Key Points Question What is the comparative effectiveness of single-agent immune checkpoint inhibitors (ICIs) vs taxane chemotherapy in populations of patients with metastatic castration-resistant prostate cancer (mCRPC) defined by levels of tumor mutational burden (TMB)? Findings In this comparative effectiveness study of 741 patients with mCRPC, patients with TMB of 10 mutations per megabase (mt/Mb) or greater had significantly longer time to next treatment and overall survival with ICIs vs taxanes. Meaning These findings suggest that in scenarios where taxane use is considered, ICIs are a viable alternate treatment option for patients with mCRPC and TMB of 10 mt/Mb or greater.

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PURPOSE To study the impact of standard-of-care hormonal therapies on metastatic prostate cancer (mPC) clinical genomic profiles in real-world practice, with a focus on homologous recombination-repair (HRR) genes. PATIENTS AND METHODS Targeted next-generation sequencing of 1,302 patients with mPC was pursued using the FoundationOne or FoundationOne CDx assays. Longitudinal clinical data for correlative analysis were curated via technology-enabled abstraction of electronic health records. Genomic biomarkers, including individual gene aberrations and genome-wide loss-of-heterozygosity (gLOH) scores, were compared according to biopsy location and time of sample acquisition (androgen deprivation therapy [ADT]-naïve, ADT-progression and post-ADT, and novel hormonal therapies [NHT]-progression), using chi-square and Wilcoxon rank-sum tests. Multivariable analysis used linear regression. False-discovery rate of 0.05 was applied to account for multiple comparisons. RESULTS Eight hundred forty (65%), 132 (10%), and 330 (25%) biopsies were ADT-naïve, ADT-progression, and NHT-progression, respectively. Later-stage samples were enriched for AR, MYC, TP53, PTEN, and RB1 aberrations (all adjusted P values < .05), but prevalence of HRR-related BRCA2, ATM, and CDK12 aberrations remained stable. Primary and metastatic ADT-naïve biopsies presented similar prevalence of TP53 (36% v 31%) and BRCA2 (8% v 7%) aberrations; 81% of ADT-naïve BRCA2-mutated samples presented BRCA2 biallelic loss. Higher gLOH scores were independently associated with HRR genes ( BRCA2, PALB2, and FANCA), TP53, and RB1 aberrations, and with prior exposure to hormonal therapies in multivariable analysis. CONCLUSION Prevalence of HRR-gene aberrations remains stable along mPC progression, supporting the use of diagnostic biopsies to guide poly (ADP-ribose) polymerase inhibitor treatment in metastatic castration-resistant prostate cancer. gLOH scores increase with emerging resistance to hormonal therapies, independently of individual HRR gene mutations.

PURPOSE APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including breast cancer (BC). In this study, we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival on CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) and immune checkpoint inhibitors. METHODS Comprehensive genomic profiling results from 29,833 BC samples were analyzed for tumor mutational burden and APOBEC signatures. For clinical outcomes, a deidentified nationwide (United States–based) BC Clinico-Genomic Database (CGDB) was evaluated with log-rank and Cox models. Patients with hormone receptor–positive (HR+) human epidermal growth factor receptor 2–negative (HER2–) BC who received first-line ET and CDK4/6i were included. Eligible patients from Mayo Clinic and Duke University were HR+ HER2– BC with sequencing data between September 2013 and July 2020. RESULTS Of 29,833 samples sequenced, 7.9% were APOBEC+ with a high rate in invasive lobular carcinoma (16.7%) and in metastatic tumors (9.7%) relative to locally biopsied BC (4.3%; P < .001). In CGDB, 857 patients with HR+ HER2– BC received ET plus CDK4/6i in the first line. APOBEC+ patients had significantly shorter TTD on ET plus CDK4/6i than APOBEC– patients, 7.8 (95% CI, 4.3 to 14.6) versus 12.4 months (95% CI, 11.2 to 14.1; hazard ratio, 1.6; 95% CI, 1.03 to 2.39; P = .0036). Clinical benefit to immune checkpoint inhibitors was observed in HR+ HER2–, APOBEC+, tumor mutational burden–high patients, with four of nine CGDB patients (TTD 0.3-11.3 months) and four of six patients in Duke/Mayo cohorts (TTD 0.9-40.5 months) with a TTD of ≥ 3 months. CONCLUSION APOBEC+ HR+ HER2– patients had shorter TTD on first-line ET plus CDK4/6i relative to APOBEC– patients. Further research is needed to optimize the treatment of APOBEC+ HR+ HER2– BC and to investigate the efficacy of immunotherapeutic strategies in this population.

