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4127 Background: NENs can occur in many locations but have limited precision therapy options. DLL3 is a cell surface protein that is emerging as a promising therapeutic target in NENs including neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC). Our recent study indicated that ̃77% of NEPCs expressed DLL3, with expression in circulating tumor cells being highly concordant with matched biopsies. While there are ongoing clinical trials of drugs targeting DLL3, the repertoire of clinical and genomic features shared across other DLL3-expressing NEN cancers is ill-defined. Methods: We analyzed WES and WTS data from NENs identified across 29 different sites of origin using the Caris Life Sciences platform, excluding SCLC and including neuroendocrine carcinomas and neuroendocrine tumors. We used values above or below median DLL3 expression of all NEN samples to define DDL3-High/Low (H/L). Significance of molecular alterations in DLL3-H vs L was determined using Fisher’s-Exact/Mann Whitney/X2 test with Benjamini-Hochberg correction. Results: DLL3 expression across all 2672 NEN samples was observed in 27 of 29 NENs after excluding SCLC. NENs of anus, prostate, lung, bladder, and bile duct exhibited the greatest median DLL3 expression, whereas adrenal gland, small bowel, and nervous system displayed the lowest. Certain tissues of origin displayed more robust DLL3 expression, with 71% (50/66) of NEPC, 75% (87/122) of lung, and 77.3% (51/66) of bladder being DLL3-H compared to 14.4% (13/90) of adrenal and 7.9% (12/151) of small bowel NENs. DLL3-H NENs were associated with TMB-high status ( > 10 muts/Mb; 12.1% vs 4.5%, OR 2.7, q < 0.001) and more genomic alterations in several driver genes, including tumor suppressors TP53 (51% vs 23%, OR 2.3, q < 0.001) and RB1 (42% vs 10%, OR 4.2, q < 0.001), and oncogenes KRAS (14% vs 5.4%, OR 2.5, q < 0.001), MYC (5.7% vs 0.9%, OR 6.3, q < 0.001) and CCNE1 (5.3% vs 1.3%, OR 4.0, q = 0.001). Conversely, DLL3-L NENs exhibited more alterations in CTNNB1 (2.2% vs 5.2%, OR 0.42, q = 0.04), MEN1 (3.3% vs 11%, OR 0.30, q < 0.001), and BCOR (1.3% vs 4.1%, OR 0.32, q = 0.02). DLL3-H NENs also had significantly more alterations in PIK3CA (6.4% vs 3.0%, OR 2.1, q = 0.04), chromatin remodeling genes KMT2D (6.7% vs 2.6% OR 2.6, q = 0.005) and CREBBP (3.2% vs 0.9%, OR 3.6, q = 0.03), and WNT signaling gene APC (9.7% vs 5.2%, OR 1.9, q = 0.02). Conclusions: We confirmed DLL3 expression in NENs across different tissues of origin, with highest expression in poorly differentiated NENs. DLL3-H expression was associated with genomic features considered “undruggable” based on current precision therapy approaches. Therefore, DLL3-targeted therapies may serve as a promising strategy for NEN patients with functional loss of tumor suppressors TP53 and RB1, as well as increased activity of KRAS, WNT and MYC signaling.

TPS5107 Background: Despite a growing number of treatment options for first line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Androgen receptor (AR) signaling inhibition increases genomic instability with double-strand DNA breaks & co-inhibition of AR & PARP induces synthetic lethality in multiple preclinical models. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy as demonstrated in a ph 3 clinical trial of abiraterone & olaparib where this combination improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with abiraterone alone. A ph 1b trial has since shown that enzalutamide plus rucaparib has acceptable safety profile & no significant drug-drug interactions (S-DDI). Methods: CASPAR/A031902 (NCT04455750) is a ph 3 study in which 984 pts will be randomized 1:1 to enzalutamide plus rucaparib or placebo. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). Treatment will be continued until disease progression & crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or nonmeasurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, & no medications with S-DDI with enzalutamide/rucaparib. Hierarchical co-primary endpoints are rPFS & overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 & 21 months in control & combination arms, respectively) & 80% power to detect an HR of 0.80 in OS (median OS of 32 & 40 months, respectively). Key secondary endpoints are rPFS & OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; & differences in adverse events & quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF) & EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA-based testing for alterations in HRR genes. Enrollment to CASPAR began in July 2021 & the study is available for participation to all US-NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180888. Clinical trial information: NCT04455750.

3150 Background: Histone deacetylase (HDAC) inhibition downregulates HIF-1a, which may be effective in overcoming resistance to VEGF-targeting tyrosine kinase inhibitors. We report the updated survival follow-up for patients treated with abexinostat and pazopanib in a phase Ib trial. Methods: Patients with solid tumor malignancies were enrolled in this phase Ib, open-label trial (NCT01543763) of abexinostat in combination with pazopanib (3+3 design), with a dose expansion restricted to renal cell carcinoma (RCC). Patients received a 1-week run-in period with abexinostat alone, and then combination abexinostat with pazopanib during a 28-day treatment cycle until disease progression, unacceptable toxicity or study withdrawal. Plasma samples from 29 patients were sent for metabolomics analysis. Results: 51 patients were enrolled: N = 36 patients in dose escalation, N = 15 in dose expansion. At the time of last report in 2017, 5 patients remained on study treatment: N = 4 with RCC, and N = 1 with thymic neuroendocrine carcinoma. 4 of these patients have now had disease progression. Median duration of therapy measured 44.9 months (range 39.8-102.2). One patient with metastatic RCC (patient 1) remains on study treatment, after progression on 5 prior lines of systemic therapy. With updated survival follow-up, median OS measured 12.4 months in the dose escalation arm and 27.65 months in the RCC dose expansion cohort. Overall median duration of therapy in all 51 patients measured 5.6 months (range 1-103 months). Progression-free survival among patients with high PBMC HDAC2 expression (> 0.4) remains longer compared to those with low expression (median 6.3 vs. 3.7 months, p = 0.0041). Metabolomics analysis demonstrated a negative correlation between HDAC2 and N6-acetyllysine, suggesting that baseline HDAC2 may impact efficacy of HDAC inhibition. Conclusions: The combination of abexinostat with pazopanib appears promising, with the potential for long-term responses particularly in patients with metastatic RCC. This has led to an ongoing phase III trial examining this combination in RCC. Clinical trial information: NCT01543763. [Table: see text]

3125 Background: Fumarate Hydratase (FH) encodes an essential enzyme in the TCA cycle. Inactivating germline mutations in FH lead to hereditary leiomyomatosis and renal cell cancer syndrome with risk of development of certain cancers. Sporadic FH mutations have been described in different cancers but implications of somatic mutations on cancer outcomes and survival are not well described. Here, we characterize the molecular landscape of FH-mutant cancers. Methods: Tumors analyzed using NGS (NextSeq, 592 genes; NovaSeq, WES), IHC, and WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 tested by 22c3, 28-8 (Agilent) and SP-142 (Spring Biosciences) IHC (>1%). MSI tested by FA, IHC, and NGS. TMB measured by totaling somatic mutations per tumor (TMB-h > 10 mutations/MB). Real-world overall survival was extracted from insurance claims data and calculated from first treatment to last contact using K-M survival curves for molecularly defined cohorts. Statistical significance was determined using chi-square and Wilcoxon rank-sum test, adjusted for multiple comparisons (q

