Prior Definitive Therapy Research Articles

LIBRETTO-432: A phase 3 study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive (RET+) NSCLC.

TPS216 Background: Around 30% of NSCLC patients (pts) present with stage IB-IIIA disease. Standard treatment options are definitive locoregional therapies w/wo chemotherapy (CT) and/or immunotherapy, followed by surveillance until disease recurrence. Targeted therapies are standard for metastatic NSCLC with driver alterations and recent Phase III trial data has emerged in support of their use in the adjuvant setting for stage IB-IIIA (ADAURA and ALINA). RET is a key oncogenic driver in NSCLC and a promising target for adjuvant targeted therapy. Selpercatinib, a highly selective, potent and CNS active RET inhibitor, recently demonstrated longer PFS than platinum-based CT as 1L treatment in pts with RET+ advanced NSCLC (Zhou et al. NEJM 2023). LIBRETTO-432 is a Phase 3, global, multicenter, randomized, double-blind, controlled trial evaluating efficacy and safety of adjuvant selpercatinib v Placebo in pts with RET+ Stage IB-IIIA NSCLC following completion of definitive therapies with curative intent, and other adjuvant therapy if indicated (NCT04819100). Methods: Pts (n≈170) will be randomized (1:1) to selpercatinib BID [160mg ≥50kg; 120mg <50kg], or Placebo, in continuous 28-day cycles for a maximum treatment duration of 3y. Stratification factors include disease stage (IB/II/IIIA) and prior definitive therapy. Treatment will continue until disease recurrence/progression, unacceptable toxicity, or another protocol-defined reason. Crossover is allowed for Placebo pts who experience disease recurrence/progression. Key eligibility criteria include age ≥18 y; histologically confirmed Stage IB/II/IIIA NSCLC; RET+ tumor by PCR/NGS; prior definitive locoregional therapy with curative intent (surgery, radiotherapy) for Stage IB/II/IIIA NSCLC; and ECOG performance status 0-1. Maximum time allowed from definitive therapy completion to randomization is 26 w. Key exclusion criteria are evidence of other known oncogenic drivers; SCLC; and disease recurrence/progression following definitive therapy. Primary endpoint is investigator-assessed event-free survival (IAEFS) in the primary analysis population (pts with Stage II-IIIA). EFS is defined as time from randomization until locoregional disease recurrence with histopathological confirmation, distant disease recurrence per RECIST v1.1 or histopathological confirmation, or death. Gated secondary endpoints include IAEFS in the overall population (pts with Stage IB-IIIA) and OS in both primary analysis and overall populations. Non-gated secondary efficacy endpoints include BICR-assessed EFS, BICR and investigator-assessed time to distant disease recurrence in the CNS, and PFS on next line of treatment. Recruitment is ongoing, with enrollment across ~170 sites and 30 countries. Results from this trial will further inform the value of RET inhibition and genomic testing for adjuvant NSCLC pts. Clinical trial information: NCT04819100 .

Utility of 64Cu-Sarcophagine-Bombesin PET/CT in Men with Biochemically Recurrent Prostate Cancer and Negative or Equivocal Findings on 68Ga-PSMA-11 PET/CT.