Purpose: Alpelisib is a phosphatidylinositol 3-kinase alpha (PI3Kα)-selective inhibitor approved for the treatment of hormone receptor positive/HER2 negative (HR+/HER2-) PIK3CA-mutated advanced breast cancer (ABC) based on the SOLAR-1 trial, which defined 11 substitutions in exons 7, 9, and 20 in PIK3CA (SOLAR1m). We report alpelisib effectiveness for ABC harboring SOLAR1m, as well as other pathogenic PIK3CA mutations (OTHERm) using comprehensive genomic profiling (CGP). Experimental Design: 33,977 tissue and 1,587 liquid biopsies were analyzed using hybrid-capture-based CGP covering the entire coding sequence of PIK3CA. Clinical characteristics and treatment history were available for 10,750 ABC patients in the de-identified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB). Results: PIK3CAm were detected in 11,767 / 33,977 (35%) of tissue biopsies, including 2,300 (7%) samples with OTHERm and no SOLAR1m. Liquid biopsy had 77% sensitivity detecting PIK3CAm, increasing to 95% with ctDNA fraction ≥2%. In patients with HR+/HER2- ABC and PIK3CAm receiving alpelisib/fulvestrant (ALP+FUL; n = 182) or fulvestrant alone (FUL; n = 119), median real-world progression free survival (rwPFS) was 5.9 months on ALP+FUL [95%CI: 5.1 - 7.4] versus 3.1 months on FUL [95%CI: 2.7 - 3.7] (p &lt; 0.0001). In patients with OTHERm, median rwPFS was 4.0 months on ALP+FUL [95%CI: 2.8 - 10.1] versus 2.5 months on FUL [95%CI: 2.2 - 3.7] (p = 0.0054). Conclusions: CGP detects diverse PIK3CAm in a greater number of patients with ABC than PCR hotspot testing; 20% of patients with PIK3CAm do not have SOLAR1m. These patients may derive benefit from alpelisib.

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1068 Background: ALP was approved by the FDA for treatment of HR+/HER2- advanced BC with activating PIK3CAm based on the phase 3 SOLAR-1 trial. Enrollment used 11 PIK3CAm (SOLAR1m) in PIK3CA exons 7, 9 and 20. We report the prevalence of SOLAR1m and other predicted activating mutations elsewhere in the PIK3CA gene (OTHERm) in pts with BC, as well as rw clinical outcomes of ALP treatment in these pts. Methods: Comprehensive genomic profiling (CGP) results from 31,765 tissue and 4,147 liquid biopsies from pts with BC were analyzed. Clinical characteristics and treatment history were available for 1,579 pts with PIK3CAm in a de-identified Flatiron Health-Foundation Medicine clinico-genomic database (data obtained from ̃800 US sites, 1/2011 - 9/2020, via technology-enabled abstraction of clinician notes and radiology/pathology reports). 3 cohorts were considered. Cohort A: HR+/HER2- pts receiving fulvestrant (FUL) alone (n = 124) or ALP/FUL (n = 111) in treatment line ≥2L were considered in survival analysis. Rw progression-free survival (rwPFS) from start of treatment was estimated with Kaplan-Meier analysis and hazard ratios from Cox proportional hazards models adjusted for survival bias. Cohort B: 627 HR+/HER2- pts who received a clinical report with ALP listed (report date after 5/2019) Cohort C: 36 pts with OTHERm only, any receptor subtype, treated with ALP in any combination. Results: Among 31,765 BC tissue biopsies, 10,869 (34%) had PIK3CAm. 8,750 (28%) had SOLAR1m, and of these 1,146 had ≥1 additional OTHERm. 2,119 pts (6.7%) had ≥1 OTHERm without any SOLAR1m. OTHERm more common in the presence of a SOLAR1m were: E726K, E418K, E365K, E453Q, and H1048R (p < 0.0001). OTHERm more common in absence of a SOLAR1m were: N345K, G1049R, Q546K, and indels disrupting PIK3R1 binding (p < 0.0001). Among 4,147 liquid biopsies, detection rates were comparable to tissue: 1,391 (34%) had PIK3CAm and 1159 (28%) had SOLAR1m. In Cohort A, median rwPFS was 4.1 mo on FUL [95%CI: 3-6.2] versus 6.5 mo on ALP/FUL [95%CI: 4.8-9.5] (p = 0.027). In Cohort B, 202/524 (39%) pts with a SOLAR1m were treated with ALP, compared to 28/103 (27%) pts who had OTHERm only. Pts with SOLAR1m received ALP treatment earlier: median [interquartile range] 4L [3-6] versus 5.5L [4-8]. In Cohort C, rwPFS > 6 months was observed in 5 pts bearing: N345K, Q75E, R38C, G106_108del, and N345K/N1044K. Conclusions: This study validates the activity of ALP among a diverse real world population, showing pts with PIK3CA mutations have longer rwPFS on ALP/FUL than FUL alone. Pts with SOLAR1m were more likely to be treated with ALP- and tended to be treated in earlier line setting- than pts with OTHERm. No consistent effect in a small subset of pts with OTHERm treated with ALP was observed, but there is evidence that OTHERm may differ in their degree of PI3K activation, oncogenicity, and ALP sensitivity. Liquid biopsy CGP detected PIK3CAm at similar rates to tissue biopsy.