Introduction: In the phase 3 study involving the use of durvalumab with or without tremelimumab in combination with platinum-based chemotherapy in untreated extensive -stage SCLC (CASPIAN study), first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone (p = 0.0047). We report exploratory subgroup analyses of treatment patterns and outcomes according to the presence of baseline brain or central nervous system metastases.Methods: Patients (WHO performance status 0 or 1), including those with asymptomatic or treated-and-stable brain metastases, were randomized to four cycles of dur-valumab plus EP followed by maintenance durvalumab until progression or up to six cycles of EP and optional prophy-lactic cranial irradiation. Prespecified analyses of OS and progression-free survival (PFS) in subgroups with or without brain metastases used unstratified-Cox proportional hazards models. The data cutoff was on January 27, 2020.Results: At baseline, 28 out of 268 patients (10.4%) in the durvalumab plus EP arm and 27 out of 269 patients (10.0%) in the EP arm had known brain metastases, of whom 3 of 28 (10.7%) and 4 of 27 (14.8%) had previous brain radio-therapy, respectively. Durvalumab plus EP (versus EP alone) prolonged OS (hazard ratio, 95% confidence interval) in patients with (0.79, 0.44-1.41) or without (0.76, 0.62-0.92) brain metastases, with similar PFS results (0.73, 0.42-1.29 and 0.80, 0.66-0.97, respectively). Among patients without brain metastases, similar proportions in each arm developed new brain lesions as part of their first progression (8.8% and 9.5%), although 8.3% in the EP arm received prophy-lactic cranial irradiation. Similar proportions in each arm received subsequent brain radiotherapy (20.5% and 21.2%), although more common in patients with than without baseline brain metastases (45.5% and 18.0%).Conclusions: The OS and PFS benefit with first-line durvalumab plus EP were maintained irrespective of the presence of brain metastases, further supporting its standard-of-care use.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

In the Phase 3, open-label CASPIAN study, first-line durvalumab (anti-PD-L1) + etoposide and cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) (data cut-off [DCO]: Mar 11, 2019): HR 0.73 (95% CI 0.59–0.91; p=0.0047). This benefit was sustained with >2 years of median follow-up (DCO: Jan 27, 2020): HR 0.75 (95% CI 0.62‒0.91; nominal p=0.0032). Although not statistically significant, a numerical improvement in OS was observed with durvalumab + tremelimumab (anti-CTLA-4) + EP versus EP: HR 0.82 (95% CI 0.68‒1.00; p=0.0451).

We developed and evaluated a method for making early predictions of best overall response (BOR) and overall survival at 6 months (OS6) in patients with cancer treated with immunotherapy. This method combines machine learning with modeling of longitudinal tumor size data. We applied our method to data from durvalumab-exposed patients with recurrent/metastatic head and neck cancer. A fivefold cross-validation was used for model selection. Independent trial data, with various degrees of data truncation, were used for model validation. Mean classification error rates (90% confidence intervals [CIs]) from cross-validation were 5.99% (90% CI 2.98%-7.50%) for BOR and 19.8% (90% CI 15.8%-39.3%) for OS6. During model validation, the area under the receiver operating characteristic curves was preserved for BOR (0.97, 0.97, and 0.94) and OS6 (0.85, 0.84, and 0.82) at 24, 18, and 12 weeks, respectively. These results suggest our method predicts trial outcomes accurately from early data and could be used to aid drug development.

