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BackgroundObservational studies suggest that higher levels of 25-hydroxyvitamin D3 (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown.Patients and methodsWe prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards.ResultsPatients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44-0.86), compared with those in the lowest quintile (Ptrend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (Ptrend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status.ConclusionHigher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted.Clinicaltrials.gov identifierNCT00003835.

Background Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. Patients and methods Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. Results Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [−2.47; 95% confidence interval (CI) −7.27, 2.33; P  =   0.31]. Analysis of physical functioning scores showed a significant between-group difference (−4.45 points; 95% CI −8.75, −0.16; P  =   0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [ P  =   0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P  =   0.32; HR 1.38; 95% CI 0.73, 2.63). Conclusions HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. ClincalTrials.gov number NCT02184195. [ABSTRACT FROM AUTHOR]

Background The unmet need for effective and tolerable mPC treatments is high. PC pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) have shown response to the PARP inhibitor olaparib (O; Kaufman 2015). POLO (NCT02184195), the first Phase III trial to evaluate the efficacy of maintenance PARP inhibitor treatment in PC, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) from maintenance O vs placebo (P) for pts with a gBRCAm and mPC whose disease had not progressed during PBC (median 7.4 vs 3.8 months; hazard ratio [HR] 0.53; 95% CI 0.35–0.82; P = 0.004). At 2 years, 22.1% of pts on O vs 9.6% of pts on P were progression free. At an interim overall survival analysis (46% maturity), the HR was 0.91 (95% CI 0.56–1.46; P = 0.68). Safety was consistent with the known profile for O (Golan 2019). Methods POLO is a randomized, double-blind, placebo-controlled trial of pts with a gBRCAm and pancreatic adenocarcinoma who had received ≥16 weeks of first-line PBC for mPC without progression. There was no limit to duration of chemotherapy. Pts were randomized 3:2 to maintenance O tablets (300 mg bid) or P. Treatment began 4–8 weeks after the last PBC dose, continuing until investigator-assessed progression or unacceptable toxicity. The primary endpoint, PFS, and objective response were assessed by blinded independent central review (modified RECIST 1.1). Results Objective response rate among pts with measurable disease at baseline was 23.1% (18/78) in the O and 11.5% (6/52) in the P arm (odds ratio 2.30; 95% CI 0.89–6.76; P = 0.103). Table: 126O Best objective response in the full study population   Olaparib (N = 92)  Placebo (N = 62)  Pts who achieved a response, n (%)  18 (19.6)  6 (9.7)  Pts who achieved a complete response, n (%)  2* (2.2)  0  Median duration of response, months  24.9  3.7  Median time to response, months  5.4  3.6  Pts with stable disease for ≥7 weeks, n (%)  45 (48.9)  34 (54.8)  Pts with continued no evidence of disease, n (%)†  5 (5.4)  0  Disease control rate at 16 weeks, %‡  53.3  37.1    Olaparib (N = 92)  Placebo (N = 62)  Pts who achieved a response, n (%)  18 (19.6)  6 (9.7)  Pts who achieved a complete response, n (%)  2* (2.2)  0  Median duration of response, months  24.9  3.7  Median time to response, months  5.4  3.6  Pts with stable disease for ≥7 weeks, n (%)  45 (48.9)  34 (54.8)  Pts with continued no evidence of disease, n (%)†  5 (5.4)  0  Disease control rate at 16 weeks, %‡  53.3  37.1  * One pt had a partial response to first-line chemotherapy, the other had stable disease; †Applicable to pts who entered the study with no evidence of disease; ‡Proportion of pts with a response, or ≥ 15 weeks of stable disease or no evidence of disease. Table: 126O Best objective response in the full study population   Olaparib (N = 92)  Placebo (N = 62)  Pts who achieved a response, n (%)  18 (19.6)  6 (9.7)  Pts who achieved a complete response, n (%)  2* (2.2)  0  Median duration of response, months  24.9  3.7  Median time to response, months  5.4  3.6  Pts with stable disease for ≥7 weeks, n (%)  45 (48.9)  34 (54.8)  Pts with continued no evidence of disease, n (%)†  5 (5.4)  0  Disease control rate at 16 weeks, %‡  53.3  37.1    Olaparib (N = 92)  Placebo (N = 62)  Pts who achieved a response, n (%)  18 (19.6)  6 (9.7)  Pts who achieved a complete response, n (%)  2* (2.2)  0  Median duration of response, months  24.9  3.7  Median time to response, months  5.4  3.6  Pts with stable disease for ≥7 weeks, n (%)  45 (48.9)  34 (54.8)  Pts with continued no evidence of disease, n (%)†  5 (5.4)  0  Disease control rate at 16 weeks, %‡  53.3  37.1  * One pt had a partial response to first-line chemotherapy, the other had stable disease; †Applicable to pts who entered the study with no evidence of disease; ‡Proportion of pts with a response, or ≥ 15 weeks of stable disease or no evidence of disease. Conclusions Pts with a gBRCAm and mPC whose disease had not progressed on PBC derived a statistically significant and clinically meaningful PFS benefit from maintenance O. O-arm pts were more likely to maintain disease control or achieve a response than P-arm pts, and responses were durable, lasting a median of more than 2 years. Clinical trial identification NCT02184195. Editorial