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.

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.

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5002 Background: ABI and ENZ are indicated as 1st line therapy for mCRPC but have not been directly compared. Optimal sequencing of these agents has not been prospectively evaluated and predictive biomarkers are lacking. Methods: Multicenter, phase 2 study randomizing treatment-naïve mCRPC pts to ABI vs ENZ, with cross over at PSA progression. Primary endpoints: response and time to PSA progression (TTPP, PCWG3 criteria) after 2nd line therapy. Reported here are secondary endpoints: PSA ≥50% decline (PSA50) from baseline, TTPP with 1stline therapy, and correlation with deep targeted sequencing of 73 mCRPC genes in circulating tumor DNA (ctDNA). Results: Accrual completed October 2016 with 202 pts randomized (ABI:ENZ = 101:101). Median follow-up 12.8 months. Baseline characteristics were similar between arms: median for age was 75 years (range 49-94), PSA 36.1 (1.7-2817), HGB 130 (89-165), ALK PHOS 105 (31-6600), LDH 207 (77-3098). ECOG PS was 0-1 in 83%, presence of metastases in bone/liver/lung in 83%/6%/10%. With 1stline therapy for ABI vs ENZ, PSA50 at 12 weeks was 53% vs 73% (P = 0.004), no PSA decline occurred in 21% vs 15% (P = 0.243), and median TTPP was 7.4 vs 8.0 months (HR = 0.88, 95% CI 0.61, 1.27). Baseline ctDNA fraction was >2% in 60% of patients, and associated with worse TTPP (HR 1.80, P=0.005). Baseline pathogenic ctDNA alterations in AR, TP53, RB1, and DNA repair (BRCA2, ATM) genes were associated with a shorter TTPP (univariate analysis: TABLE). On multivariate analysis including clinical factors, TP53 and BRCA2/ATM alterations remained significant (HR = 2.54 (95%CI 1.55-4.19) and HR = 2.68 (1.58-4.54)). Pts with a PSA increase as best response were enriched for alterations in DNA repair (P <0.001), TP53 (P = 0.005), RB1 (P = 0.04), and (in 1 pt) a genomically truncated AR. Conclusions: There was a difference in PSA response for 1stline ABI vs ENZ, but no difference for TTPP. Baseline pathogenic ctDNA alterations, particularly in TP53 and BRCA2, identify pts with poor outcomes. Clinical trial information: NCT02125357. [Table: see text]

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