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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

PURPOSE For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk. METHODS Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases. RESULTS Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel. CONCLUSION In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population. [Media: see text]

PURPOSE Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) demonstrated survival benefit versus bevacizumab, carboplatin, and paclitaxel (BCP) in chemotherapy-naïve nonsquamous non–small-cell lung cancer (NSCLC). We present safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in nonsquamous NSCLC. METHODS Patients were randomly assigned to receive atezolizumab, carboplatin, and paclitaxel (ACP), ABCP, or BCP. Coprimary end points were overall survival and investigator-assessed progression-free survival. The incidence, nature, and severity of adverse events (AEs) were assessed. PROs, a secondary end point, were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core 30 and EORTC QLQ-Lung Cancer 13. RESULTS Overall, 400 (ACP), 393 (ABCP), and 394 (BCP) patients were safety evaluable (ie, intention-to-treat population that received one or more doses of any study treatment). More patients had grade 3/4 treatment-related AEs during the induction versus maintenance phase (ACP, 40.5% v 8.2%; ABCP, 48.6% v 21.2%; BCP, 44.7% v 11.1%). During induction, the incidence of serious AEs (SAEs) was 28.3%, 28.5%, and 26.4% in the ACP, ABCP, and BCP arms, respectively. During maintenance, SAE incidences were 20.0%, 26.3%, and 13.0%, respectively. Completion rates of the PRO questionnaires were > 88% at baseline and remained ≥ 70% throughout most study visits. Across arms, patients on average reported no clinically meaningful worsening of global health status or physical functioning scores through cycle 13. Patients across arms rated common symptoms with chemotherapy and immunotherapy similarly. CONCLUSION ABCP seems tolerable and manageable versus ACP and BCP in first-line nonsquamous NSCLC. Treatment tolerability differed between induction and maintenance phases across treatment arms. PROs reflect a minimal treatment burden (eg, health-related quality of life, symptoms) with each regimen.

713 Background: The FOLH1 gene encodes prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein that is highly expressed in prostate cancer cells and on endothelial cells in the neovasculature of solid tumors, including RCC. PSMA has been used as a target for diagnostic imaging and therapeutic radioligand therapy. We utilized a database of molecularly profiled RCC tumors to evaluate associations with FOLH1 expression. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed for RCC patient specimens (n=1765) through Caris Life Sciences (Phoenix, AZ). FOLH1-High/Low expression were defined as ≥75th/

15 Background: In ARASENS (NCT02799602), DARO plus ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI: 0.57–0.80; P

TPS297 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor. In the phase 3 ARAMIS study (NCT02200614) in nonmetastatic castration-resistant prostate cancer (CRPC), DARO + ADT significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT, with a favorable tolerability and safety profile. In the phase 3 ARASENS study (NCT02799602) in metastatic hormone-sensitive prostate cancer (mHSPC), DARO + ADT + docetaxel significantly reduced the risk of death by 32.5% vs ADT + docetaxel (hazard ratio 0.68; 95% confidence interval 0.57–0.80; P

TPS398 Background: Randomized data from the interferon era demonstrated survival benefits of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN in most IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in mRCC now includes multiple first-line combination immunotherapy approvals. Five-year follow-up from the Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and durable objective responses with ipilimumab and nivolumab (I/N) compared to sunitinib. However, patients with a primary kidney lesion in situ appeared to have less benefit than patients with prior nephrectomy. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an enhanced systemic anti-tumor immune response. We hypothesize that SBRT to the primary kidney mass will enhance the efficacy of I/N compared to standard of care I/N alone in this unique subset of de novo mRCC patients. We also hypothesize that the combination of SBRT and I/N will lead to upregulation of key components of immune modulation as well as unique perturbation of the host gut microbiome compared to I/N alone. Methods: This phase II trial randomizes untreated mRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven mRCC (any histology) and IMDC intermediate/poor risk disease. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include: (1) immune and genomic profiling of liquid biopsies; (2) transcriptional profiling of baseline tumor biopsies; and (3) interrogation of the gut microbiome and bacterial functionality. Blood and fecal samples will be prospectively collected at baseline, prior to cycle 2 of each arm, and at time of disease progression or the 12-month mark, whichever comes first. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α = 0.1, power = 80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Trial is enrolling in Canada and Australia. Clinical trial information: NCT04090710.