e17005 Background: BRAF is a proto-oncogene that is altered in various cancers and is a druggable target. Particularly, the selective BRAF kinase inhibitors Dabrafenib and Vemurafenib are FDA approved for melanoma and thyroid cancer that harbor the activating BRAF V600 hotspot mutations. In pre-clinical studies, activated BRAF promotes tumor cell function across many additional cancer types in which therapeutics have not been considered. We propose that identifying BRAF-activated cancers will guide future pre-clinical investigations and potentially expand the usage of existing BRAF-targeting therapeutics. Methods: We utilized bioinformatics to investigate the molecular profiles of pan-cancer cohorts from two platforms based on distinct sequencing technology. This included a custom curated dataset (whole exome, 6 studies, 39 cancer types, n = 12,019) and GENIE9.1 (targeted gene panel, 62 cancer types, n = 78,619). Studies were included based on genomic modalities (copy number alterations, mutations, gene fusions). We cataloged the frequency and all types of BRAF genomic alterations pan-cancer. We also examined other genomic features, including tumor mutational burden (TMB) and fraction of the genome altered (FGA), and their association with types of BRAF alterations across cancer types. Results: In both platforms, we found that BRAF alterations were observed across over 80% of cancer types. Melanoma, thyroid, and colorectal tumors exhibited the greatest rates of mutations. Regarding gene body rearrangements, we noted endocrine-driven cancers including ovarian and metastatic prostate tumors (mPC) exhibited relative robust rates of amplification. In addition, thyroid carcinoma and mPC harbored recurrent BRAF gene fusion events. In mPC, we found that the BRAF gene fusions often included an N-terminus gene fragment from known androgen-target genes (TMPRSS2 and SND1). These fusion events represented a dysregulated hormone-driven mechanism of BRAF activation. We also found that hotspot missense mutations were cancer-type specific, including K601 hotspots in mPC, G469 hotspots in non-small cell lung cancers, and G466 hotspots in ovarian cancers. Lastly, BRAF-amplified endocrine tumors harbored a 1.5-fold increase in FGA medians, whereas BRAF-mutated lung and colorectal tumors exhibited a 1.6-fold increase in TMB medians. Conclusions: Our molecular analysis revealed that cancers accrued activated BRAF through cancer-type-specific and divergent genomic mechanisms. These molecular features provide genomic evidence to expand the application of BRAF-targeted therapies in additional cancer lineages, including mPC. BRAF mutations were also associated with genomic biomarkers, such as TMB, which may predict response to immune therapies. This suggests that BRAF alterations can be considered as an additional feature to aid therapy selection.

Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase (HSD3B1) rs1047303, 5-alpha-reductase 2 (SRD5A2) rs523349, and solute carrier organic ion (SLCO2B1) rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622, 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, p = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, p = 0.03). We confirmed that the gain-of-function allele in HSD3B1 rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality, however, further validation is required.

Background : Combination therapy with docetaxel and androgen deprivation therapy (ADT) prolongs overall survival in men with metastatic hormone-sensitive prostate cancer (mHSPC). We assessed the benefits and adverse effects of docetaxel and ADT in relation to advancing age. Methods : We performed a post-hoc analysis of the CHAARTED trial comparing docetaxel and ADT versus ADT alone (n=773). Patients were stratified in age groups 70 years old. Multivariable-adjusted progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier curves and compared using multivariable Cox regressions with calculated interaction terms between age group and treatment arm. In the combination arm, the incidence of at least one adverse event (Grade ≥ 3) and the number of adverse events per patient were compared for each age group using multivariable logistic and linear regressions, respectively. Results : After adjusting for clinical variables, docetaxel's effect did not vary by age group for PFS and OS. There was no significant difference in the odds ratio of at least one adverse event (p>0.1 for age groups 60-70 and >70 years old compared to 70 years old experienced +0.37 more adverse events per patient compared to men age Conclusions : PFS and OS were similar across age groups for the combination of docetaxel and ADT compared to ADT. Older men experienced a modest increase in adverse events per patient, highlighting the importance of balancing treatment benefits and adverse effects in this age group.

OBJECTIVES Unequivocal clinical progression (UCP)-a worsening of clinical status with or without radiographic progression (RAD)-represents a distinct mode of disease progression in metastatic prostate cancer. We evaluated the prevalence, risk factors and the impact of UCP on survival outcomes. METHODS A post-hoc analysis of the COU-AA-302, a randomised phase 3 study of abiraterone plus prednisone (AAP) versus prednisone was performed. Baseline characteristics were summarised. Cox proportional-hazards model and Kaplan-Meier method were used for survival and time to event analyses, respectively. Iterative multiple imputation method was used for correlation between clinicoradiographic progression-free survival (crPFS) and overall survival (OS). RESULTS Of 736 patients with disease progression, 280 (38%) had UCP-only and 124 (17%) had UCP plus RAD. Prognostic index model high-risk group was associated with increased likelihood of UCP (p

Simple Summary B7-H3 costimulatory ligand has sparked tremendous interest as a target for antibody-directed therapy of solid tumors. This is attributed to high expression of B7-H3 on the surface of tumor and low expression on normal tissues. Natural killer cells are known as key effectors of the innate immune system against cancer and are being explored clinically in a number of immunotherapy settings. Here, we describe a unique platform technology incorporating a cytokine as a bispecific antibody cross-linker to create a tri-specific NK cell engager, or TriKE, directed against the antigen B7-H3. The data shows this immunotherapeutic construct promotes specific natural killer cell expansion. It also induces antibody-dependent cellular cytotoxicity due to simultaneous recognition of both natural killer cells and B7-H3-expressing cancer cells. Finally, using a xenogeneic mouse model, the data shows that the TriKE induces better natural killer cell-mediated control of ovarian cancer. Taken together, the findings presented here indicate that a B7-H3-targeted TriKE has the potential to enhance natural killer cell immunotherapy in solid tumor settings and supports further development. Abstract We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKETM) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Background: Aberrations in TP53, PTEN and RB1 are key drivers of therapy resistance in prostate cancer. Up to 50% of prostate cancers harbor ETS gene rearrangements, a potentially compounding aggressive biological event. Little is known about the impact of aggregate aberrations and gene fusion events in prostate cancer. Methods: Using cBioportal for Cancer Genomics, an open-access resource for exploration of multidimensional cancer genomics data, we integrate whole-exome sequencing, gene expression, and histopathology with longitudinal clinical outcomes. Subsets of prostate tumors with aberrations in all three genes TP53, PTEN and RB1 were identified and correlated with prevalence of gene fusions. Prostate tumors with aberrations in TP53, PTEN, and RB1 were termed “triple aberrant prostate cancer” (TAPC). Results: Of 479 metastatic prostate tumors, 195 (40.7%) were TAPC, versus 21 of 594 (3.5%) of primary prostate tumors. Patients with metastatic TAPC showed a trend toward poorer overall survival than patients harboring 0, 1 or 2 of these aberrations. Twenty-five distinct fusions were identified, all involving ETS transcription factors. Both primary and metastatic prostate cancers with ETS fusions were significantly more likely to be TAPC than those without ETS fusions. Conclusions: This study identified a unique molecular signature consisting of combined aberrations in TP53, PTEN and RB1 that is associated with poorer overall survival, as well as increasing prevalence of ETS gene fusions and differential gene expression patterns favoring aggressive disease and tumor progression. Identification of this subset of patients could inform prognostic decisions and provide a rationale for more aggressive or unique therapeutic approaches.

Significance The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with metastatic castration-resistant prostate cancer. However, not all patients respond, and de novo resistance mechanisms are largely unknown. To clarify mechanisms that contribute to enzalutamide resistance, we conducted a single-arm enzalutamide clinical trial. Metastatic tissue biopsies were required prior to study entry so we could attempt to identify molecular features associated with de novo resistance. Transcriptional profiling identified specific gene sets—including those linked to reduced AR transcriptional activity and a stemness program—that were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance., The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline

PURPOSE BRCA1 or BRCA2 ( BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study. METHODS We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate. RESULTS Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients). CONCLUSION Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.

TPS194 Background: Despite a growing number of treatment options for first line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Androgen receptor (AR) signaling inhibition increases genomic instability with double-strand DNA breaks & co-inhibition of AR & PARP induces synthetic lethality in multiple preclinical models. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy as demonstrated in a ph 2 clinical trial of abiraterone & olaparib where this combination improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with abiraterone alone. A ph 1b trial has since shown that enzalutamide plus rucaparib has acceptable safety profile & no significant drug-drug interactions (S-DDI). Methods: CASPAR/A031902 (NCT04455750) is a ph 3 study in which 984 pts will be randomized 1:1 to enzalutamide plus rucaparib or placebo. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). Treatment will be continued until disease progression & crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or nonmeasurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, & no medications with S-DDI with enzalutamide/rucaparib. Hierarchical co-primary endpoints are rPFS & overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 & 21 months in control & combination arms, respectively) & 80% power to detect an HR of 0.80 in OS (median OS of 32 & 40 months, respectively). Key secondary endpoints are rPFS & OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; & differences in adverse events & quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF) & EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA-based testing for alterations in HRR genes. Enrollment to CASPAR began in July 2021 & the study is available for participation to all US-NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180888; Clovis Oncology; http://acknowledgments.alliancefound.org Clinical trial information: NCT04455750.

