutation and clinical complete or partial response after platinum-based chemotherapy. Most patients in the maintenance setting are well following first-line treatment; thus, it is important to show that extending PFS is not at the expense of decreased health-related quality of life because of toxicity. We assessed the duration of ‘good quality of life’ while on maintenance therapy based on time without significant symptoms of toxicity (TWiST) and quality-adjusted PFS (QAPFS) which both incorporate the adverse effects experienced by patients on maintenance therapy.

Methods

Patients were randomized 2:1 to olaparib tablets 300 mg bid or placebo. Patient-centred outcomes were assessed by QAPFS (product of adjusted mean estimate of the EuroQol 5D-5L single-index utility score from randomization to disease progression and mean PFS time) and TWiST (period without significant symptoms post-randomization and before disease progression or censoring for progression) in a post hoc analysis in the full analysis set.

Results

Of 391 randomized patients, 260 received olaparib and 130 placebo (1 patient did not receive placebo). Mean QAPFS and TWiST improved to a clinically meaningful extent with olaparib vs placebo, with highly significant between-group improvements of at least 12 months (Table).

Table: 224O

Conclusions

There were clinically meaningful patient-centred benefits with maintenance olaparib in both QAPFS and TWiST supporting the substantial benefit of PFS improvement seen with olaparib in newly diagnosed advanced OC.

Clinical trial identification

NCT01844986.

Editorial acknowledgement

Medical writing assistance was provided by Gillian Keating, MBChB, from Mudskipper Business Ltd, 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.

Disclosure

M.L. Friedlander: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy: Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy, Uncompensated: AbbVie. K.N. Moore: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Advaxis; Advisory / Consultancy: Clovis; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Immunogen; Advisory / Consultancy: VBL Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Janssen; Advisory / Consultancy: Aravive; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Samumed; Advisory / Consultancy: Oncomed. N. Colombo: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Biocad; Advisory / Consultancy: Seattle Genetics. A. Oaknin: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Genmab. A. Floquet: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy, Congress support: Roche; Advisory / Consultancy, Congress support: PharmaMar; Advisory / Consultancy, Congress support: Tesaro. A. Leary: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Biocad; Advisory / Consultancy: Tesaro; Advisory / Consultancy: MSD; Advisory / Consultancy: GamaMabs; Advisory / Consultancy: Seattle Genetics. G.S. Sonke: Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): Roche. C. Gourley: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Tesaro; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Nucana; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Foundation One; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Sierra Oncology; Honoraria (self), Advisory / Consultancy: Cor2Ed; Research grant / Funding (self): Novartis; Research grant / Funding (self): Aprea. S. Banerjee: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Tesaro; Honoraria (self): Clovis Oncology; Honoraria (self): Merck; Honoraria (self): PharmaMar; Honoraria (self): Roche; Honoraria (self): Seattle Genetics; Honoraria (self): Nucana. A. Oza: Non-remunerated activity/ies, Steering Committee: AstraZeneca; Non-remunerated activity/ies, Steering Committee: Clovis Oncology; Non-remunerated activity/ies, Steering Committee: Tesaro. A. González-Martín: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Roche; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Genmab; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD. C. Aghajanian: Honoraria (self): Tesaro; Honoraria (self): ImmunoGen; Honoraria (self): Clovis Oncology. E. Lowe: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. R. Hettle: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E. Flood: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Disilvestro: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro. All other authors have declared no conflicts of interest.

Background

In SOLO1 (NCT01844986), maintenance OL significantly improved progression-free survival vs PL (HR 0.30; 95% CI 0.23–0.41; Moore et al. NEJM 2018) following response to first-line platinum chemotherapy in pts with BRCA-mutated advanced OC. We compared pt health status pre- and post-radiological progression (RECIST) in SOLO1 using the EQ-5D-5L descriptive system and visual analogue scale (VAS).