147 Background: Darolutamide (DARO) significantly improved metastasis-free survival by ~2 y and reduced the risk of death by 31% vs placebo, with a favorable safety profile in patients (pts) with nmCRPC (ARAMIS study; NCT02200614). We report long-term safety and tolerability with continued DARO treatment in the ARAMIS Rollover Study (ROS; NCT04464226). Methods: Following the primary analysis of double-blind (DB) treatment, the ARAMIS study was unblinded, and all pts were permitted to continue on open-label (OL) DARO. After study completion, pts could continue DARO in the ROS if they had no evidence of metastases and were benefitting clinically. Of 955 pts initially randomized to DARO, 954 pts started DB DARO, 466 continued to OL DARO, and 294 entered the ROS. Pts received DARO 600 mg orally twice daily. DARO safety and treatment duration are described for the 954 pts over the DB, DB+OL, and DB+OL+ROS periods, with a data cutoff of Jan 31, 2022. Results: The median (range) treatment duration was 1.5 y (0.0–4.0) for DB DARO, 2.1 y (0.0–4.9) for DB+OL DARO, and 2.8 y (0.0–6.8) for DB+OL+ROS DARO. By the data cutoff date, 62.4% of the 954 pts had received DARO for ≥2 years, 30.1% for ≥4 years, and 12.8% for ≥5 yrs; 24.0% were still receiving DARO at data cutoff. Incidences of treatment-emergent adverse events (TEAEs) increased slightly as expected with longer observation time: any grade (DB 85.7%; DB+OL 89.8%; DB+OL+ROS 91.5%), grade 3/4 (26.3%; 31.8%; 35.5%), serious (26.1%; 32.1%; 38.5%), and leading to treatment discontinuation (8.9%; 10.5%; 12.9%). Increases in incidences of TEAEs of special interest across the DB, DB+OL, and DB+OL+ROS periods were mostly minimal. Conclusions: Approximately 30% of pts with nmCRPC remained on DARO for ≥4 y, suggesting long-term clinical benefit. The favorable safety profile of DARO was maintained with long-term exposure. No new safety concerns were observed with longer DARO treatment in the ROS. Clinical trial information: NCT04464226 . [Table: see text]

e18608 Background: Incremental delays in cancer time to treatment initiation (TTI) have been shown to cause a proportional, independent increased risk of disease specific mortality for breast cancer, colorectal cancer (CRC), head and neck (HNC), non-small cell lung cancer (NSCLC) and pancreatic cancer. A portion of delays can be attributed to increasingly complex workup with modern imaging, genomic, and multidisciplinary/multimodality treatment paradigms. However, studies suggest delays are associated with racial and socioeconomic disparities, implicating a target for addressing inequitable care. Given Montefiore Medical Center (MMC) serves a racially diverse, socioeconomically challenged population, we sought to evaluate the association between patient factors and TTI to identify factors associated with TTI delay. Methods: Retrospective cohort study at an urban community-based academic center of patients diagnosed with or referred for curative intent treatment of breast cancer, CRC, HNC, NSCLC, and pancreatic cancer at MMC from January 2019 to December 2021. Variables of interest included tumor staging, primary treatment modality, marital status, Charlson Comorbidity Index (CCI) score, tobacco use, zip code, insurance type, language preference, primary care provider status, and inpatient (IP) admission or emergency room visit 30 days prior to diagnosis. Results: A total of 3430 patients (F=2376, M=1054) were identified (mean age 64.2 ± 13.3). Demographics are summarized in Table. The Median TTI was 21 days (7, 41 IQR). In assessing factors associated with TTI delay, patients who were IP 30 days before diagnosis were significantly more likely to have timely TTI for breast cancer (p