In the phase 3 CASPIAN trial, 1L D+EP significantly improved OS vs EP (HR 0.73 [95% CI 0.59-0.91; p=0.0047]) in pts with ES-SCLC, with sustained benefit after >2 yr median follow-up (HR 0.75 [95% CI 0.62-0.91; nominal p=0.0032]). Landmark analyses indicated 22% of pts were alive at 24m with the addition of D±T to EP. Here we assess the clinical characteristics and outcomes of pts deriving long-term benefit, as well as the relationship between TMB and efficacy outcomes in the ITT population. 805 pts with ES-SCLC were randomised 1:1:1 to D+EP, D+T+EP, or EP. Exploratory subgroup analyses defined long-term clinical benefit as PFS ≥12m. Tumour tissue was mandated at screening, if available. TMB was assessed in tissue (tTMB) using the FoundationOne CDx platform. 45 (17%), 42 (16%), and 12 (5%) pts treated with D+EP, D+T+EP, and EP had PFS ≥12m, respectively (data cutoff 27 Jan 2020). In all arms, the PFS ≥12m subgroup had a higher incidence of favorable prognostic factors (more women and pts with PS 0, fewer pts with brain/liver metastases). In the D+EP arm, pts with PFS ≥12m received more D (median 25 vs 7 cycles) and had improved ORR (96% vs 63%), median DoR (NR vs 4m) and OS at 24m (77% vs 11%) compared with the PFS <12m subgroup. Similar results were observed with EP and when both IO arms were combined. Safety and additional efficacy outcomes in the subgroups will be presented. Across all 3 arms, 283 pts (35% of ITT) were evaluable for tTMB. tTMB was not predictive of a differential treatment effect for D±T+EP vs EP (OS, PFS, or ORR). Across all arms, pts with PFS ≥12m had exceptional 2 yr OS rates >75%, despite some having poor prognostic factors such as baseline brain or liver metastases. There were >3 times more pts deriving long-term benefit when treated with durvalumab + EP vs EP alone. Further investigation into predictive factors for long-term benefit with durvalumab is ongoing.

In the phase III CASPIAN trial, 1L D+EP significantly improved OS vs EP (HR 0.73 [95% CI 0.59‒0.91; p=0.0047]) in pts with ES-SCLC, with sustained benefit after >2 yr median follow-up (HR 0.75 [95% CI 0.62‒0.91; nominal p=0.0032]). Landmark analyses indicated 22% of pts were alive at 24m with the addition of D±T to EP. Here we assess the clinical characteristics and outcomes of pts deriving long-term benefit, as well as the relationship between TMB and efficacy outcomes in the ITT population. 805 pts with ES-SCLC were randomised 1:1:1 to D+EP, D+T+EP, or EP. Exploratory subgroup analyses defined long-term clinical benefit as PFS ≥12m. Tumour tissue was mandated at screening, if available. TMB was assessed in tissue (tTMB) using the FoundationOne CDx platform. 45 (17%), 42 (16%), and 12 (5%) pts treated with D+EP, D+T+EP, and EP had PFS ≥12m, respectively (data cutoff 27 Jan 2020). In all arms, the PFS ≥12m subgroup had a higher incidence of favorable prognostic factors (more women and pts with PS 0, fewer pts with brain/liver metastases). In the D+EP arm, pts with PFS ≥12m received more D (median 25 vs 7 cycles) and had improved ORR (96% vs 63%), median DoR (NR vs 4m) and OS at 24m (77% vs 11%) compared with the PFS <12m subgroup (Table). Similar results were observed with EP and when both IO arms were combined. Safety and additional efficacy outcomes in the subgroups will be presented. Across all 3 arms, 283 pts (35% of ITT) were evaluable for tTMB. tTMB was not predictive of a differential treatment effect for D±T+EP vs EP (OS, PFS, or ORR).Table: 379MOD+EPIO arms combinedPFS ≥12m n=45PFS <12m n=220PFS ≥12m n=87PFS <12m n=444Ongoing durvalumab at DCO, n (%)27 (60)5 (2)50 (57)12 (3)Durvalumab cycles, median (range)25 (6–37)7 (1–28)25 (2–37)6 (1–33)Male, %60736375Never / ever smoker, %9 / 918 / 929 / 917 / 93PS 0 / 1, %47 / 5335 / 6548 / 5236 / 64Brain mets, %711314Liver mets, %20442346ORR, n/N (%)43/45 (96)139/220 (63)82/87 (94)256/443 (58)Median DoR, m (95% CI)NR (18–NE)4 (3.5–5)NR (24–NE)4 (4–5)OS at 24m, % (95% CI)77 (61–87)11 (7–16)82 (72–89)11 (8–14) Open table in a new tab . Across all arms, pts with PFS ≥12m had exceptional 2 yr OS rates >75%, despite some having poor prognostic factors such as baseline brain or liver metastases. There were >3 times more pts deriving long-term benefit when treated with durvalumab + EP vs EP alone. Further investigation into predictive factors for long-term benefit with durvalumab is ongoing.