382 Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by inactivating germline mutations in fumarate hydratase ( FH), predisposing individuals to development of certain cancers. Sporadic FH mutations have been described in different types of cancers, including kidney cancers, but the implications of somatic mutations are not well described. Here, we characterize the molecular landscape of kidney tumors with FH mutations. Methods: Tumors were analyzed using next generation sequencing of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq). Immune cell fraction was estimated by immune deconvolution (Quantiseq). Significance was determined by chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value

287 Background: RCC has a distinct pattern of metastatic spread with common sites of metastasis including the lung, bone, and liver. Less common sites include the brain, adrenal gland, and pancreas. While the pattern of metastatic spread has prognostic significance, the biology driving tropism to specific organ sites has not been fully characterized. We utilized a multi-institutional real-world dataset to examine genomic alterations and transcriptional signatures across the spectrum of metastatic sites in patients with RCC. Methods: RCC tissue specimens derived from the kidney and distant metastatic sites were sequenced utilizing a commercially available Clinical Laboratory Improvement Amendments (CLIA)-certified assay by Caris Life Sciences. Whole exome and transcriptome sequencing was performed. Molecular subgroups were defined according to the IMmotion151 metastatic RCC subtypes, with subgroups determined by a weighted average of gene expression levels. Molecular analysis and PD-L1 expression (SP142) were described by metastasis site. Results: 657 RCC samples from 653 patients underwent molecular profiling. The median age was 62 years (range 14-90) and the majority were male (70.6%). The most common histology was clear cell RCC (n = 509, 77.5%), followed by papillary (n = 63, 9.6%), chromophobe (n = 30, 4.6%), medullary (n = 8, 1.2%), collecting duct (n = 6, 0.9%), and mixed (n = 41, 6.2%). Specimen source included the kidney (n = 340, 51.8%), lung (n = 75, 11.4%), bone (n = 45, 6.8%), lymph nodes (n = 34, 5.2%), liver (n = 28, 4.3%), endocrine glands (adrenal, pancreas, and thyroid; n = 23, 3.5%), brain/CNS (n = 16, 2.4%), and other metastatic sites (n = 96, 14.6%). Compared to kidney, several genes were mutated at higher rates for select metastatic sites, including PBRM1 (59.5% bone, 59.1% endocrine, and 45.9% lung vs 33.8% kidney, p< 0.05) and KDM5C (27.8% endocrine, 29.2% lymph nodes, and 35.3% soft tissue vs 9.3% kidney, p< 0.05). When evaluating metastatic specimens versus kidney specimens, bone metastases had a significantly higher proportion of tumors classified as ‘Angio/stromal’ (n = 19, 42.2%; vs n = 52, 15.4%; p< 0.0001), while liver metastases had a higher proportion of the ‘complement/Ω-oxidation’ subgroup (n = 17, 60.7%; vs n = 48, 14.1%; p< 0.0001). PD-L1 expression in metastatic sites (range 6.8%-21.7%, with exception of 0% in GI; p= 0.09 to 0.99) was not significantly different from the kidney (16.6%). Conclusions: In our contemporary real-world analysis, we demonstrate differential patterns of molecular alterations among sites of metastasis in RCC. Our observations elucidate the biology underlying heterogeneous disease outcomes associated with site of metastasis. Application of predictive signatures by site of metastasis may help inform personalized therapy strategies in advanced RCC. Further studies are warranted to validate our findings.

TPS213 Background: Alterations in the cell cycle signaling pathway are common in mCRPC and may contribute to resistance to AR-targeted therapies. Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) have revolutionized the therapeutic landscape in ER+ breast cancer and have demonstrated robust anti-tumor activity in multiple pre-clinical mCRPC models such as enzalutamide-resistant cell lines, including those with the androgen-receptor splice variant 7 (AR-V7). Pre-clinical synergy has also been seen in multiple studies of CDK4/6i and anti-programmed death 1 (PD-1) or PD-ligand-1 (PD-L1). Additionally, loss of function alterations of CDK12, found in 5-7% of mCRPC, may confer vulnerability to anti-PD-L1 agents. Methods: This multi-center study will enroll 54 unselected mCRPC patients (pts), randomized 1:1 to abema (arm A) or abema + atezo (arm B); and 21 pts with known loss of function mutations in CDK12 (arm C) treated with atezo (n = 5) or abema + atezo (n = 16). All pts will undergo on-treatment (6-week) tumor biopsy. Treatment will be continued until disease progression and crossover is prohibited. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-1, biopsy-proven prostate adenocarcinoma, progressive metastatic disease per Prostate Cancer Working Group 3 (PCWG3), progression/intolerance to ≥ 1 novel antiandrogen in hormone-sensitive or CRPC setting, ineligible for docetaxel/cabazitaxel (progression within 12 months of taxane, pt refusal, investigator discretion), no uncontrolled comorbidity or history of pneumonitis/ILD. Arms A & B will use two stage design for co-primary endpoints of progression-free survival at 6 months using PCWG3 (6m-PFS) and objective response rate (ORR). If ≥ 1/12 pts meet either co-primary endpoint, 2nd stage will open to enroll 15 more pts in that arm. Treatment will be deemed to have meaningful clinical activity (MCA) if ≥ 6/27 meet 6m-PFS or ≥ 5/27 have an ORR. This will provide 86% power for 6m-PFS (34% vs. 12%) and 85% power for ORR (30% vs. 10%) at a one-sided α = 0.08. For MCA in arm C, 16 patients treated with abema+atezo will provide 80-85% power for 6m-PFS (34% vs. 12%) at a one-sided α = 0.05 using a one-sample log-rank test. Primary safety endpoint is the incidence of dose-limiting toxicities in pts receiving abema+atezo. Key secondary endpoints are clinical benefit rate (ORR + stable disease), duration of response and overall survival in arms A and B, and safety events in all arms. Primary exploratory endpoint is comparison of tumoral FoxP3+/CD8+ ratio in pts treated with abema vs. abema + atezo. Additional exploratory endpoints will evaluate association between response and genomic alterations identified from tissue or circulating tumor-derived exosomes. Enrollment began in July 2021 and projected enrollment goal is 3 years (NCT04751929). Clinical trial information: NCT04751929.

4 Background: Penile squamous cell carcinoma (SCC) is a rare and aggressive malignancy with few treatments in the advanced setting and little success of immune-checkpoint inhibitions (ICI). Around half of penile SCC cases are linked to HPV infection. We aimed to report the landscape of somatic alterations and ICI-related biomarkers in penile SCC in the Caris Life Sciences dataset and to establish signatures for HPV-dependent and HPV-independent oncogenesis. Methods: Penile SCC tumors were analyzed using next-generation sequencing of DNA (TruSeq, 45 genes; NextSeq, 592 genes and NovaSeq, whole exome sequencing (WES)) and RNA (NovaSeq). PD-L1 expression was tested by IHC using SP142. Microsatellite instability (MSI) was tested by fragment analysis, IHC and NGS. Tumor mutational burden (TMB) was measured by counting all somatic mutations found per tumor (TMB-high: >10 mutations per MB). HPV16/18 status was determined using WES when available. Significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value 1%), 10.7% had high TMB, and 1.1% had dMMR/MSI-H. Of the 108 tumors, 29 had HPV status tested by WES (HPV16/18+, n=13 and HPV16/18-, n=16). KMT2C mutations (33% vs 0%) and FGF3 amplifications (30.8% vs 0%) were specific to HPV16/18+ tumors, while CDKN2A mutations (37.5% vs 0%) were exclusive to HPV16/18- tumors. HPV16/18+ tumors also had a trend towards decreased TP53 (7.7% vs 63%) and TERT promoter (25% vs 77%) alterations (Table). TMB-high were exclusively found in the HPV16/18+ group (30.8% vs 0%), while PD-L1 and dMMR/MSI-H status were comparable between the two groups. Conclusions: To our knowledge, our comprehensive NGS study of penile SCC somatic alterations is the largest to date. HPV16/18+ vs HPV16/18- penile SCC were molecularly distinct tumors, consistent with previous reports. Our finding that TMB-high was exclusive to patients with HPV16/18+ tumors requires confirmation in larger datasets and could be used for better patient stratification in ICI clinical trials.[Table: see text]

