Primary resistance to androgen receptor (AR) directed therapies in metastatic castrationresistant prostate cancer (mCRPC) is poorly understood. We randomized 202 treatment-naive mCRPC patients to abiraterone or enzalutamide, and performed whole exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR directed therapy in mCRPC and identify potential minimally-invasive biomarkers. Statement of SignificanceLeveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely-used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.
Purpose The standard of care for second-line therapy in patients with advanced pancreatic cancer after gemcitabine-based therapy is not clearly defined. The CONKO-003 phase III study reported a survival benefit with second-line fluorouracil (FU) and oxaliplatin using the oxaliplatin, folinic acid, and FU (OFF) regimen. PANCREOX was a phase III multicenter trial to evaluate the benefit of FU and oxaliplatin administered as modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) versus infusional FU/leucovorin (LV) in this setting. Patients and Methods Patients with confirmed advanced pancreatic cancer who were previously treated with gemcitabine therapy and with an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. A total of 108 patients were randomly assigned to receive biweekly mFOLFOX6 or infusional FU/LV until progression. Progression-free survival (PFS) was the primary end point. Results Baseline patient characteristics were similar in both arms. No difference was observed in PFS (median, 3.1 months v 2.9 months; P = .99). Overall survival (OS) was inferior in patients assigned to mFOLFOX6 (median, 6.1 months v 9.9 months; P = .02). Increased toxicity was observed with the addition of oxaliplatin, with grade 3/4 adverse events occurring in 63% of patients who received mFOLFOX6 and 11% of those who received FU/LV. More patients in the mFOLFOX6 arm withdrew from study due to adverse events than in the FU/LV arm (20% v 2%), whereas the use of postprogression therapy was significantly higher in the FU/LV arm (25% v 7%; P = .015). No significant differences were observed in time to deterioration on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 global health scale. Conclusion No benefit was observed with the addition of oxaliplatin, administered as mFOLFOX6, versus infusional FU/LV in patients with advanced pancreatic cancer previously treated with first-line gemcitabine.
Background Abiraterone + prednisone (abiraterone) and enzalutamide are both indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We aimed to determine the best sequence in which to utilize both agents as well as their second-line efficacy. Methods In this multicentre, randomized, open-label phase II crossover trial conducted across 6 cancer centres in British Columbia, Canada, patients ≥ 18 years with newly-diagnosed mCRPC without neuroendocrine differentiation and ECOG performance status ≤ 2 were randomized 1:1 using simple randomization to receive abiraterone 1000 mg orally daily plus prednisone 5 mg orally twice daily followed by enzalutamide 160 mg orally daily (arm A), or the opposite sequence (arm B). Primary endpoints were time to second PSA progression and PSA response rate (≥ 30% decline) on second-line therapy, analyzed by intention-to-treat in randomized patients and patients that crossed over, respectively. The trial is registered with ClinicalTrials.gov, number NCT02125357. The trial is completed and final analyses are reported here. Findings 202 patients were randomized (101 to each arm) between October 21, 2014 and December 13, 2016. At the time of data cutoff 73 and 75 patients had crossed over in arm A and B, respectively. Time to second PSA progression was longer in arm A (median 19•3 vs 15•2 months, HR = 0•66, 95% CI 0•45-0•97, p = 0•036), at a median followup of 22•8 months (IQR 10•3-33•4). Second-line PSA response rates were 36% for enzalutamide and 4% for abiraterone (p < 0•0001). The most common grade 3-4 adverse events were hypertension (27 [27%] of 101 patients in arm A vs 18 [18%] of 101 in arm B) and fatigue (10 [10%] vs 4 [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in arm A and 20 (20%) of 101 in arm B. There were no treatment related deaths.
Purpose: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance. Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). Results: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements. Conclusions: Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.
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