In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long-term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients.

The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.

To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinumsensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing. Additionally, NGS identified somatic mutations absent from germline testing in 10% (20/209) of the patients. Somatic mutations had > 80% biallelic inactivation frequency and were predominantly clonal, suggesting that BRCA1/2 loss occurs early in the development of these cancers. Clinical outcomes between placebo-and olaparib-treated patients with somatic BRCA1/2 mutations were similar to those with germline BRCA1/2 mutations, indicating that patients with somatic BRCA1/2 mutations benefit from treatment with olaparib.

Background: Olaparib is a PARP inhibitor approved in Europe as maintenance treatment after response to platinum-based chemotherapy in patients (pts) with relapsed, epithelial ovarian cancer (EOC) who harbour a mutation in BRCA. Approval was based on the results of study 19 (NCT00753545). We tested whether TP53 mutations categorized according to their functional effects influence overall survival (OS) in a cohort of 195 EOC pts randomized to olaparib or placebo after platinum-based chemotherapy in study 19. Methods:TP53 status was assessed in anonymized archival tumor samples at Foundation Medicine.TP53 mutations were classified, blinded to treatment and clinical outcome, as "disruptive" (D) and "non disruptive" (ND) according to the degree of disturbance of p53 protein function and structure. Particularly, TP53 (D) mutations are associated with a severe disturbance in the DNA repair activities of the p53 protein. Overall survival (OS) and progression-free survival (PFS) were explored by TP53 and BRCA mutation status. Data cut-off was May 2016. Results: 95 pts had TP53(D) and 100 pts TP53(ND) tumours. Hazard ratios (HR) for PFS in the overall, BRCAm and BRCAwt populations were comparable between TP53(D) and TP53(ND). Pts with TP53(D) derived a statistically significant benefit from olaparib treatment, with median OS of 39.5 months (m) for olaparib and 24.0 m for placebo and a HR = 0.57 (95%CI = [0.35, 0.92]) versus HR = 0.73 (95%CI = [0.46, 1.15]) in the case of pts with TP53(ND). When including BRCA status in the analysis; all pts with BRCA mutations (n = 108) derived a benefit from olaparib in terms of OS, irrespective of TP53 status. In the BRCA wt group, pts with TP53(D) treated with olaparib had an OS of 35.0 m vs. 25.5 m for those receiving placebo (n = 47, HR = 0.80 [0.40, 1.52]). Finally, only pts with TP53(ND) and BRCAwt did not derive any benefit in median OS from olaparib treatment (n = 40, HR = 1.58 [0.77, 3.35]). Conclusions: EOC patients BRCA wt with TP53 disruptive mutations may derive a survival benefit of olaparib treatment. Further studies are required to confirm this finding. Legal entity responsible for the study: Instituto Oncologico Dr Rosell. Astra Zeneca Funding: None Disclosure: A. Fielding, B.A. Dougherty, Z. Lai, D. Hodgson, P. Rowe, S. Spencer, A. Gasco Hernandez: Astra Zeneca employee J. Lobera: Astra Zeneca All other authors have declared no conflicts of interest.

