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Background Proof of the clinical utility of a biomarker is when its use informs a management decision and improves patient outcomes relative to when it is not used. Objective To model the clinical benefit of the nuclear-localized androgen receptor splice variant 7 (AR-V7) test for men with progressing metastatic castration-resistant prostate cancer (mCRPC) at the second line of therapy or greater to inform the choice of an androgen receptor signaling inhibitor (ARSI) or a taxane. Design, setting, and participants The study population was a cross-sectional cohort of 193 unique patients with progressing mCRPC from whom 255 samples were drawn at the time of the second line or later treatment decision who then received an ARSI or taxane, with up to 3 yr of additional follow-up Circulating tumor cells (CTCs) were identified from blood samples and tested for AR-V7. Physicians were blinded to AR-V7 status and the testing laboratory was blinded to outcomes. Outcome measurements and statistical analyses We measured physician propensity for choosing an ARSI or taxane based on patient prognosis. We also measured overall survival (OS) adjusted for physician propensity by drug class; OS data were analyzed both without and with knowledge of nuclear-localized AR-V7 status. Results and limitations Treating physicians had a propensity for choosing a taxane over an ARSI for patients with more advanced disease or who received an ARSI as the immediate prior therapy. After adjusting for physician propensity, discernible OS differences were not observed between taxane- and ARSI-treated patients (median 15.6 vs 14.4 mo; p =0.11). Patients with detectable nuclear-localized AR-V7 in CTCs had superior survival with taxanes over ARSIs (median 9.8 vs 5.7 mo; p = 0.041). AR-V7–negative patients had superior survival on ARSIs over taxanes (p = 0.033) but overlapping curves limit the interpretation. Mutivariable models showed a robust interaction between AR-V7 status and drug, and a lower risk of death on taxanes for AR-V7–positive men. Conclusions Use of the nuclear-localized AR-V7 CTC test to inform treatment choice can improve patient outcomes relative to decisions based solely on standard-of-care measures. Patient summary Men with metastatic prostate cancer who test positive for AR-V7 protein in circulating tumor cells are likely to live longer if taxane chemotherapy is used.

Chromosomal instability (CIN) increases a tumor cell's ability to acquire chromosomal alterations, a mechanism by which tumor cells evolve, adapt, and resist therapeutics. We sought to develop a biomarker of CIN in circulating tumor cells (CTC) that are more likely to reflect the genetic diversity of patient's disease than a single-site biopsy and be assessed rapidly so as to inform treatment management decisions in real time. Large-scale transitions (LST) are genomic alterations defined as chromosomal breakages that generate chromosomal gains or losses of greater than or equal to10 Mb. Here we studied the relationship between the number of LST in an individual CTC determined by direct sequencing and morphologic features of the cells. This relationship was then used to develop a computer vision algorithm that utilizes CTC image features to predict the presence of a high (9 or more) versus low (8 or fewer) LST number in a single cell. As LSTs are a primary functional component of homologous recombination deficient cellular phenotypes, the image-based algorithm was studied prospectively on 10,240 CTCs in 367 blood samples obtained from 294 patients with progressing metastatic castration-resistant prostate cancer taken prior to starting a standard-of-care approved therapy. The resultant computer vision-based biomarker of CIN in CTCs in a pretreatment sample strongly associated with poor overall survival times in patients treated with androgen receptor signaling inhibitors and taxanes. Significance: A rapidly assessable biomarker of chromosomal instability in CTC is associated with poor outcomes when detected in men with progressing mCRPC.

Purpose: The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear. Experimental Design: In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume. Results: Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40–2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28–6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors. Conclusions: This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.

Importance The anti–programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. Objective To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti–PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. Design, Setting, and Participants In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. Main Outcomes and Measures Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases. Results Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome–associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti–PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. Conclusions and Relevance The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti–PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.

5045Background: Studies in PTEN-deficient prostate cancer (PC) models have shown additive anti-tumor activity when ENZA is combined with PI3K pathway inhibition due to modulation of reciprocal feed...

5053Background: Biomarkers to predict outcomes for individual patients (pts) on standard of care Rx is an unmet medical need in the treatment of mCRPC. Using baseline (BL) blood draws, we previousl...

5020Background: Immune checkpoint blockade has shown clinical benefit in mismatch repair deficient (dMMR) cancers, leading to accelerated FDA approval of pembrolizumab, a PD1-targeting agent, for t...

TPS5093Background: Retinoblastoma (RB) loss of function has been identified as a process by which castration-resistant tumors develop. Up to 60% of CRPC tumors show loss of RB function. This can dr...

e16507Background: We hypothesized that combining abiraterone acetate (AA), an androgen biosynthesis inhibitor shown to induce prostate cancer apoptosis for patients (pts) with mCRPC, with Ipilimuma...

e16529Background: MLN0128 is a first-in-class, dual mTOR inhibitor that has the potential to overcome resistance seen with standard rapalogs through inhibition of both TORC1 and TORC2. This phase I...

TPS3115 Background: A phase I dose-escalating study to assess safety, dose and targeting efficiency of genetically modified autologous human T cells targeted to PSMA was initiated. Preclinical models demonstrated anti-tumor activity and accumulation, migration, and persistence of these cells to tumor. The autologous PSMA-targeted T cells utilizes the P28z second generation chimeric antigen receptor following iv cyclophosphamide (Cy). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, rendering T cells sensitive to ganciclovir for immediate T cell elimination. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize these T cells Methods: Autologous T cells are activated from a leukapheresis product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts were dosed from 107 to 3 x 107 CAR+ T cells/kg.All 7 pts received 300mg/m2 of Cy one day before infusion. Baseline and post treatment imaging included FDG, FDHT and 18F-FIAU PET scans. Results: Three pts in cohort 1 received 1 x 107 CAR+ T cells/kg safely. A fourth pt received the same dose with a modified vector with higher copy number. One pt had stable disease for > 6 months; a second pt has stable scans for > 20 months; the third and fourth patients progressed. Of 3 pts in cohort 2, one received 1.5 x 107 CAR+ T cells/kg and 2 received 3 x 107 CAR+ cell/kg. All 3 had intermittent fever spikes up to 39oC associated with increased levels of IL-4, IL-8, IP-10, sIL-2ra and IL-6 suggesting T cell activation. CAR+ cells persisted in the circulation for up to 2 weeks. Scans with 18F-FIAU labeling suggests that imaging may be cell dose dependent. Conclusions: We have shown that pts can be safely treated with an ex vivo transduction, expansion and therapeutic protocol for the generation of PSMA targeted T cells. Cytokine production suggests in vivo activation and persistence of T cells in blood for up to 2 weeks. Ongoing imaging with 18F may be suboptimal; a second cohort of pts will be studied with 124I-FIAU. Clinical trial information: NCTO1140373.