Methods

EQ-5D-5L data were collected at baseline, day 29, every 12 weeks for 3 years, then every 24 weeks until data cut off (May 2018). Using the last EQ-5D-5L pre-progression as baseline, we assessed changes in each domain score, the proportion reporting any problem (levels 2–5) by domain, and Paretian classification of health change (PCHC) at first post-progression EQ-5D-5L. Impact of progression on VAS was assessed by mixed-effects repeated measures analysis. Data were pooled across study arms.

Results

74/100 OL pts and 81/95 PL pts with RECIST progression completed the EQ-5D-5L pre- and post-progression. Pre-progression, any problems were reported in 56%, 54%, 40%, 31% and 5% for anxiety/depression, pain/discomfort, usual activity, mobility, and self care respectively. Post-progression, proportions reporting problems with anxiety/ depression (68%), pain/discomfort (65%) and self care (15%) increased, while usual activity (43%) and mobility (30%) were unchanged. Across all levels, worsening was reported in anxiety/depression (34%), pain/discomfort (27%) and self care (13%). By PCHC, 56% reported worsening in at least one domain, with 37% reporting worse overall health status immediately post-progression. Progression was associated with a statistically significant and meaningful reduction in VAS (-0.0714, P < 0.0001).

Conclusions

Radiological progression after response to first-line platinum chemotherapy is associated with worsening health status, with anxiety/depression and pain/discomfort most affected. These results highlight the impact of progression on pts and pt-reported health benefits of delaying progression with maintenance OL.

Clinical trial identification

NCT01844986.

Editorial acknowledgement

Medical writing assistance was provided by Catherine Risebro, PhD, from Mudskipper Business Ltd, funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M.L. Friedlander: Honoraria (self), Honoraria (institution), Advisory / Consultancy: AstraZeneca; Non-remunerated activity/ies, Consulting: AbbVie; Research grant / Funding (institution): Beigene; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Takeda. R. Hettle: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E. Parkhomenko: Honoraria (institution), Advisory / Consultancy, Full / Part-time employment, Employee of Parexel, which has received consultancy fees from AstraZeneca: AstraZeneca.

Background

PAOLA-1/ENGOT-ov25 (NCT02477644) is the first phase III trial to evaluate the efficacy and safety of a PARP inhibitor with bev as first-line (1L) maintenance therapy for advanced OC, regardless of BRCA1/2 mutation (BRCAm) status.

Methods

PAOLA-1 is a randomized, double-blind, international phase III trial. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer. Pts had received standard PCh plus bev and were in clinical complete or partial response. Pts were randomized (2:1) to olaparib tablets (300 mg bid for up to 24 months [m]) plus bev (15 mg/kg, d1, q3w, for 15 m including when combined with PCh) or placebo (pbo) plus bev, stratified by 1L treatment outcome and tumour BRCAm status. The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population (PFS; modified RECIST v1.1).

Results

537 pts were randomized to olaparib plus bev and 269 to pbo plus bev. Pt characteristics were well balanced. Median follow-up was 22.7 m in the olaparib arm and 24.0 m in the pbo arm. PFS was significantly increased in the olaparib arm. PFS2 is immature.

Table: LBA10

Grade ≥3 AEs were reported by 57% vs 51% of olaparib and pbo pts; the most common were hypertension (19% vs 30%) and anaemia (17% vs < 1%). There were five treatment emergent AEs of death (olaparib, n = 1; pbo, n = 4). Olaparib and pbo dose interruptions, reductions and discontinuations occurred in 54% vs 24%, 41% vs 7% and 20% vs 6% of pts, respectively. There was no clinically meaningful difference in health-related quality of life.

Conclusions

Addition of olaparib to bev maintenance therapy following 1L PCh plus bev led to a statistically significant and clinically meaningful PFS benefit in pts with advanced OC. The PFS benefit in pts with a tBRCAm and in HRD-positive pts was substantial.

Clinical trial identification

NCT02477644, release date 28 February 2019.