Background In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm).Methods In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1: 1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system. Patients were stratified by ancestry, time to progression on penultimate platinum, and response to most recent platinum. Patients and investigators were masked to treatment assignment by the use of unique identifiers generated during randomisation. The primary endpoint of the trial was progression-free survival. In this updated analysis, we present data for overall survival, a secondary endpoint, from the third data analysis after more than 5 years' follow-up (intention-to-treat population). We did the updated overall survival analysis, described in this Article at 77% data maturity, using a two-sided a of 0.95%. As the study was not powered to assess overall survival, this analysis should be regarded as descriptive and the p values are nominal. We analysed randomly assigned patients for overall survival and all patients who received at least one dose of treatment for safety. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT00753545.Findings Between Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to olaparib (n=136) or placebo (n=129). 136 patients had deleterious BRCAm. The data cutoff for this analysis was Sept 30, 2015. An overall survival advantage was seen with maintenance olaparib versus placebo in all patients (hazard ratio [HR] 0.73 [95% CI 0.55-0.96]; nominal p=0.025, which did not meet the required threshold for statistical significance [p<0.0095]; median overall survival was 29.8 months [95% CI 26.9-35.7] for those treated with olaparib vs 27.8 months [24.9-33.7] for those treated with placebo), and in patients with BRCAm (HR 0.62 [95% CI 0.41-0.94] nominal p=0.025; 34.9 months [95% CI 29.2-54.6] vs 30.2 months [23.1-40.7]). The overall survival data in patients with BRCA wild-type were HR 0.83 (95% CI 0.55-1.24, nominal p=0.37; 24.5 months [19.8-35.0] for those treated with olaparib vs 26.6 months [23.1-32.5] for those treated with placebo). 11 (15%) of 74 patients with BRCAm received maintenance olaparib for 5 years or more. Overall, common grade 3 or worse adverse events in the olaparib and placebo groups were fatigue (11 [8%] of 136 patients vs four [3%] of 128) and anaemia (eight [6%] vs one [1%]). 30 (22%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group reported serious adverse events. In patients treated for 2 years or more, adverse events in the olaparib and placebo groups included low-grade nausea (24 [75%] of 32 patients vs two [40%] of five), fatigue (18 [56%] of 32 vs two [40%] of five), vomiting (12 [38%] of 32 vs zero), and anaemia (eight [25%] of 32 vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment.Interpretation Despite not reaching statistical significance, patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer.

BACKGROUND Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression‐free survival in comparison with a placebo for patients with platinum‐sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation ( BRCA m), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment. METHODS In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCA m. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCA m patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank‐preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCA m patients. RESULTS The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28‐0.97) for the 97 BRCA m patients, whereas for the interim OS analysis with all 136 BRCA m patients, it was 0.73 (95% CI, 0.45‐1.17). The supportive RPSFT analysis HR was approximately 0.66. CONCLUSIONS The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCA m patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity. Cancer 2016;122:1844–52 . © 2016 American Cancer Society .