Background Surgical and medical androgen deprivation therapy (ADT) strategies are comparable in their ability to suppress serum testosterone levels as treatment in patients with metastatic prostate cancer but differ with regard to cost and impact on quality of life. Medical ADT is associated with better long-term quality of life due to the flexibility of possible therapy interruption but comes with a higher cumulative cost. In the current study, the authors examined whether surgical ADT (ie, bilateral orchiectomy) was used differentially by race/ethnicity and other social factors. Methods The authors identified patients with metastatic disease at the time of diagnosis through the California Cancer Registry. The association between race/ethnicity and receipt of surgical ADT was modeled using multivariable Firth logistic regression adjusting for age, Gleason score, prostate-specific antigen level, clinical tumor and lymph node classification, neighborhood socioeconomic status (SES), insurance, marital status, comorbidities, initial treatment (radiotherapy, chemotherapy), location of care, rural/urban area of residence, and year of diagnosis. Results The authors examined a total of 10,675 patients with metastatic prostate cancer, 11.4% of whom were non-Hispanic black, 8.4% of whom were Asian/Pacific Islander, 18.5% of whom were Hispanic/Latino, and 60.5% of whom were non-Hispanic white. In the multivariable model, patients found to be more likely to receive surgical ADT were Hispanic/Latino (odds ratio [OR], 1.32; 95% confidence interval [95% CI], 1.01-1.72), were from a low neighborhood SES (OR, 1.96; 95% CI, 1.34-2.89) or rural area (OR, 1.49; 95% CI, 1.15-1.92), and had Medicaid/public insurance (OR, 2.21; 95% CI, 1.58-3.10). Patients with military/Veterans Affairs insurance were significantly less likely to receive surgical ADT compared with patients with private insurance (OR, 0.34; 95% CI, 0.13-0.88). Conclusions Race/ethnicity, neighborhood SES, and insurance status appear to be significantly associated with receipt of surgical ADT. Future research will need to characterize other differences in initial treatments among men with advanced prostate cancer based on race/ethnicity and aim to better understand what factors drive the association between surgical ADT among men of Hispanic origin or those from areas with low neighborhood SES.

Background: A lack of diversity among clinical trial (CT) participants remains a critical problem. Few studies have examined recruitment variability in cancer treatment CTs by cancer type. Given the increasing organ-specific specialization of oncologic care, an understanding of this variability may affect institutional recruitment practices. Methods: This study examines three data sources from 2010 through 2014. The analyzed sample includes 3,580 CT participants identified in the institutional Clinical Trials Management System (CTMS) database and 20,305 incident cases of invasive cancer within a Comprehensive Cancer Center (CCC) institutional catchment area. A total of 341,114 incident cases of primary invasive cancer were identified through the California Cancer Registry (CCR). The primary study measurements were sociodemographic characteristics of the three populations (age, sex, race/ethnicity, and health insurance). Results: Racial/ethnic disparities were observed, with more incident cases of Whites seen in cancer center (68%) and enrolled in CTs (72%) compared to incident cases in catchment area (67%) (p

Recent advances in genetic sequencing and recent studies focusing on the broader use of Poly ADP Ribose polymerase (PARP) inhibitors have led to an upsurge of interest in DNA repair mutations as they relate to prostate cancer. This review outlines ongoing studies and recent publications as they relate to the prevalence and detection of DNA repair mutations in metastatic prostate cancer. The detection of these mutations through multiple diagnostic approaches is discussed, including germline sequencing, somatic sequencing, cell-free DNA assays, and circulating tumor cell assays. The clinical course of patients with prostate cancer and DNA repair gene mutations is explored in addition to therapeutic strategies for this population. In men with metastatic prostate cancer, it is reasonable to obtain germline genetic sequencing as well as somatic tumor genomic sequencing to help guide further treatment decisions that may include PARP inhibitors or carboplatin in the future. In the future, in men with metastatic castrate resistant prostate cancer with progression on PARP inhibitors, cell-free DNA sequencing may help elucidate mechanisms of resistance, which include reversion mutations.

PURPOSE: To evaluate the use of abiraterone acetate (1000 mg) plus prednisone (5mg) [AA+P] in patients with high-risk non-metastatic castration resistant prostate cancer (nmCRPC). MATERIALS AND METHODS: Patients considered at high risk for progression to metastatic disease (PSA≥10 ng/mL or PSADT≤10 months) received AA+P daily (28-day cycles). The primary endpoint was the proportion of patients achieving PSA50 during cycles 1–6. Secondary endpoints included time to PSA progression, time to radiographic evidence of disease progression, and safety. RESULTS: Of 131 enrolled patients, 44 (34%) remain on treatment, with a median follow-up of 40.0 months. Median age was 72 (48–90) years. Most patients (82.4%) were white; 14.5% were black. Median screening PSA was 11.9 ng/dL and PSADT was 3.4 months. PSA was significantly reduced (p

Background Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging is a highly sensitive tool for the detection of prostate cancer metastases. However, the effect of primary and secondary androgen deprivation therapy (ADT) on PSMA PET uptake has not been described. Objective To prospectively evaluate changes in 68Ga-PSMA-11 PET uptake on initiation of androgen receptor (AR)-targeted therapy. Design, setting, and participants Prospective single-institution study of patients with metastatic castration-sensitive (n = 4) and castration-resistant prostate cancer (n = 4) starting treatment with ADT and enzalutamide, respectively, who underwent serial 68Ga-PSMA-11 PET imaging before and after treatment initiation. Outcome measurements and statistical analysis The percentage change in 68Ga-PSMA-11 PET uptake from baseline was descriptively reported and graphically represented. Results and limitations Early increases in PSMA PET tracer uptake in at least one metastatic lesion were observed in six out of seven patients who achieved subsequent prostate-specific antigen declines of >50% from baseline. Overall, 22 of 45 metastatic lesions (49%) exhibited early increases in PSMA uptake that were indicative of a flare effect rather than disease progression. Considerable intra- and interpatient heterogeneity was observed in the temporal pattern of PSMA uptake on treatment initiation. Study limitations include the sample size, the variable timing for scan acquisition, and limited long-term follow up. Conclusions Tumor flare in PSMA PET tracer uptake in the absence of disease progression is variably observed on initiation of AR-targeted treatment. Further studies are needed to delineate the factors controlling PSMA expression to optimize the diagnostic yield. Patient summary Flares of increased prostate-specific membrane antigen (PSMA) tracer uptake on positron emission tomography scans are variably observed following initiation of hormone therapy for prostate cancer and do not necessarily represent disease progression. There was considerable variability in PSMA expression between patients, and further studies are needed to understand the factors controlling PSMA expression.

Background Recent literature suggests that living in a rural setting may be associated with adverse cancer outcomes. This study examines the burden of travel from home to cancer center for clinical trial (CT) enrollees. Materials and Methods Patients from the University of California San Francisco Clinical Trial Management System database who enrolled in a cancer CT for a breast, genitourinary, or gastrointestinal malignancy between 1993 and 2014 were included. Cancer type, household zip code, race/ethnicity, phase of study, study sponsor, and year of signed consent were exported. Distance traveled from home to center was calculated using a GoogleMaps application programming interface. The relationships of distance with phase of CT, household income, and race/ethnicity were examined. Results A total of 1,600 patients were enrolled in breast (55.8%), genitourinary (29.4%), or gastrointestinal (14.9%) cancer CTs. The overall median unidirectional distance traveled from home to study site was 25.8 miles (interquartile range [IQR] 11.5–75.3). Of the trial sponsors examined, principal investigator (56.4%), industry (22.2%), cooperative group (11.6%), and National Institutes of Health (NIH; 9.8%), the longest distance traveled was for NIH-sponsored trials, with a median of 39.4 miles (p Conclusion This study found that the burden of travel is highest among patients enrolled in NIH-sponsored trials, phase I studies, or living in low-income areas. These data suggest that travel burden for cancer CT participants may be significant. Implications for Practice This study is one of the first to measure travel distance for patients in cancer clinical trials using a real-world GoogleMaps calculator. Out-of-pocket expenses such as travel are not typically covered by health care payers; therefore, patients may face considerable cost to attend each study visit. Using a single-center clinical trials enrollment database, this study found that the burden of travel is highest for patients enrolled in National Institutes of Health-sponsored trials and phase I studies, as well as for patients living in low-income areas. Results suggest that a significant proportion of patients enrolled in clinical trials face a substantial travel burden.