Editorial acknowledgement

Laura Smart, MChem, from Mudskipper Business Ltd, funded by ARCAGY Research, AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

K. Fujiwara: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Chugai Roche; Honoraria (self): Zeria; Honoraria (self): Taiho; Honoraria (self): Nihon Kayaku; Honoraria (self): Kyowahakko Kirin; Honoraria (self): Janssen; Honoraria (self): Daiichi Sankyo; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Kaken. P. Harter: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self): Sotio; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self): Stryker; Honoraria (self): Zai Lab; Honoraria (self), Advisory / Consultancy: MSD/Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: Clovis; Advisory / Consultancy: Immunogen. A. Leary: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Research grant / Funding (institution): Gamamabs; Advisory / Consultancy: Gridstone; Advisory / Consultancy: Biocad; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Inivata; Research grant / Funding (institution): Sanofi; Travel / Accommodation / Expenses: Roche. D. Perol: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): BMS. S. Pignata: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Pfizer; Honoraria (self): Incyte; Honoraria (self): Novartis; Honoraria (self): PharmaMar; Honoraria (self): Clovis; Honoraria (self): Tesaro. A. González-Martín: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Immunogen; Advisory / Consultancy, Speaker Bureau / Expert testimony: PharmaMar; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Genmad; Advisory / Consultancy: Novartis. E. Petru: Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Tesaro; Honoraria (institution), Advisory / Consultancy: Merck-Sharp Dohme. N. Colombo: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Biocad; Honoraria (self), Advisory / Consultancy: Takeda. J. Mäenpää: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: MSD. F. Selle: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: MSD France; Honoraria (self): PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Tesaro; Honoraria (self): Clovis; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca. N. de Gregorio: Advisory / Consultancy: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: PharmaMar. D. Lorusso: Honoraria (self), Advisory / Consultancy: Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Clovis; Advisory / Consultancy: Immunogen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Officer / Board of Directors: GCIG. E.M. Guerra Alia: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: GEICO; Speaker Bureau / Expert testimony: Senpe; Travel / Accommodation / Expenses: Baxter. C. Lefeuvre-Plesse: Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Pfizer. P. Buderath: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): DFG; Research grant / Funding (institution): Deutsche Krebsgesellschaft; Travel / Accommodation / Expenses: PharmaMar. A. Lortholary: Honoraria (self): AstraZeneca; Honoraria (self): Tesaro. A. Burges: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Tesaro; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. E. Pujade-Lauraine: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer. I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer.

Background

Identification of germline BRCA mutations in ovarian cancer patients allows clinicians to take appropriate medical management and preventative measures for patients and their relatives. However, due to the cost, shortage of trained genetic counsellors and clinical geneticists, and lack of awareness among clinicians, there is inadequate genetic testing in most part of Asia, including Malaysia. Mainstreaming genetic counselling may help to increase the accessibility to genetic testing. The aim of this study is to determine the prevalence of BRCA1 and BRCA2 mutations in the population, feasibility of mainstreaming and the psychosocial impact of genetic testing in Malaysian ovarian cancer patients.

Background

Identification of germline BRCA mutations in ovarian cancer patients allows clinicians to make treatment decisions and manage risks. Due to the lack of genetic counsellors, clinical geneticists and awareness among clinicians, there is minimal testing regionally. Mainstreaming genetic counselling may improve this access. This study aims to determine the prevalence of BRCA mutations, feasibility of mainstreaming and the psychosocial impact of genetic testing in Malaysian ovarian cancer patients.

Methods

This study aimed to recruit 800 patients with non-mucinous epithelial ovarian, peritoneal or fallopian tube cancer regardless of age or family history, via mainstreaming or referral to genetic services. Genetic Counselling Satisfaction Scale (GCSS), Decisional Conflict Scale (DCS), Psychosocial Aspect of Hereditary Cancer (PAHC) and Cancer Worry Scale (CWS) were used to measure the feasibility and psychosocial outcomes. Mainstreaming clinicians provided feedback through a survey.