5501 Background: In a phase II study (NCT00753545, Study 19), maintenance monotherapy with the EU/US-approved PARP inhibitor olaparib significantly improved PFS, and times to first and second subsequent therapy or death (TFST and TSST), vs placebo in PSR SOC pts. Pts with a BRCA1/2 mutation (BRCAm) derived the greatest benefit from olaparib. Analyses after a data cut-off (DCO) on Nov 26, 2012 did not show a significant OS improvement with olaparib in the full analysis set (FAS) (58% maturity; HR 0.88, 95% CI 0.64–1.21, P =0.44) or BRCAm subgroup (52% maturity; HR 0.73, 95% CI 0.45–1.17, P= 0.19) (Ledermann et al, Lancet Oncol 2014). We report updated OS, evaluated after 77% of pts had died (DCO: Sep 30, 2015). Methods: Pts received olaparib (400 mg bid, capsules) or placebo after response to platinum-based therapy. BRCAm status was known for 254/265 pts (96%) from germline or tumor tests. Results: Maintenance olaparib gave pts an OS advantage vs placebo; analyses suggest that the results seen in the FAS may have been driven by the BRCAm group. Investigations into the contribution of pts who were non-BRCAm buthomologous recombination repair deficient are ongoing. In the FAS, 5-yr survival was 29.2% and 20.4% in the olaparib and placebo arms, respectively (36.9% and 24.3% in BRCAm pts). At the 2015 DCO, 15 pts remained on olaparib (BRCAm, n = 8) and 1 on placebo (BRCAm, n = 1). 18/136 FAS pts (13.2%) received olaparib for > 5 yrs (by subgroup: 11/74 BRCAm pts [14.9%]; 7/62 non-BRCAm pts [11.3%]). There was no change to the safety profile and no new cases of MDS/AML were reported since the 2012 DCO. Conclusions: There is an OS advantage for pts in Study 19 receiving maintenance olaparib after response to platinum therapy. Long-term treatment with maintenance olaparib was observed.This analysis supports prior Study 19 data in pts with BRCAm PSR SOC showing a significant PFS benefit and delay to TFST and TSST with olaparib. Clinical trial information: NCT00753545. FAS (77% maturity) BRCAm (70% maturity) Olaparib n = 136 Placebo n = 129 Olaparib n = 74 Placebo n = 62 Events, n (%) 94 (70) 109 (84) 47 (64) 48 (77) Median OS, mo 29.8 27.8 34.9 30.2 HR (95% CI) 0.73 (0.55–0.96) 0.62 (0.41–0.94)

Maintenance monotherapy with the poly(ADP-ribose) polymerase inhibitor olaparib significantly prolongs progression-free survival over placebo in patients with platinum-sensitive relapsed serous ovarian cancer, with greatest benefit seen in patients with a BRCA1/2 mutation (BRCAm). Preservation of health-related quality of life (HRQoL) is important during maintenance therapy; we evaluated the effect of olaparib on HRQoL in this Phase II trial (NCT00753545, Study 19). Patients received olaparib 400 mg b.i.d. (capsules) or placebo until progression. Patient-reported HRQoL and disease-related symptoms were evaluated using the FACT-Ovarian (FACT-O) questionnaire (completed at baseline and every 28 days until progression), the FACT/NCCN Ovarian Symptom Index (FOSI) and the Trial Outcome Index (TOI). TOI of the FACT-O was the primary measure. Overall, 265 women were randomised to maintenance olaparib (n=136) or placebo (n=129). Compliance for HRQoL assessment was high (∼80% over time). Most patients in both arms reported a best response of ‘no change’ on TOI (81%) and other HRQoL measures. There were no statistically significant differences in time to worsening or improvement rates of TOI, FOSI and FACT-O scores in the overall, BRCAm and germline BRCAm populations. Maintenance treatment with olaparib was well tolerated and had no adverse impact on HRQoL in this study of patients with platinum-sensitive relapsed serous ovarian cancer who had responded to their most recent platinum-based therapy (partial or complete response). Interpretation of the HRQoL results in this population may differ from patients who have not responded to their most recent platinum-based therapy.