Despite a high detection rate of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT in biochemical recurrence (BCR) of prostate cancer, a significant proportion of men have negative 68Ga-PSMA-11 PET/CT results. Gastrin-releasing peptide receptor, targeted by the copper-chelated bombesin analog 64Cu-sarcophagine-bombesin (SAR-BBN) PET/CT, is also overexpressed in prostate cancer. In this prospective imaging study, we investigate the detection rate of 64Cu-SAR-BBN PET/CT in patients with BCR and negative or equivocal 68Ga-PSMA-11 PET/CT results. Methods: Men with confirmed adenocarcinoma of the prostate, prior definitive therapy, and BCR (defined as a prostate-specific antigen [PSA] level > 0.2 ng/mL) with negative or equivocal 68Ga-PSMA-11 PET/CT results within 3 mo were eligible for enrollment. 64Cu-SAR-BBN PET/CT scans were acquired at 1 and 3 h after administration of 200 MBq of 64Cu-SAR-BBN, with further delayed imaging undertaken optionally at 24 h. PSA (ng/mL) was determined at baseline. All PET (PSMA and bombesin) scans were assessed visually. Images were read with masking of the clinical results by 2 experienced nuclear medicine specialists, with a third reader in cases of discordance. Accuracy was defined using a standard of truth that included biopsy confirmation, confirmatory imaging, or response to targeted treatment. Results: Twenty-five patients were enrolled. Prior definitive therapy was radical prostatectomy (n = 24, 96%) or radiotherapy (n = 1, 4%). The median time since definitive therapy was 7 y (interquartile range [IQR], 4-11 y), and the Gleason score was 7 or less (n = 15, 60%), 8 (n = 3, 12%), or 9 (n = 7, 28%). The median PSA was 0.69 ng/mL (IQR, 0.28-2.45 ng/mL). Baseline PSMA PET scans were negative in 19 patients (76%) and equivocal in 6 (24%). 64Cu-SAR-BBN PET-avid disease was identified in 44% (11/25): 12% (3/25) with local recurrence, 20% (5/25) with pelvic node metastases, and 12% (3/25) with distant metastases. The κ-score between readers was 0.49 (95% CI, 0.16-0.82). Patients were followed up for a median of 10 mo (IQR, 9-12 mo). Bombesin PET/CT results were true-positive in 5 of 25 patients (20%), false-positive in 2 of 25 (8%), false-negative in 7 of 25 (28%), and unverified in 11 of 25 (44%). Conclusion: 64Cu-SAR-BBN PET/CT demonstrated sites of disease recurrence in 44% of BCR cases with negative or equivocal 68Ga-PSMA-11 PET/CT results. Further evaluation to confirm diagnostic benefit is warranted.

LIBRETTO-432: A phase 3 study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive (RET+) NSCLC.

TPS8115 Background: Around 30% of NSCLC patients (pts) present with stage IB-IIIA disease. Standard treatment options are definitive locoregional therapies w/wo chemotherapy (CT) and/or immunotherapy, followed by surveillance until disease recurrence. Targeted therapies are standard for metastatic NSCLC with driver alterations and recent Phase III trial data has emerged in support of their use in the adjuvant setting for stage IB-IIIA (ADAURA and ALINA). RET is a key oncogenic driver in NSCLC and a promising target for adjuvant targeted therapy. Selpercatinib, a highly selective, potent and CNS active RET inhibitor, recently demonstrated longer PFS than platinum-based CT as 1L treatment in pts with RET+ advanced NSCLC (Zhou et al. NEJM 2023). LIBRETTO-432 is a Phase 3, global, multicenter, randomized, double-blind, controlled trial evaluating efficacy and safety of adjuvant selpercatinib v Placebo in pts with RET+ Stage IB-IIIA NSCLC following completion of definitive therapies with curative intent, and other adjuvant therapy if indicated (NCT04819100). Methods: Pts (n≈170) will be randomized (1:1) to selpercatinib BID [160mg ≥50kg; 120mg < 50kg], or Placebo, in continuous 28-day cycles for a maximum treatment duration of 3y. Stratification factors include disease stage (IB/II/IIIA) and prior definitive therapy. Treatment will continue until disease recurrence/progression, unacceptable toxicity, or another protocol-defined reason. Crossover is allowed for Placebo pts who experience disease recurrence/progression. Key eligibility criteria include age ≥18 y; histologically confirmed Stage IB/II/IIIA NSCLC; RET+ tumor by PCR/NGS; prior definitive locoregional therapy with curative intent (surgery, radiotherapy) for Stage IB/II/IIIA NSCLC; and ECOG performance status 0-1. Maximum time allowed from definitive therapy completion to randomization is 26 w. Key exclusion criteria are evidence of other known oncogenic drivers; SCLC; and disease recurrence/progression following definitive therapy. Primary endpoint is investigator-assessed event-free survival (IAEFS) in the primary analysis population (pts with Stage II-IIIA). EFS is defined as time from randomization until locoregional disease recurrence with histopathological confirmation, distant disease recurrence per RECIST v1.1 or histopathological confirmation, or death. Gated secondary endpoints include IAEFS in the overall population (pts with Stage IB-IIIA) and OS in both primary analysis and overall populations. Non-gated secondary efficacy endpoints include BICR-assessed EFS, BICR and investigator-assessed time to distant disease recurrence in the CNS, and PFS on next line of treatment. Recruitment is ongoing, with enrollment across ~170 sites and 30 countries. Results from this trial will further inform the value of RET inhibition and genomic testing for adjuvant NSCLC pts. Clinical trial information: NCT04819100 .

Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): Minimum 3-year survival follow-up.

4032 Background: RATIONALE-306 (NCT03783442) is the first global study to investigate anti-programmed cell death protein 1 therapy in combination with different chemotherapy (chemo) options in the first-line (1L) treatment of advanced/metastatic esophageal squamous cell carcinoma (ESCC). At interim analysis (IA), tislelizumab (TIS) plus chemo demonstrated a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo (PBO) plus chemo, with a manageable safety profile. Here, we report updated efficacy and safety data with minimum 3 years’ follow-up after study unblinding at IA. Methods: Adults with unresectable locally advanced recurrent/metastatic ESCC and no prior systemic treatment for advanced disease were enrolled and randomized (1:1; stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg (Arm A) or PBO (Arm B) IV every 3 weeks plus chemo (platinum plus fluoropyrimidine or platinum plus paclitaxel), until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), all per INV, and safety. Results: In total, 649 patients (pts) were randomized (Arm A, n=326; Arm B, n=323). At a minimum study follow-up of 36.0 months, improvements in OS, PFS, and DoR in Arm A versus B (Table) were maintained relative to the IA. The hazard ratio (HR) for OS with TIS plus chemo versus PBO plus chemo was 0.70 (95% confidence interval: 0.59, 0.83). Similar to the IA, incidences of any-grade (96.6% vs 96.3%) or grade ≥3 (67.0% vs 64.5%) treatment-related adverse events (TRAEs) were comparable between Arms A and B, respectively; treatment-emergent adverse events leading to treatment discontinuation were higher in Arm A (32.1%) versus B (22.1%). In Arm A versus B, respectively, serious TRAEs occurred in 29.9% vs 19.6% of pts; TRAEs leading to death occurred in 1.9% and 1.2%. Conclusions: After minimum 3 years’ follow-up, 1L TIS plus chemo continued to demonstrate clinically meaningful improvements in OS and PFS and durable antitumor response benefit versus PBO plus chemo in pts with advanced/metastatic ESCC, with no new safety signals. Clinical trial information: NCT03783442 . [Table: see text]

Abstract CT076: Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis

Abstract Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, + chemotherapy (chemo) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo + chemo, with a manageable safety profile, as a first line (1L) treatment for patients (pts) with advanced or metastatic esophageal squamous cell carcinoma (ESCC) at interim analysis of the phase 3 RATIONALE-306 study. We report data from the China subgroup analysis. Methods: In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Pts were randomized (1:1); stratified by region, prior definitive therapy, and investigator-chosen chemo (platinum + fluoropyrimidine or platinum + paclitaxel). Pts received tislelizumab (T) 200 mg intravenously + chemo (C) (Arm T+C) or placebo (P) + chemo (Arm P+C) once every three weeks; treatment continued until disease progression by investigator per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included investigator-assessed progression-free survival (PFS) per RECIST v1.1, objective response rate (ORR), and duration of response (DoR), in addition to safety. Results: Of 649 pts in the overall population, 370 (57.0%) were enrolled from China. At data cutoff (Feb 28, 2022), the median study follow-up in the China subgroup (ITT population) was 15.8 months (mo) in Arm T+C (n=182) and 10.6 mo in Arm P+C (n=188). Longer OS (median OS 16.6 mo vs 11.2 mo; unstratified hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.54, 0.89) and PFS (median PFS 8.3 mo vs 5.6 mo; unstratified HR 0.58, 95% CI 0.45, 0.75) indicate survival benefit in Arm T+C vs P+C, respectively. Arm T+C had higher response rates and more durable responses than Arm P+C; ORR was 64.8% vs 44.1% (odds ratio 2.33 [95% CI 1.53, 3.55]) respectively, and median DoR was 7.4 mo (95% CI 5.6, 9.5) vs 5.7 mo (95% CI 4.3, 7.5), respectively. Similar proportions of pts in Arm T+C vs P+C had ≥1 treatment-related adverse event (TRAE; 98.8% vs 98.9%) and ≥grade 3 TRAEs (72.9% vs 73.4%). Serious TRAEs occurred in 27.6% vs 21.2% of pts in Arm T+C vs P+C, and TRAEs leading to death occurred in 2.9% vs 1.6% of pts, respectively. Treatment-emergent adverse events leading to discontinuation occurred in 28.2% vs 17.4%, in Arm T+C vs P+C. Conclusions: In the China subgroup, 1L tislelizumab + chemo demonstrated clinically meaningful improvement in OS, PFS, ORR, and DoR vs placebo + chemo in pts with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Emma Ashman, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Citation Format: Yongqian Shu, Yueyin Pan, Ping Lu, Yi Jiang, Jingdong Zhang, Xiaohong Wu, Yuanhu Yao, Lin Shen, Yi Ba, Zhiyong He, Yuxian Bai, Jianhua Chen, Guohua Yu, Yanyan Peng, Hongqian Wu, Lei Wang, Liyun Li, Jianming Xu. Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT076.