5044 Background: Darolutamide (DARO), a highly potent and structurally distinct androgen receptor inhibitor, prolonged metastasis-free survival by nearly 2 years and reduced the risk of death by 31% vs placebo (PBO) with a favorable tolerability profile in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in ARAMIS. We present post-hoc analyses of ARAMIS to evaluate the association between metastatic progression with prostate-specific antigen (PSA) and clinical progression and to describe the distribution of metastatic progression between groups. Methods: Pts with nmCRPC were randomized 2:1 to DARO (n=955) or PBO (n=554) while continuing androgen-deprivation therapy. Descriptive analyses were performed using the primary data cutoff (Sept 3, 2018) for the double-blind period. Post-baseline metastases were based on central review of conventional radiographic imaging every 16 weeks. PSA and pain progression were defined per primary analysis ( N Engl J Med. 2019;380:1235-46). Results: Metastatic progression was observed in 13.6% of DARO and 28.5% of PBO pts. Most pts had isolated progression as bone (DARO 46%, PBO 39%) or lymph node (32%; 40%) metastasis (Table). Pts with radiographic progression had shorter median time from initial diagnosis to study treatment (DARO 72.9, PBO 74.4 months) vs the overall ARAMIS population (86.2, 84.2 months). Of all pts with metastatic progression, baseline PSA levels (ng/mL) were similar in DARO (12.6) and PBO pts (15.1); DARO pts had lower median PSA before metastasis (16.7) vs PBO pts (48.0) and median absolute/relative PSA decrease from baseline of -0.7/-3.2% vs an increase for PBO pts of 29.5/181%. PSA progression before metastasis was observed in 55.6% (160/288) of pts, occurring in fewer DARO (45.4%) vs PBO pts (63.9%) (treatment difference 18.5%; nominal 95% CI 6.5%–30.6%). The median time between PSA progression and metastasis was 7.0 months with DARO vs 5.6 months with PBO. Pain progression before metastatic progression was rare and similar between groups (DARO 16.9%, PBO 17.7%). Conclusions: DARO significantly reduced risk of metastatic progression and improved overall survival vs PBO without changing the pattern of metastatic progression. Many pts with nmCRPC experienced metastatic progression without PSA progression, and pain progression was rare. These results support the use of imaging with PSA monitoring to properly identify disease progression in pts with nmCRPC. Clinical trial information: TBC. [Table: see text]