Background Abiraterone and enzalutamide use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude and clinical relevance of this association in real-world prostate cancer (PC) population remain unknown. Materials and methods We retrospectively reviewed the MarketScan claims databases (1 January 2013 to 30 September 2018) to identify adults with diagnosis of metastatic PC who received treatment with androgen deprivation therapy (ADT) and novel antiandrogen agents (abiraterone or enzalutamide). The primary CV outcome measure was composite outcome of acute myocardial infarction (MI) or stroke. Secondary outcomes were individual risks of MI or stroke. We used an intention-to-treat approach to analyze the CV outcomes associated with drug exposure among patients with metastatic PC. Cox regression model was used to estimate the independent association of two drugs with CV risk after adjustment for age, baseline atrial fibrillation, and Charlson Comorbidity Index. Results A total of 6294 patients with metastatic PC who were treated with ADT and either abiraterone or enzalutamide were included in the final analysis. Of these, 4017 (63.8%) patients used abiraterone and 2217 (32.2%) patients used enzalutamide. During the study period, 255 (6.3%) primary endpoint events occurred, resulting in an incidence rate of 4.3 per 100 patient-years. In multivariable analysis, abiraterone use was associated with a 31% increased risk of MI or stroke compared to enzalutamide (hazard ratio 1.31; 95% confidence interval 1.05-1.63; P = 0.01). The incidence rate was similar in patients who switched initial therapy from abiraterone to enzalutamide or vice versa (5.0 versus 5.6 per 100 patient-years, respectively). Conclusions To our knowledge, this is the first real-world assessment of MI and stroke among metastatic PC patients receiving novel anti-androgens. Our findings of increased MI and stroke risk with abiraterone compared with enzalutamide are consistent with data from clinical trials and suggest that enzalutamide may be preferable for prostate cancer patients at high CV risk., Highlights • Abiraterone and enzalutamide have comparable efficacy but substantial differences in CV toxicity. • We identified metastatic PC patients treated with ADT and abiraterone or enzalutamide from insurance claims-based database. • Abiraterone use was associated with a 31% increased risk for MI or stroke when compared to enzalutamide. • Enzalutamide may be preferable in patients with baseline high CV risk.

Androgen deprivation therapy (ADT) is associated with numerous toxicities that are potentially modifiable. We sought to evaluate the impact of participation in a multidisciplinary clinic, STAND (Supportive Therapy in Androgen Deprivation) Clinic, designed to provide individualized lifestyle modification and management of ADT-related side effects.This phase II study recruited men with prostate cancer who had started ADT6 months prior to enrollment, and in whom ADT was planned for at least 12 months following enrollment. Patients were randomized in a 1:1 ratio to either the STAND Clinic or usual care. Patients randomized to the STAND Clinic were provided monthly multidisciplinary assessment and counseling on exercise, nutrition, and symptom management for 12 months on a rotating schedule. Primary outcome was change from baseline to 12 months in percent body fat. Feasibility outcomes were also assessed by measuring percentage of completed visits. Secondary outcomes included change from baseline to 12 months in 3 domains: (1) metabolic impact and bone health, (2) quality of life (QOL), and (3) physical activity.A total of 25 men were randomized to STAND clinic, and 23 were randomized to usual care. The study did not meet its accrual target of 32 men in each arm and was closed early due to lack of financial support. Overall, 91% (295 of 325) of STAND clinic visits were completed. Eighteen out of the 25 patients in STAND clinic arm (72%) completed all 12 months of STAND clinic visits, and 80% (20 of 25) completed the first 6 months. For all primary and secondary outcomes, there were no statistically significant differences between treatment arms.Individualized and comprehensive management of ADT toxicities in a multidisciplinary clinic was well attended by patients. However, we did not find any differences in the outcomes assessed between the intervention arm and control.

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), is approved in the US as monotherapy for patients (pts) with BRCA1/2-mutated mCRPC after androgen receptor (AR)-directed therapy and a taxane. Synthetic lethality has been observed in studies combining AR-directed therapy (eg, enzalutamide) and a PARPi, independent of DNA-damage repair (DDR) gene defects. The RAMP study (NCT04179396) is investigating the safety and potential drug-drug interactions (DDIs) between rucaparib and enzalutamide in unselected mCRPC pts. In this exploratory analysis, we evaluated the association between treatment response and gene alterations of known clinical significance in mCRPC. Methods: Enrolled pts were previously treated with 0-2 lines of AR-directed therapy and ≤2 lines of chemotherapy for mCRPC. A 1-week run-in of rucaparib monotherapy (600 mg BID) was followed by rucaparib (600 mg BID) + enzalutamide (160 mg QD). Primary endpoints were pharmacokinetics (PK) and safety, including dose-limiting toxicities (DLTs). Change in prostate-specific antigen (PSA) levels from baseline was a secondary endpoint. As an exploratory objective, plasma and/or tissue samples were profiled for genomic alterations using a Foundation Medicine, Inc., assay to evaluate the relationship between genomics and clinical outcome. Results: As of Oct 1, 2020, 8 pts had received treatment; 7 were evaluable for PK and 6 for DLTs. The median age was 68.5 years and 7/8 (88%) pts had received 1 or 2 prior AR-directed therapies. The PK and overall safety profiles of rucaparib + enzalutamide were consistent with each as a single agent, and no DLTs were reported. Overall, 6/8 (75%) pts had a PSA decline, with 4/8 (50%) pts meeting criteria for a confirmed PSA response (≥50% decrease from baseline). Genomic data were available for 6/8 (75%) pts, all of whom had received prior AR-directed therapy. Of the 4/6 (66%) pts who had one or more somatic AR alterations, 3 had a PSA decline (best PSA change of -99%, -22%, and -17% from baseline) with the combination treatment. One pt had a DDR gene mutation, a subclonal ( Conclusions: A combination of enzalutamide and rucaparib had an acceptable safety profile and no clinically significant DDIs. In this small pt set, pts previously treated with AR-directed therapies showed responses to the combination even in the presence of AR alterations and in the absence of DDR gene alterations. These genomic and early efficacy data support further studies of rucaparib and enzalutamide at the recommended combination dose (rucaparib 600 mg BID + enzalutamide 160 mg QD), including in the phase 3 CASPAR study in biomarker-unselected mCRPC pts (NCT04455750). Citation Format: Arpit Rao, Charles J. Ryan, David Morris, Vasileios Assikis, Gautam Jha, Adriel-John Ablaza, Jenn Habeck, Andrea Loehr, Jim Xiao, Esha A. Gangolli. Genomic characteristics and response to rucaparib and enzalutamide in the phase 1b RAMP study of metastatic castration-resistant prostate cancer (mCRPC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 445.

Purpose of review There are currently limited data to guide the optimal management of patients with low-volume metastatic castration-resistant prostate cancer (mCRPC). In this review, we critically assess the most relevant clinical data, and discuss opportunities for advancing therapeutic options in this patient population. Recent findings Over the past decade, treatment options for mCRPC have expanded beyond taxanes to include abiraterone/prednisone, enzalutamide, sipuleucel-T, and radium-223. However, only a subset of patients in the landmark phase 3 studies would meet criteria consistent with low-volume mCRPC, and optimal treatment approach for this patient population is unclear. There is emerging evidence that mCRPC patients who harbor low-volume or indolent disease may derive the most benefit from immunotherapy. Whereas prospective data are lacking, stereotactic body radiation appears to be well tolerated and effective for local control of metastases in oligometastatic CRPC. Summary Prospective studies are needed to establish optimal therapeutic approaches in carefully selected low-volume mCRPC patients. Advances in functional imaging and molecular profiling should provide opportunities to optimize patient selection for effective treatment strategies.