Randomized, global, phase 3 study of tislelizumab (TIS) + chemotherapy (chemo) versus placebo (PBO) + chemo as first-line (1L) treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC) (RATIONALE-306): Non-Asia subgroup.

340 Background: TIS, an anti-programmed cell death protein 1 (PD-1) antibody, + chemo as 1L therapy demonstrated statistically significant and clinically meaningful improvement in overall survival (OS) vs PBO + chemo in patients with advanced or metastatic ESCC (hazard ratio [HR] 0.66 [95% confidence interval (CI) 0.54, 0.80]; P< 0.0001), with a manageable safety profile, at interim analysis of the phase 3, double-blind RATIONALE-306 study (NCT03783442). Here, we report data from the non-Asia subgroup (Europe, Northern America, and Oceania). Methods: Adults with advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were randomized 1:1, (stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg intravenously (IV) once every 3 weeks (Q3W) (Arm A) or PBO IV Q3W (Arm B), with platinum + fluoropyrimidine, or platinum + paclitaxel until disease progression by INV per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included: progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) by INV per RECIST v1.1; OS in the programmed death-ligand 1 score ≥10%; and safety. Results: Of 649 randomized patients, 163 (25.1%) were from the non-Asia subgroup (Arm A, n = 83; Arm B, n = 80). At data cutoff (Feb 28, 2022), the median study follow-up time in the non-Asia subgroup was 16.0 months (mo) in Arm A vs 8.4 mo in Arm B. OS (median 16.3 vs 9.0 mo; unstratified HR 0.66 [95% CI 0.45, 0.96]) and PFS (median 7.7 vs 5.5 mo; unstratified HR 0.59 [95% CI 0.41, 0.83]) were improved in Arm A vs Arm B, respectively. Arm A had higher ORR (61.4% vs 41.3%, odds ratio 2.27 [95% CI 1.21, 4.25]) and longer median DoR (7.1 mo [95% CI 5.6, 9.6] vs 5.7 mo [95% CI 3.8, 8.3]) than Arm B. More patients in Arm A vs Arm B experienced ≥1 treatment-related adverse event (TRAE; 94.0% vs 88.5%), serious TRAEs (25.3% vs 17.9%), and discontinuation due to treatment-emergent AEs (42.2% vs 35.9%, respectively). Similar proportions of patients in Arm A vs Arm B had ≥grade 3 TRAEs (56.6% vs 52.6%), and TRAEs leading to death (1.2% vs 1.3%), respectively. Conclusions: In the non-Asia subgroup, 1L TIS + chemo showed a clinically meaningful improvement in OS vs PBO + chemo in patients with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Clinical trial information: NCT03783442 .