e17051 Background: Patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) are responsive to androgen deprivation therapy (ADT), but within 1–3 years most will develop metastatic castration-resistant prostate cancer (mCRPC). The CHAARTED trial showed a clear benefit of adding docetaxel (DTX) to ADT, prolonging median overall survival (OS) by 10.4 months (mo). ARASEC is a single-arm US study evaluating darolutamide + ADT in pts with mHSPC. Participants will be matched for comparison using patient-level data to the ADT alone arm of CHAARTED. The TIMES study evaluated a potential time bias in treatment patterns and clinical outcomes in pts with mHSPC before and after the OS analysis of CHAARTED was reported. Methods: This retrospective study used Flatiron Metastatic PC Core Registry data from January 1, 2013, to June 30, 2020, and the sample was divided into two cohorts: before and after June 30, 2016 (cohort 1: pre-CHAARTED; cohort 2: post-CHAARTED). Differences in OS and time to mCRPC were assessed using Cox proportional hazard models, controlling for baseline characteristics, including age, initial mHSPC treatment, Gleason score, and time from PC diagnosis to mHSPC. The test for equivalence used hazard ratio (HR) limits of 0.80 to 1.25 at a 2-sided 0.05 level. Results: Data from 9256 pts with mHSPC (4503 in cohort 1; 4753 in cohort 2) were analyzed; median age was 73 years for both cohorts. M1 status at initial diagnosis was 55% in cohort 1 and 60% in cohort 2. All other clinical characteristics and laboratory values were similar. Initial mHSPC treatment with DTX was 10.5% and 13.9%, whereas treatment with novel anti-hormonal agents (NAH) was 1.6% and 18.3% in cohorts 1 and 2, respectively. The percentage of pts who started with first-generation androgen receptor inhibitors decreased from 29.3% in cohort 1 to 19.6% in cohort 2, whereas the percentage of pts receiving ADT alone and/or supportive care remained stable (25.7% and 26.5%, respectively). In cohorts 1 and 2, treatment records during the mHSPC period could not be retrieved for 32.9% and 21.7% of pts, respectively. Median OS was 5.4 months longer for cohort 1 (43.7 mo) vs cohort 2 (38.3 mo). In multivariate analyses, cohort 2 had poorer survival, with an HR slightly outside the predefined limits for equivalence (HR 1.19; 95% CI 1.09, 1.29; P < 0.0001). The HR for time to mCRPC fell within the predefined limits (HR 1.16; 95% CI 1.09, 1.23). Conclusions: Changes in treatment patterns were observed following CHAARTED. Although DTX and NAH have demonstrated prolonged survival, their use increased only from 12% to 32%, comparing the cohorts before and after 2016, which is not in line with guideline recommendations. Clinical outcomes, despite the influence of multiple factors, have changed minimally during the past 5 years, suggesting that the risk of historical time bias associated with using the CHAARTED ADT alone arm as a comparator for ARASEC is low.

2505 Background: Immunoglobulin-like transcript 3 (ILT3) is an inhibitory receptor associated with immune tolerance and T-cell suppression within the tumor microenvironment. MK-0482, a novel humanized IgG4 mAb targeting ILT3, is undergoing phase 1 evaluation ± pembrolizumab (pembro) in advanced solid tumors (NCT03918278; MK-0482-001). Dose escalation data are presented. Methods: Eligible patients with advanced solid tumors were enrolled into sequentially escalating dose cohorts of MK-0482 monotherapy (0.2-2250 mg) or MK-0482 (7.5-2250 mg) + pembro 200 mg; both were administered IV Q3W for up to 35 cycles or until progressive disease (PD), unacceptable toxicity, death, or withdrawal. Patients receiving MK-0482 monotherapy could cross over to MK-0482 + pembro after PD. Primary objectives were safety, tolerability, and determination of the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included assessing pharmacokinetics (PK), blood receptor occupancy (RO), anti–drug antibodies (ADA), and objective response rate (ORR) per RECIST v1.1 by investigator assessment. Results: Seventy-five patients were enrolled (n = 29, MK-0482 monotherapy; n = 46, MK-0482 + pembro); 8 patients crossed over to receive the combination. Median age was 63 years (range, 34-86); 73% had ECOG PS 1, 72% received ≥2 lines of prior anticancer therapy, and 32% received prior PD-1/PD-L1 inhibitors. Treatment-related AEs (TRAEs; any-grade/grade 3 or 4) were reported in 34%/7% of patients with MK-0482 monotherapy, 67%/4% with MK-0482 + pembro, and 50%/13% in those who crossed over. The most common TRAEs (≥10% of all patients) were pyrexia (10%) with MK-0482 monotherapy; fatigue (24%) and arthralgia, diarrhea, hyperthyroidism, hypothyroidism, and pruritus (11% each) with MK-0482 + pembro; and arthralgia (25%), hyperthyroidism and hypothyroidism (13% each) for patients who crossed over. Dose-limiting toxicities occurred in 2 patients who received MK-0482 + pembro: 1 grade 5 myositis (MK-0482 750 mg; the only TRAE leading to death) and 1 grade 2 myositis (MK-0482 2250 mg). Preliminary PK and blood RO data suggested that target-mediated drug disposition of MK-0482 was likely saturated in blood mononuclear cells at doses ≥75 mg. ADA to MK-0482 was observed in ̃20% of patients, but no clear impact on MK-0482 PK was observed. A confirmed ORR of 15% (8 PR) was observed in patients who received MK-0482 + pembro, including patients who crossed over; no confirmed responses were observed in patients who received MK-0482 monotherapy. MK-0482 750 mg + pembro was selected as the RP2D based on the totality of data. Conclusions: MK-0482 ± pembro was generally well tolerated, and combination therapy provided modest antitumor activity in patients with heavily pretreated advanced solid tumors. The RP2D of MK-0482 + pembro is under further evaluation in tumor-specific cohorts. Clinical trial information: NCT03918278.