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment. Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain. Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

Objective Natural killer (NK) cells represent a powerful immunotherapeutic target as they lyse tumors directly, do not require differentiation, and can elicit potent inflammatory responses. The objective of these studies was to use an IL-15 super-agonist complex, ALT-803 (Altor BioScience Corporation), to enhance the function of both normal and ovarian cancer patient derived NK cells by increasing cytotoxicity and cytokine production. Methods NK cell function from normal donor peripheral blood mononuclear cells (PBMCs) and ovarian cancer patient ascites was assessed using flow cytometry and chromium release assays ±ALT-803 stimulation. To evaluate the ability of ALT-803 to enhance NK cell function in vivo against ovarian cancer, we used a MA148-luc ovarian cancer NOD scid gamma (NSG) xenogeneic mouse model with transferred human NK cells. Results ALT-803 potently enhanced functionality of NK cells against all ovarian cancer cell lines with significant increases seen in CD107a, IFNγ and TNFα expression depending on target cell line. Function was also rescued in NK cells derived from ovarian cancer patient ascites. Finally, only animals treated with intraperitoneal ALT-803 displayed an NK dependent significant decrease in tumor. Conclusions ALT-803 enhances NK cell cytotoxicity against ovarian cancer in vitro and in vivo and is able to rescue functionality of NK cells derived from ovarian cancer patient ascites. These findings suggest that ALT-803 has the potential to enhance NK cell-based immunotherapeutic approaches for the treatment of ovarian cancer.

Purpose: The purpose of this prospective study was to estimate the effect of 68Ga-prostate specific membrane antigen (PSMA)-11 PET on intended management of patients with biochemically recurrent prostate cancer. Methods: Pre- and post-imaging surveys were filled out by referring providers in patients with biochemical recurrence who were imaged using 68Ga-PSMA-11 PET. Inclusion criteria for this study required a PSA doubling time of less than 12 months after initial treatment (NCT02611882). Of the 150 consecutive patients imaged, 126 surveys were completed (84% response rate). Responses were categorized as major, minor, no change or unknown change. Results: 103 (82%) of patients had disease detected on 68Ga-PSMA-11 PET. Based on survey results, there were 67 (53.2%) patients with major changes, and 8 (6.4%) patients with minor changes in management. The proportion of cases resulting in a change in management did not significantly differ by baseline PSA level. In patients with PSA levels below 0.2 ng/dL, 7 of 12 patients had disease detected on PSMA PET scan, five of whom had a major change in management. Conclusion:68Ga-PSMA-11 PET resulted in a major change in management in 53% of patients with biochemical recurrence. Further studies are warranted to investigate whether PSMA-based management strategies result in improved outcomes for patients.

Abiraterone acetate 1000 mg/day, combined with prednisone 5 mg PO twice daily, is indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate is the oral prodrug of abiraterone, a specific CYP17 inhibitor that blocks androgen biosynthesis within the adrenal glands, testes and tumor microenvironment. In a phase III trial of men with asymptomatic or minimally symptomatic, chemotherapy-naïve mCRPC, treatment with oral abiraterone acetate plus prednisone led to a statistically significant improvement in the co-primary endpoints of overall survival and radiographic progression-free survival when compared with placebo plus prednisone. In long-term follow-up of phase III trials, the incidence of corticosteroid-associated adverse events was 25.5% in the abiraterone acetate plus prednisone arm compared with 23.3% in the placebo plus prednisone arm. The need for regular patient monitoring and appropriate management of symptoms during long-term use of prednisone must be placed in context with the improvement in survival seen with abiraterone plus prednisone. Within the multidisciplinary environment that is emerging to meet quality and cost imperatives, abiraterone acetate plus prednisone is suitable for use in the chemotherapy-naïve population with minimal symptoms as well as in patients who have been treated with docetaxel and may have symptomatic disease. Ongoing trials are evaluating the role of abiraterone acetate plus prednisone in patients with nonmetastatic CRPC and metastatic hormone-sensitive prostate cancer, while further trials in the mCRPC setting are evaluating its use in combination regimens.

Contains fulltext : 174128.pdf (Publisher’s version ) (Closed access) In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (>/=50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6-not estimable) for subsequent abiraterone acetate plus prednisone and 2.8 mo (range 1.8-not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with abiraterone acetate plus prednisone or enzalutamide for patients who progressed on abiraterone acetate is associated with limited clinical benefit. PATIENT SUMMARY: This analysis showed limited clinical benefit for subsequent abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone.

Background: Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interestnamely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trialENTHUSE M1in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0·791; Bayes factor >5) and surpassed the reference model (iAUC 0·743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3·32, 95% CI 2·394·62, p, European Union within the ERC grant LatentCauses supported the work of C.F and I.K. German Research Foundation (DFG) within the Collaborative Research Centre 1243, subproject A17 awarded to C.F. German Federal Ministry of Education and Research (BMBF) through the Research Consortium e:AtheroMED (Systems medicine of myocardial infarction and stroke) under the auspices of the e:Med Programme (grant # 01ZX1313C) supported the work of D.P.A., P.D., C.F., C.K., I.K., N.K., M.L., H.S. and J.F.S. at the Institute of Computational Biology. NIH Grants RR025747-01, MH086633 and 1UL1TR001111, and NSF Grants SES-1357666, DMS-14-07655 and BCS0826844 supported the work of C.H., J.I., E.L., Y.W., H.Y., H.Z. and J.Z. NSFC Grant Nos. 61332013, 61572139 supported the work of X.L, Y.L, Y.Z., and S.Z. National Natural Science Foundation of China grants [Nos. 61422309, 61379092] was awarded to S.Z. The Patrick C. Walsh Prostate Research Fund and the Johns Hopkins Individualized Health Initiative supported the work of R.Y.C., D.D., Y.D., Z.J., K.R., Z.W. and Y.Z. FCT Ph.D. Grant SFRH/BD/80925/2011 was awarded to S.C. Clinical Persona Inc., East Palo Alto, CA supported the work of L.B. and D.K. The Finnish Cultural Foundation and the Drug Research Doctoral Programme (DRDP) at the University of Turku supported T.D.L. The National Research Foundation Singapore and the Singapore Ministry of Education, under its Research Centres of Excellence initiative, supported the work of J.G. and K.T. A grant from the Russian Science Foundation 14-24-00155 was awarded to M.D.K. A*MIDEX grant (no. ANR-11-IDEX-0001-02) was awarded to P.J.B. NSERC supported the work of R.G. The Israeli Centers of Research Excellence (I-CORE) program (Center No. 4/11) supported the work of E.G. Academy of Finland (grants 292611, 269862, 272437, 279163, 295504), National Cancer Institute (16X064), and Cancer Society of Finland supported the work of T.A. Academy of Finland (grant 268531) supported the work of T.M

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Background: Multiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS. Methods: Data from 1,050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were evaluated. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment, 6 week and progression serum assays for T, A and DHEA were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Changes in T, A and DHEA levels from baseline to 6 weeks were calculated as the ratio of 6-week over baseline. The proportional hazards model was used to assess the prognostic significance of changes in T, A, and DHEA from baseline to 6 weeks in predicting OS adjusting for known prognostic factors. Results: Median baseline values for T, A, and, DHEA were 1.0, 13.5 and 8.1, ng/dL respectively while 6 week levels were 0.64, 7.0 and 6.8, ng/dL respectively. Median OS for low testosterone decline is 20.9 months vs 26.3 months for high testosterone decline. In multivariable analysis including known prognostic variables, change in testosterone levels was independently associated with greater OS; the hazard ratio for death with each unit increase in the 6-week/baseline ratio is 1.02 (95% CI=1.01–1.03, p=0.001). Decline in A and DHEA were not significant predictors of OS. In multivariable analysis change in the serum changes did not predict PFS however the ratio of T at 6-weeks over baseline was prognostic of ≥50% decline in PSA with an odds ratio of 0.93 (95% CI=0.85–0.98, p-value=0.039). Conclusions: Declines in testosterone during docetaxel treatment is associated with a longer survival, consistent with a favorable prognostic significance of higher serum androgens in the CRPC.