P01.01 LIBRETTO-432: A Placebo-Controlled Phase 3 Study of Adjuvant Selpercatinib in Stage IB-IIIA RET Fusion-Positive NSCLC

Approximately 30% of patients diagnosed with NSCLC present with early-stage (IB-IIIA) disease. Standard treatment options for these patients are definitive locoregional therapies with/without adjuvant chemotherapy, followed by surveillance until disease recurrence. While targeted therapies are standard treatment for metastatic NSCLC with driver mutations, their use in the early-stage setting is still being characterized. Selpercatinib, a highly selective, potent and CNS active RET inhibitor, demonstrated robust and sustained antitumor activity with manageable toxicity in patients with RET fusion-positive advanced NSCLC. There is a growing evidence demonstrating that oncogene addiction in NSCLC could be actionable regardless of disease stage. LIBRETTO-432 is a Phase 3, global, multicenter, randomized, double-blind, controlled trial evaluating the efficacy and safety of adjuvant selpercatinib versus placebo in patients with RET fusion-positive Stage IB-IIIA NSCLC following completion of definitive radiotherapy or surgery with a curative intent, and other adjuvant therapy if indicated (NCT04819100). Patients (n≈170) will be randomized (1:1) to Arm A (selpercatinib twice daily [160mg ≥50kg; 120mg <50kg]), or B (placebo), in continuous 28-day cycles for a maximum treatment duration of 3 years (Figure 1). Stratification factors include disease stage (Stage IB/II/IIIA) and prior definitive therapy (surgery, radiotherapy). Crossover is allowed for Arm B patients who experience disease recurrence. Treatment will continue until disease recurrence, unacceptable toxicity, withdrawal, or death. Key eligibility criteria include age ≥18 years; histologically confirmed Stage IB/II/IIIA NSCLC; mandatory brain MRI during screening to rule out metastasis; presence of activating RET fusion in tumor by PCR/NGS (local or central testing); received definitive locoregional therapy with curative intent (surgery, radiotherapy) for Stage IB/II/IIIA NSCLC; and ECOG performance status 0-1. Maximum time allowed between definitive therapy completion and randomization must be within 26 weeks. Key exclusion criteria are presence of other known oncogenic drivers; evidence of SCLC; and evidence of disease recurrence following definitive therapy. The primary endpoint is investigator-assessed event-free survival (EFS) in the primary analysis population. EFS is defined as time from randomization until locoregional disease recurrence with histopathological confirmation, distant disease recurrence per RECIST v1.1 or histopathological confirmation, or death. Gated secondary endpoints include investigator-assessed EFS in the overall population and overall survival in both the primary analysis and overall population. Non-gated secondary efficacy endpoints include blinded independent central review (BICR)-assessed EFS, time to distant disease recurrence in the CNS assessed by investigator and BICR, and progression-free survival on the next line of treatment. ▪▪▪ ▪▪▪

Adjuvant nivolumab following salvage resection in head and neck squamous cell carcinoma patients previously treated with definitive therapy: A single-arm phase II multi-institutional study.

6031 Background: Salvage surgery for locally recurrent head and neck squamous cell carcinoma (rHNSCC) results in local control rates of 33-50% but only 20-40% of patients achieve long-term survival necessitating additional therapy (Haque et al., Oral Oncol. 2019). Many patients are ineligible for re-irradiation and chemotherapy alone after salvage surgeryhas shown no survival benefit. The clinical activity and tolerability of immune checkpoint inhibitors has been demonstrated in metastatic HNSCC, but the benefit after salvage surgery (SS) has not been studied. Here we report the results of a multi-center phase II investigation of nivolumab, a PD-1 inhibitor, after SS in recurrent HNSCC (NCT03355560). Methods: HNSCC patients undergoing curative-intent SS were enrolled to receive 6 months of nivolumab beginning 4-11 weeks after surgery. All received radiation with or without chemotherapy as prior definitive therapy and had no other curative treatment options at the time of surgery. Key exclusion criteria included: distant metastatic disease, gross residual disease, or a history of immunodeficiency, autoimmunity, or pneumonitis. The primary endpoint was 2-year disease-free survival (DFS) measured by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Results: 39 patients were enrolled. Median age was 68 years (range, 49-85). 12/39 (31%) were female. 34/39 (87%) were white. Disease sites included oropharynx 9/39 (23%), oral cavity 14/39 (36%), and larynx 16/39 (41%). P16 status was 26% (+), 48% (-), and 26% (unknown). 17/39 (44%) had high risk pathologic features (positive margins or extranodal spread) at time of SS. 28/39 (72%) patients experienced treatment-related adverse events (TRAE), the most common of which were fatigue (26%), hypothyroidism (10%) and acneiform rash (13%). Grade 3-4 TRAEs were rare, occurring in 3/39 (8%) patients and included diarrhea, oral pain, neck pain, productive cough, stridor, and COPD exacerbation. 3/39 (8%) required treatment discontinuation and there were no grade 5 events. The 2-year DFS was 60% (95%CI 0.39-0.91). 2-year overall survival was 74% (95% CI 0.54-1). In single-cell multiplex cytokine analysis, patients who relapsed following adjuvant nivolumab had a significantly higher proportion of peripheral blood CD8 T cells which displayed a polyfunctional cytokine profile. IFN-γ and Granzyme were the dominant CD8 cytokines in both responders and non-responders, however CD8 expression of MIP1a and TNF-α were significantly higher in patients who ultimately relapsed. Conclusions: Nivolumab after salvage surgery in rHNSCC is well tolerated and shows promising antitumor activity in this high-risk patient population with unmet need. Immunotherapy after salvage surgery should be studied in randomized clinical trials. Clinical trial information: NCT03355560.