1052 Background: Dysregulating mutations in PIK3CA, encoding the PI3K p110α subunit, occur in ̃40% of HR+/HER2– BCs. Inavolisib is a PI3Kα-specific inhibitor that also promotes degradation of mutant p110α. It has demonstrated encouraging preliminary antitumor activity in pts with PIK3CA-mutated HR+ BC as a monotherapy, and in combo with other anticancer agents. Methods: We included pts from NCT03006172 on treatment ≥1 year with inavolisib alone (Arm A), or in combo with palbo + letrozole (letro) (B), letro (C), fulvestrant (fulv) (D), or palbo + fulv (E; + metformin in Arm F for pts with body mass index ≥30 and/or HbA1c ≥5.7%). Inavolisib was administered orally daily (PO QD) at 3, 6, 9, or 12 mg (3+3 dose-escalation design); letro at 2.5 mg PO QD; palbo at 125 mg PO QD for 21/28 days; and fulv at 500 mg intramuscularly every 4 weeks, in 28-day cycles until intolerable toxicity/disease progression. Safety was assessed by NCI-CTCAE v4. Results: 57 female pts were included (cutoff 07/26/21; N = 1, 18, 6, 12, 15, 5 in Arms A–F); median age: 57 years (range 33–80); median lines of prior therapy: 2 (1–7). All but 2 pts, both in Arm B (3 mg), were assigned the 9 mg inavolisib recommended phase 3 dose. Overall median treatment duration: 19 months (range 12–45); median inavolisib cumulative dose intensity, 95%. The most frequent treatment-related adverse events (AEs; in ≥20 pts/35%) were hyperglycemia (68%), stomatitis (68%; grouped terms), neutropenia (58%), diarrhea (51%), nausea (39%), alopecia (35%), and rash (35%; grouped terms). The most frequent treatment-related Grade (G) 3–4 AEs (≥2 pts/4%) were neutropenia (47%), hyperglycemia (16%), leukopenia (9%), thrombocytopenia (9%), lymphopenia (7%), weight decreased, and hypokalemia (4% each). G3–4 neutropenia, leukopenia, thrombocytopenia, and lymphopenia were all reported in palbo arms. One G5 AE of pleural effusion was reported (disease progression-related). 39 pts (68%) had ≥1 AE resulting in study treatment modification (drug interruption/dose reduction/treatment withdrawal); 11 (19%) had an inavolisib dose reduction and 2 (4%) discontinued treatment due to an AE (1 related G2 diarrhea, 1 unrelated G3 cerebrovascular disorder). AEs typically occurred during the first 6 months and tended to be less frequent in later cycles. No new safety signals were observed with long-term inavolisib use. Conclusions: These data indicate acceptable long-term tolerability. The safety profile of pts on study treatment with inavolisib alone or in combo with endocrine-based anticancer therapies for ≥1 year was similar to that reported for the overall study population. Updated data will be presented. A phase 3 study of inavolisib + palbo + fulv is enrolling (NCT04191499; INAVO120). Clinical trial information: NCT03006172.