Author(s): Kaplan, Celia P; Siegel, Adam; Leykin, Yan; Palmer, Nynikka R; Borno, Hala; Bielenberg, Jessica; Livaudais-Toman, Jennifer; Ryan, Charles; Small, Eric J | Abstract: BackgroundTo address limitations in recruitment and enrollment of diverse, low-literacy patients into prostate cancer clinical trials, we evaluated the feasibility, acceptability, and efficacy of an English and Spanish, Internet-based, multilevel recruitment intervention.MethodsIntervention components included (1) a low-literacy, bilingual, automated, Internet-based clinical trial matching tool; (2) a bilingual nurse who assisted individuals with questions and enrollment; and (3) a targeted, Internet-based advertising campaign. We evaluated (a) completion of matching tool, (b) expression of interest in a clinical trial, (c) number of patients who matched to clinical trials at a single institution, (d) discussion of risks and benefits of clinical trials (via follow-up interviews), and (e) effect of the advertising on completing the matching tool. Feasibility, acceptability, and preliminary estimates of efficacy were measured through user engagement with the matching tool and subsequent qualitative interviews with these same users.ResultsDuring the 28-week study period, 523 users provided demographic information, 263 were identified with prostate cancer, 192 (73%) matched to at least one clinical trial, and 29 (15.1%) of those who matched provided contact information. During the study period, 17 prostate cancer clinical trials were available for matching. We completed follow-up interviews with 14 of the 29 men who provided contact information. Of the 14, 85.7% discussed the risks and benefits of clinical trials with their physician, and 35.7% enrolled in a clinical trial. The Internet-based advertising campaign resulted in an increased number of matching tool completions.ConclusionsOur study demonstrates that an Internet-based clinical trial matching tool that is advertised using a targeted Internet-based campaign can provide an effective means to reach diverse, low-literacy patients. When implemented at scale and over a longer duration, such interventions may help increase trial participation among underrepresented populations.

5063 Background: ATM mutations, one of a family of DNA repair defects prevalent in prostate cancer, have been included in a list of actionable mutations for PARP inhibitor (PARPi) therapeutic trials. Despite preclinical evidence, PARPi have shown minimal clinical activity in ATM mutant prostate cancer (ATMmPCa). The present analysis explores co-occurring genomic alterations that may drive outcomes of metastatic PCa (mPCa) patients with tumors harboring ATM mutations and provide clues for understanding therapy resistance and potential targets. Methods: This study included molecular profiling analysis of 1375 cases of mPCa. Tumors were analyzed using next-generation sequencing (NGS), whole transcriptome sequencing (WTS), and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). dMMR/MSI-H status was determined by IHC, NGS, and fragment analysis and tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. We performed differential gene expression analysis of HR-associated transcripts such as ATR, PARP1-3, RAD50, RAD51A/B/C/D and RAD54. Significance was determined using the ꭓ2 test and Benjamini-Hochberg method. Results: Fifty-nine (4.2%) cases harbored pathogenic ATM mutations, 84 (6.2%) harbored BRCA2 mutations. 1018 tumors (74%) were deemed homologous recombination proficient (HRP) and 155 tumors (11.3%) were HR Deficient (HRD); harboring one or more mutation in HR-related genes excluding ATM and BRCA2. The mutation rate of TP53 was significantly lower in ATMmPCa (12.0%) compared to BRCA2mPCa (35%), HRD (35%) and HRP (46.6%) tumors. ATMmPCa showed higher rates of SMAD2 (3.7%/1%) and FLCN (5.2%/0.3%) alterations compared to HRP cases. PARP1 and RAD51D gene expression was reduced in ATMmPCa compared to HRP (p < 0.05) and BRCA2mPCa ( p < 0.05) tumors, respectively. No differences in gene expression levels were detected for ATR, PARP2, PARP3, RAD50, and RAD54. Chromosomal segments demonstrating differential CNA in ATMmPCa vs HRP, HRD, or BRCA2mPCa included FGF19, FGF4, PTPN11, ALDH2, DAXX, BCL7A, CCND1, BMPR1A and MEF2B (Q-value < 0.05 determined by ꭓ2). The most common CNA in ATMmPCa was CCND1, present in approximately 13% (7/55) of cases. Compared to BRCA2mPCa and HRD cases, ATMmPCa cases are less likely to display markers of immunotherapy response such as dMMR/MSI-H or TMB ≥10 mutations/MB. Conclusions: ATMmPCa demonstrated several differences in co-occurring alterations compared to BRCA2mPCa, HRD and HRP mPCa. ATMmPCa tumors were less likely to harbor alterations in TP53 compared to BRCA2, HRD or HRP tumors. CNA in ATMmPCa occurred in 9 genes across distinct mPCa molecular subtypes and were enriched for those associated with the 11q13 amplicon harboring Cyclin D1. The FGF and PTPN11 related pathways are potentially targetable pathways in ATMmPC and may merit further study.

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.

80 Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was granted accelerated approval by the US Food and Drug Administration for patients with BRCA+ mCRPC based on results from the phase 2 TRITON2 study (NCT02952534). The TP53 tumor suppressor gene is among the most frequently mutated genes in human cancers, including mCRPC, and alterations in TP53, PTEN, and RB1 are associated with poor prognosis in patients with prostate cancer and other tumor types. We present data on co-occurring alterations in patients with BRCA+ mCRPC treated with rucaparib in TRITON2. Methods: Patients had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy and were treated with rucaparib 600 mg BID. Tissue and/or cell-free DNA extracted from plasma samples were profiled comprehensively for genomic alterations using Foundation Medicine, Inc., next-generation sequencing assays. Objective response rate (ORR) was assessed per modified Response Evaluation Criteria in Solid Tumors and Prostate Cancer Working Group 3 criteria by independent radiologic review of patients with measurable disease. Prostate-specific antigen (PSA) response rate (≥50% decrease from baseline) was assessed in all patients. Results: Tissue and/or plasma samples were available for 114/115 patients with BRCA+ mCRPC (visit cutoff date: Dec. 23, 2019). Among patients with BRCA+ mCRPC who had samples available for comprehensive genomic profiling, 36.8% (42/114) had a co-occurring alteration in TP53. Deleterious alterations in PTEN were observed in 34.2% (39/114) of patients, 44% (17/39) of which were homozygous deletions of PTEN. RB1 loss was observed in 12.3% (14/114) of patients and was seen more frequently in patients with measurable disease (18.0%, 11/61) than in patients with non-measurable disease (5.7%, 3/53). Although patients with and without TP53 mutations had generally similar baseline demographics and disease characteristics, visceral disease was more prevalent in patients with TP53 mutations (54.8%; 23/42) than in those without them (29.2%; 21/72). Similar ORR and PSA response rates were seen in patients with BRCA+ mCRPC with or without TP53 mutation, with a non-significant trend towards lower response rates in patients with co-occurring TP53 alterations. Conclusions: Results from TRITON2 showed antitumor activity for rucaparib in patients with BRCA+ mCRPC associated with or without co-occurring alterations in TP53. Demographics and additional efficacy analyses in genomic subgroups with co-occurring alterations in TP53, PTEN, and RB1 will be reported. Clinical trial information: NCT02952534. [Table: see text]

TPS181 Background: Treatment with novel antiandrogens (NAA) and androgen deprivation therapy prolongs life in men with mCRPC but approximately 40% patients (pts) have radiographic progression within the first year. Inhibition of androgen receptor signaling results in increased double-strand DNA breaks and genomic instability. NAA+PARP inhibitor (PARPi) combinations have shown induction of synthetic lethality by this mechanism in multiple preclinical studies. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy and an NAA+PARPi combination has shown improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with NAA alone. Methods: CASPAR (A031902) is a randomized phase 3 study in which 984 pts will be randomized on a 1:1 basis to ENZ plus RUCA/PBO. A PK substudy will precede the phase 3 portion and enroll 6-18 pts to various doses of ENZ plus RUCA to establish safety and evaluate any clinically-significant drug-drug interactions (S-DDI). Treatment will be continued until disease progression and cross-over is not allowed. Co-primary endpoints are rPFS and overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 and 21 months in control and combination arms, respectively), and 80% power to detect an HR of 0.80 in OS (median OS of 32 and 40 months, respectively). Key secondary endpoints are rPFS and OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 mutations; and differences in adverse events and quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and EQ-5D-5L. A key correlative endpoint is the concordance between tissue and plasma ctDNA-based HRR testing. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or non-measurable disease per RECIST 1.1, no prior treatment for mCRPC (prior abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, and no medications with S-DDI with ENZ/RUCA. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). CASPAR is available for participation to all US-NCTN sites starting in October 2020 with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882; acknowledgments.alliancefound.org. Clinical trial information: NCT04455750.