acknowledgement Medical writing assistance was provided by Elin Pyke, MChem, 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 D-Y. Oh: Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme. T. Golan: Honoraria (self), Research grant / Funding (self), International coordinating investigator service fee: AstraZeneca; Research grant / Funding (self): MSD Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie. P. Hammel: Research grant / Funding (self): Celgene; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self), Non-remunerated activity/ies: Erythec; Research grant / Funding (self): Halozyme. M. Reni: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Non-remunerated activity/ies, Steering committee member: Celgene; Advisory / Consultancy: Baxalta; Advisory / Consultancy: Shire; Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novocure; Advisory / Consultancy: Novartis; Advisory / Consultancy, Steering Committee member: AstraZeneca; Advisory / Consultancy, Steering Committee member: Boston Pharma. E. Van Cutsem: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Celgene; Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (self): Merck KGaA; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Roche; Advisory / Consultancy, Research grant / Funding (self): Servier; Research grant / Funding (self): Amgen; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Ipsen. T. Macarulla: Honoraria (self): Genzyme; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi/Aventis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Shire; Honoraria (self): Tesaro; Advisory / Consultancy: Baxalta; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: H3B; Advisory / Consultancy: QED; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Aslan; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Bayer, Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Hallozyme; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merimarack; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis, Novocure, Pfizer, Pharmaclynics. M.J. Hall: Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Research grant / Funding (institution): Merck; Travel / Accommodation / Expenses: Caris Lifesciences; Non-remunerated activity/ies: Myriad; Non-remunerated activity/ies: Ambry; Non-remunerated activity/ies: Invitae; Non-remunerated activity/ies: Foundation Medicine; Non-remunerated activity/ies: Caris; Non-remunerated activity/ies: Merck. J. Oh Park: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Celgene; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Shire; Advisory / Consultancy: Merck; Advisory / Consultancy: Sereno. D. Arnold: Honoraria (self): AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Bayer; Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self): Biocompatibles; Honoraria (self): Eli Lilly; Honoraria (self), Non-remunerated activity/ies: MSD; Honoraria (self), Non-remunerated activity/ies: Servier; Honoraria (self), Non-remunerated activity/ies: Sanofi; Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): Terumo; Honoraria (self), Non-remunerated activity/ies: Sirtex. A. Reinacher-Schick: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Baxalta; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Honoraria (self): Shire; Research grant / Funding (institution): Astra. G. Tortora: Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis. H. Algül: Honoraria (self): Celgene; Honoraria (self), Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Chugai. E.M. O'Reilly: Advisory / Consultancy: 3DMedcare, Agios, Alignmed, Amgen, Antengene, Aptus, Aslan, Astellas, AstraZeneca; Advisory / Consultancy: Bayer, Beigene, Bioline, BMS, Boston Scientific, Bridgebio, ; Advisory / Consultancy: Carsgen, Celgene, Casi, Cipla, CytomX; Advisory / Consultancy: Daiichi, Debio, Delcath; Advisory / Consultancy: Eisai, Exelixis, Genoscience; Advisory / Consultancy: Halozyme, Hengrui; Advisory / Consultancy: Incyte, Inovio, Ipsen; Advisory / Consultancy: Jazz, Janssen; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy: LAM, Lilly, Loxo; Advisory / Consultancy: Merck, Mina; Advisory / Consultancy: Novella; Advisory / Consultancy: Onxeo; Advisory / Consultancy: PCI Biotech, Pfizer, Pieris; Advisory / Consultancy: QED, Redhill; Advisory / Consultancy: Sanofi, Servier, Silenseed, Sillajen, Sobi; Advisory / Consultancy: Targovax, Tekmira, Twoxar; Advisory / Consultancy: Vicus, Yakult, Yiviva; Research grant / Funding (institution): ActaBiologica, Agios, Array, AstraZeneca, Bayer, Beigene, BMS, Casai, Celgene, Exelisis, Genentech, Halozyme, Incyte, Lilly, Mabvax, Novartis, OncoQuest, Polaris Puma, QED, Roche. D. McGuinness: Full / Part-time employment: AstraZeneca. K.Y. Cui: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Research grant / Funding (institution): Merck and Co. Inc. K. Schlienger: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co. Inc. G.Y. Locker: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H.L. Kindler: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Aldeyra Therapeutics; Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Erytech; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Ipsen Pharmaceuticals; Advisory / Consultancy: Kyowa; Advisory / Consultancy, Travel / Accommodation / Expenses: Paredox Therapeutics; Research grant / Funding (institution): Aduro; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Glaxo Smith Kline; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Polaris; Research grant / Funding (institution): Verastem. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]