2562 Background: The PARP inhibitorolaparib (Lynparza) is being evaluated in combination with other anticancer agents. We investigated the steady-state (ss) PK effects and safety of olaparib (tablet) co-administered with the anti-hormonal agents tamoxifen, anastrozole, or letrozole. Methods: An open-label, nonrandomized study was conducted in 79 eligible patients with advanced solid tumors. During three consecutive treatment periods, patients received: (1) olaparib 300 mg twice daily (bd) for 5 days, followed by a 4-day washout period; (2) either tamoxifen 60 mg once daily (qd) for 4 days (loading dose) then 20 mg qd to day 26 (n=30), or anastrozole 1 mg qd to day 19 (n=23), or letrozole 2.5 mg qd to day 38 (n=26); (3) same as treatment period 2 concomitantly with olaparib 300 mg bd for 5 days. Blood samples for PK analysis were taken at ss. Safety was monitored throughout. Results: Olaparib AUC0-t and Cmax decreased by 27% and 20%, respectively, when co-administered with tamoxifen. Anastrozole and letrozole had no relevant impact on ss exposure to olaparib. Olaparib had minimal effects on ss exposure to tamoxifen, anastrozole or letrozole. Most AEs were of mild or moderate severity and as expected in this patient population. Conclusions: Exposure to olaparib decreased slightly when given with tamoxifen; tamoxifen exposure increased slightly when given with olaparib. These effects were considered unlikely to be clinically significant and no dose adjustments for either drugare required. There were no drug interactions between olaparib and letrozole or anastrozole. Safety data were consistent with the known safety profiles of study drugs. Clinical trial information: NCT02093351.Comparison Reference boundary* Cmax GLS mean ratio AUC0-t GLS mean ratio Point estimate 90% CI Point estimate 90% CI T + O vs O 0.7–1.43 0.80 0.71–0.90 0.73 0.63–0.84 A + O vs O 0.7–1.43 0.94 0.84–1.04 0.89 0.76–1.05 L + O vs O 0.7–1.43 1.09 0.99–1.21 1.15 1.07–1.25 T + O vs T 0.7–1.43 1.13 1.06–1.22 1.16 1.11–1.21 A + O vs A 0.8–1.25 0.90 0.84–0.97 0.86 0.80–0.93 L + O vs L 0.8–1.25 0.94 0.91–0.98 0.95 0.91–0.99 *90% CIs falling within this boundary indicate lack of interaction. Abbreviations: O, olaparib; T, tamoxifen; A, anastrozole; L, letrozole; GLS, geometric least squares.

5550 Background: Maintenance monotherapy with the PARP inhibitor olaparib prolongs progression-free survival in PSR SOC pts with no adverse impact on HRQoL. BRCAm pts derive greater benefit. Nausea, vomiting, fatigue and anemia are consistently the most common AEs in olaparib trials. Methods: In this randomized, double-blind Phase II trial (NCT00753545), pts received olaparib 400 mg twice daily (capsules; n=136) or placebo (n=128). AEs were graded by CTCAE v3.0; the timing and severity of AEs were analyzed. Results: Olaparib-treated pts most commonly reported early but transient grade (G)1/2 AEs of nausea, vomiting, fatigue and anemia that resolved with supportive treatment without olaparib regimen changes. G>2 AEs were uncommon and manageable with dose interruptions/reductions and supportive treatment. Anemia was the most common G>2 AE. Common AEs were generally reported later for placebo pts. AEs causing discontinuation were uncommon (olaparib, n=9; placebo, n=2). BRCAm pts had a similar AE profile. Conclusions: AEs commonly reported with olaparib are of mostly mild to moderate intensity, transient and manageable without olaparib discontinuation. Clinical trial information: NCT00753545. Nausea Vomiting Fatigue and asthenia Anemia Olaparib Placebo Olaparib Placebo Olaparib Placebo Olaparib Placebo Pts with AE 96 (71) 46 (36) 47 (35) 18 (14) 84 (62) 59 (46) 29 (21) 7 (5) AE instances* 128 58 82 20 114 72 34 8 G1 101 (79) 46 (79) 58 (71) 12 (60) 66 (58) 58 (81) 5 (15) 4 (50) G2 24 (19) 12 (21) 21 (26) 7 (35) 36 (32) 10 (14) 21 (62) 3 (38) G3/4 3 (2) 0 3 (4) 1 (5) 12 (11) 4 (6) 8 (24) 1 (13) Discontinued† 1 (1) 1 (2) 0 0 0 0 0 0 Dose reduced† 5 (4) 0 4 (5) 1 (5) 9 (8) 1 (1) 6 (18) 1 (13) Interrupted† 9 (7) 1 (2) 18 (22) 1 (5) 8 (7) 2 (3) 4 (12) 0 Resolved 102 (80) 46 (79) 80 (98) 17 (85) 68 (60) 35 (49) 23 (68) 6 (75) Treated 57 (45) 10 (17) 19 (23) 3 (15) 5 (4) 3 (4) 24 (71) 2 (25) Median duration, mo (IQR)‡ 2.2 (1, 7) 0.82 (0.1, 2.4) 0.05 (0.03, 0.13) 0.1 (0.03, 0.1) 3.4 (2, 7) 2.8 (1.5, 4.3) 2.4 (1, 6.6) 0.5 (0.3, 1.4) Time to first occurrence, d (IQR) 3 (1, 15) 12 (4, 29) 49 (10, 112) 64 (25, 106) 24 (7, 57) 28 (7, 48) 28 (14, 59) 91 (49, 133) Values are n (%) unless stated. *Includes AEs considered unrelated to treatment; †AE related; ‡Includes intermittent events.