79 Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), is approved in the US as monotherapy for BRCA1/2 mutated mCRPC that has been treated with androgen receptor (AR)-directed therapy and a taxane. In previous studies, synthetic lethality was observed with a combination of AR-directed therapy (eg, enzalutamide) and a PARPi, independent of DNA-damage repair gene defects. The potential for drug-drug interaction between rucaparib and enzalutamide was recognized as enzalutamide is a strong clinical inducer of CYP3A4, a mediator of the formation of rucaparib metabolite M324. RAMP (NCT04179396) is investigating the combination of rucaparib and enzalutamide in unselected pts with mCRPC to assess PK and safety and inform subsequent studies. Methods: Eligible pts had 0–2 lines of AR-directed therapy and ≤2 lines of chemotherapy for mCRPC. Prior PARPi treatment was not allowed. A 1-week run-in of rucaparib monotherapy (600 mg BID) was followed by rucaparib (600 mg BID) + enzalutamide (160 mg QD) in continuous 28-day cycles. Trough PK was evaluated for rucaparib and enzalutamide and their metabolites (M324 and N-desmethyl enzalutamide). Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles. Primary endpoints were PK and safety for the combination. Secondary endpoints were change from baseline in prostate-specific antigen (PSA) levels and objective response rate (per modified RECIST/PCWG3). Results: As of Oct 1, 2020, 8 pts had received treatment; 7 were evaluable for PK and 6 for DLTs. The median age was 68.5 years, and 6/8 (75%) pts had ≥2 prior mCRPC therapies. Rucaparib and M324 reached apparent steady-state PK at the end of the run-in period. Concomitant treatment with enzalutamide had no significant effect on the PK of either rucaparib or M324. The PK of enzalutamide and N-desmethyl enzalutamide in the combination were also consistent with monotherapy enzalutamide PK data. No DLTs were reported. The most common grade ≥3 TEAEs among all 8 pts were anemia (n = 5) and fatigue (n = 4). Seven of 8 (87.5%) pts required a dose modification (treatment interruption or dose reduction). Four of 8 (50%) pts had a confirmed PSA response (reduction ≥50% from baseline); 1/1 (100%) pt with measurable disease achieved a confirmed complete radiographic response. At the time of data cutoff, 1/8 (12.5%) pts was on study for > 6 cycles. Conclusions: A combination of enzalutamide and rucaparib was not associated with a clinically significant effect on PK profiles of either drug. No DLTs were observed. The overall safety profile of rucaparib 600 mg BID + enzalutamide 160 mg QD was consistent with that observed in monotherapy. These PK, safety, and early efficacy data support further studies of rucaparib and enzalutamide at the recommended combination dose, including in the phase 3 CASPAR study in pts with mCRPC (NCT04455750). Clinical trial information: NCT04179396.

465 Background: UTUC is a rare genitourinary malignancy and a number of studies, limited by small sample sizes, have attempted to characterize its mutational landscape. Because immunotherapy is commonly used for this disease type, we evaluated the prevalence of microsatellite instability and characterized the mutational landscapes of UTUC in a large contemporary patient cohort. Methods: UTUC tumor samples were analyzed using next generation sequencing (NGS) (NextSeq, 592 gene panel) or whole exome sequencing (WES) (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Mismatch repair status (deficient [dMMR] or proficient [pMMR]) and microsatellite instability status (MSI-high or stable [MSS]) were detected by immunohistochemistry (IHC), fragment analysis, and NGS. Tumor mutational burden (TMB) was measured by counting all somatic mutations found per tumor (high cutoff ≥ 10 mutations per MB). PD-L1 expression was tested by IHC using PD-L1 antibody clones 22c3 (Agilent; positive cutoff CPS ≥ 10) and SP142 (Ventana; positive cutoff ≥ 5% IC). Pathogenic fusion events were detected using whole transcriptome sequencing (NovaSeq). Statistical significance was determined using the Chi-square test and adjusted for multiple comparison. Results: 538 patients with included – median (range) age 71.5 (30-89) years and 37.5% female/62.5% male. Prevalence of dMMR/MSI-H was 3.9% (21/538) and TMB-high was 22.7% (96/423). Significant molecular differences were not detected in primary vs metastatic disease or in male vs female cases. dMMR/MSI-H tumors had higher frequency of TMB-high compared to MSS tumors (100% vs. 19%, p = 0.00003). dMMR/MSI-H tumors also had a higher frequency than MSS tumors for mutations in genes involved in chromatin remodeling (ASXL 82.4%, CREBBP 60%, SMARCA4 40%, KMT2D 95%, ARIDIA 100%, KMT2A 20%, KMT2C 35.3%, NSD1 20%), DNA-damage repair (FANCG 10%, ATM 45%, ATRX 40%) and other biological pathways (RNF43 10%, PTCH1 21.4%, ERBB3 30%, CDKN2A 25%, TSC2 15%, FLNC 15%, HNF1A 20%, CIC 15%, DNMT3A 17.6%); all adjusted p < 0.05. Pathogenic fusions were detected in 3.8% (17/443) cases, with FGFR3 fusion being the most common, occurring in 2.7% (12/443) cases. PD-L1 positivity was identified in 33.2% (133/400) cases tested by 22c3 antibody and 28.4% (89/313) cases tested by SP142 antibody. No difference was seen in PD-L1 positivity between MSI-H/dMMR vs. MSS tumors. Conclusions: In the largest analysis to date, we found a 3.9% prevalence of dMMR/MSI-high rate in UTUC. All dMMR/MSI-H tumors displayed TMB-high. PD-L1 positivity was comparable between dMMR/MSI-H and MSS tumors. dMMR/MSI-H tumors had a significantly higher rate of mutations in genes involved in chromatin remodeling and DDR biological pathways. These results could inform design of targeted therapy trials in UTUC.

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

The purpose of this work was to evaluate the effect of androgen receptor (AR) inhibition on prostate-specific membrane antigen (PSMA) uptake imaged using 68Ga-PSMA-11 PET in a mouse xenograft model and in a patient with castration-sensitive prostate cancer. Methods: We imaged 3 groups of 4 mice bearing LNCaP-AR xenografts before and 7 d after treatment with ARN-509, orchiectomy, or control vehicle. Additionally, we imaged one patient with castration-sensitive prostate cancer before and 4 wk after treatment with androgen deprivation therapy (ADT). Uptake on pre- and posttreatment imaging was measured and compared. Results: PSMA uptake increased 1.5- to 2.0-fold in the xenograft mouse model after treatment with both orchiectomy and ARN-509 but not with vehicle. Patient imaging demonstrated a 7-fold increase in PSMA uptake after the initiation of ADT. Thirteen of 22 lesions in the imaged patient were visualized on PSMA PET only after treatment with ADT. Conclusion: Inhibition of the AR can increase PSMA expression in prostate cancer metastases and increase the number of lesions visualized using PSMA PET. The effect seen in cell and animal models can be recapitulated in humans. A better understanding of the temporal changes in PSMA expression is needed to leverage this effect for both improved diagnosis and improved therapy.

Background Abiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs the survival of patients with metastatic castration-resistant prostate cancer (mCRPC). AA plus prednisone (P) (AA+P) is approved for the treatment of patients with mCRPC. Objective To investigate whether long-term use of low-dose P with or without AA leads to corticosteroid-associated adverse events (CA-AEs) in mCRPC patients. Design, setting, and participants The study included 2267 patients in COU-AA-301 and COU-AA-302. We used an inclusive Standardized MedDRA Queries–oriented approach to identify 112 preferred terms for known CA-AEs, and assessed the incidence of CA-AEs during 3-mo exposure intervals and across all P exposure levels. Intervention All 2267 patients received 5mg of P twice daily, and 1333/2267 received AA (1g) plus P. Results and limitations The CA-AE incidence after any P exposure was 25%, 26%, and 23% for any grade, and 5%, 5%, and 4% for grade ≥3 CA-AEs for all patients and the AA+P and P alone groups, respectively. The most common any-grade CA-AEs were hyperglycemia (7.4%, 7.8%, and 6.9% for all patients, AA+P, and P alone, respectively) and weight increase (4.3%, 3.9%, and 4.8%, respectively). When assessed by duration of exposure (3-mo intervals up to ≥30 mo), no discernable trend was observed for CA-AEs, including hyperglycemia and weight increase. The investigator-reported study discontinuation rate due to CA-AEs was 11/2267 (0.5%), and one patient had a CA-AE resulting in death. Conclusions Low-dose P given with or without AA is associated with low overall incidence of CA-AEs. The frequency of CA-AEs remained low with increased duration of exposure to P. Patient summary We assessed adverse events in patients with metastatic castration-resistant prostate cancer during long-term treatment with a low dose of a corticosteroid. We found that long-term treatment with this low-dose corticosteroid is safe and tolerable.