Results

23/28 mainstreaming sites remained active and 47/68 trained clinicians continued to provide genetic counselling. 800 patients have been recruited, 690 via mainstreaming and 110 via genetics route. 790 have been tested, 110 (13.9%) have pathogenic variants, 90 (11.4%) VUS and 590 (74.7%) negative. Majority of the patients were satisfied with their pre-test GC (mean: 23.9; SD: 2.7) and post result disclosure (mean: 24.6; SD: 2.6). Large majority (86%) did not feel conflicted. Patients with no issues in 5 out of 6 PAHC domains increased from 46% at pre-test GC to 62% at result disclosure. However, only 16% of participants showed high distress level after result disclosure, 22% of these were carriers. Generally, there were no significant differences between mainstreaming and genetics pathways. 36/47 (80%) of clinician are confident to counsel patients and want to integrate BRCA testing into their clinical practice.

Conclusions

BRCA prevalence for ovarian cancer in Malaysia is 13.9%. There is satisfaction in counselling services, acceptable psychosocial impact with no significant differences between mainstreaming and genetics pathway. Mainstreaming may improve access to genetic testing in Malaysia.

Legal entity responsible for the study

Cancer Research Malaysia.

Funding

AstraZeneca.

Disclosure

S.Y.Y. Yoon: Research grant / Funding (institution), Investigator Initiated Research Grant: AstraZeneca. A. George: Research grant / Funding (institution): Wellcome Trust; Honoraria (institution): AstraZeneca; Honoraria (institution): Roche; Honoraria (institution): Tesaro.

Background

The worldwide reported prevalence of germline pathogenic BRCA1 and BRCA2 mutations in ovarian cancer patients is 17 % (3-27 %) and that of variants of uncertain significance (VUS) is about 10 %. ^{1, 2}There is deficient data on the prevalence of BRCA mutations in Indian patients. We aimed to estimate the prevalence of germline BRCA mutations among Indian patients with ovarian, primary peritoneal or fallopian tube cancer.

Methods

This was a cross-sectional, multicenter, prospective, observational study conducted at 9 sites from different geographical regions across India which enrolled patients with new or previous diagnosis of ovarian, primary peritoneal, or fallopian tube cancer. Patients underwent blood testing using NGS based platform for germline BRCA. The calculated sample size for this study was 228, assuming 5 % precision around an estimated point prevalence of 15.8 % with a dropout rate of 10 %.

Results

A total of 239 patients were enrolled, of whom 16 were newly diagnosed, treatment naïve, and 223 had a previous diagnosis of ovarian cancer and had received between 1- 9 prior lines of therapy. Germline pathogenic or likely pathogenic BRCA1/BRCA2 mutations were seen in 61 (25.5%, 95% CI 20.12, 31.54) and VUS were seen in 10 (4.2%, 95% CI 2.02 – 7.54) patients, respectively. Among 159 patients with serous histology tumours, 48 (30.2%) had pathogenic/likely pathogenic germline BRCA1/BRCA2 mutations while 16 of 74 (16.2 %) patients with non-serous histology tumours had this finding. Of the 61 patients in this study with germline pathogenic/likely pathogenic BRCA1/BRCA2 mutation, 41 (67.1 %) did not have a family history of breast and/or ovarian cancer.

Conclusions

Approximately one-fourth of unselected ovarian cancer patients from India had germline BRCA1/BRCA2 mutations of whom, nearly two-thirds did not have a family history of breast and/or ovarian cancers.

Legal entity responsible for the study

AstraZeneca Pharma India Limited.

Funding

AstraZeneca Pharma India Limited.

Disclosure

S. Gupta: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. S. Rajappa: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. S.H. Advani: Advisory / Consultancy: AstraZeneca. A. Agarwal: Speaker Bureau / Expert testimony: AstraZeneca. S. Aggarwal: Advisory / Consultancy: AstraZeneca. C. Goswami: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. S. Dattatreya Palanki: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. D. Arya: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. R. Kodagali: Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.