Objectives: Previously, we reported that maintenance treatment with the oral poly ADP ribose polymerase (PARP) inhibitor (PARPi) olaparib (400 mg bid; capsule formulation) led to a significant improvement in progression-free survival compared with placebo in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (Ledermann et al. N Engl J Med. 2012), with the greatest clinical benefit observed in pts with a BRCA mutation (BRCAm) (Ledermann et al. Lancet Oncol. 2014). Although a statistically significant benefit in overall survival (OS) was not observed following an interim analysis (58% maturity), 12% of pts in the placebo arm (23% of BRCAm pts; 30% of germline BRCAm [gBRCAm] pts) received a PARPi after disease progression, which is hypothesized to have confounded the OS results. To explore this hypothesis, we performed an additional analysis of OS that excluded all pts from the sites where at least one pt received post-progression treatment with a PARPi.

e16026 Background: Olaparib (Lynparza), a PARP inhibitor with antitumor activity in germline (g) BRCA1/2 mutation-associated breast and ovarian cancer, has indicated antitumor activity in gBRCA1/2 mutation-associated prostate cancer (Kaufman et al. JCO 2014). Abiraterone is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) before chemotherapy and after docetaxel-based chemotherapy. Reported here is an open-label safety run-in assessment (part A) from a randomized, placebo-controlled Phase II study (NCT01972217) of olaparib in combination with abiraterone. Methods: Patients (pts) with mCRPC in prior receipt of docetaxel-based chemotherapy were initially administered olaparib 200 mg twice daily (bid) and abiraterone 1000 mg once daily (qd). After 3 pts had received ≥ 14 days’ treatment with both olaparib and abiraterone, dose-limiting toxicities (DLTs) were assessed by a safety review committee (SRC). If ≤ 1 DLT was observed, either olaparib was escalated to 300 mg bid alone for 3–7 days then combined with abiraterone 1000 mg qd (group 1), or abiraterone 1000 mg qd was administered alone for 5–7 days then in combination with olaparib 300 mg bid (group 2). Prednisone or prednisolone 5 mg bid was administered with abiraterone throughout. Results: In total, 16 pts enrolled. In the 3 pts receiving olaparib 200 mg bid and abiraterone 1000 mg qd, no DLTs were observed. In the 13 pts (group 1, n = 7; group 2, n = 6) subsequently dosed with olaparib 300 mg bid and abiraterone 1000 mg qd, no DLTs were observed in 9 who completed > 2 weeks of treatment, 3 were still receiving treatment ( < 2 weeks) and 1 (group 1) withdrew consent following an adverse event (AE) of grade 1 nausea, which was not considered a DLT by the SRC. At the time of reporting 41 AEs had been observed in 10 pts, of which nausea occurred most frequently (5 pts), followed by vomiting and loose stools (3 pts each). No serious AEs considered related to olaparib were observed. Conclusions: DLTs were not observed in any pt dosed with olaparib 200 mg bid (n = 3) or 300 mg bid (n = 9). Olaparib 300 mg bid was considered an appropriate dose for further study in combination with abiraterone in pts with mCRPC. Clinical trial information: NCT01972217.