Single-arm phase II study of low-dose paclitaxel and pembrolizumab in platinum-refractory metastatic urothelial carcinoma (UC).

433 Background: Single agent checkpoint inhibition is effective in a small proportion of platinum-refractory UC patients but improvements are needed. UC is highly inflammatory, and low-dose chemotherapy may enhance the response to immunotherapy. We evaluated whether combination therapy with low-dose paclitaxel and pembrolizumab is more efficacious than single-agent pembrolizumab which had an objective response rate (ORR) of 21% in a similar patient population in the KEYNOTE-045 study. We also incorporated multiple novel biomarker studies to explore immune regulatory mechanisms in UC. Methods: This is a prospective, single-arm phase II trial (NCT02581982) of pembrolizumab combined with low-dose paclitaxel in patients with platinum-refractory metastatic UC. Key inclusion criteria included measurable progression of disease within 12 months of platinum therapy and ECOG ≤1. Patients received pembrolizumab 200mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21 day cycle for up to 8 cycles unless clinical or radiographic disease progression or unacceptable adverse events (AEs) were observed. Responding patients could remain on pembrolizumab maintenance for up to 2 years. The primary endpoint was ORR; key secondary endpoints included overall survival (OS), 6-month progression free survival (PFS), and safety. Results: Twenty-seven patients were treated between 4/2016 - 6/2020, with a median follow up of 9.9 months. At baseline, the median age was 68 years (range 49-80), with 81% men and 78% non-Hispanic white. The majority (59%) were ECOG 1. Twenty-one of 27 (78%) received prior definitive therapy: chemoradiation in 24% and surgery in 76%. The majority (78%) of patients received prior cisplatin. 70% progressed on a cisplatin-based regimen while 30% progressed on carboplatin-based regimen within 12 months of study entry. The ORR by intention to treat was 9 of 27 patients (33%) and in patients evaluable for response by imaging was 9 of 25 (36%), including 3 with complete response. Disease control rate in evaluable patients was 72%. Six-month PFS was 46.8% (95% CI: 27.2%, 64.2%) and median OS was 11.7 months (95% CI: 8.7 mo, NR). Common ≥ grade 2 AEs were anemia (44%), lymphopenia (37%), hyperglycemia (33%), and fatigue (33%). Possible treatment-related at least grade 3 or 4 AEs occurred in 56% of subjects, including 2 immune-mediated AEs (pneumonitis and nephritis) resulting in therapy cessation but a durable partial response. There were no grade 5 events. Conclusions: This study illustrates that the addition of low-dose paclitaxel to pembrolizumab improves outcomes in patients with platinum-refractory UC, relative to single-agent pembrolizumab. No unanticipated safety signals emerged. Exploratory analyses including PDL1 status, tumor mutational burden, and change in circulating microRNAs and in immune cell populations are ongoing. Clinical trial information: NCT02581982.

Outpatient Extraperitoneal Single-Port Robotic Radical Prostatectomy

ObjectiveTo assess the safety and feasibility of extraperitoneal single-port robotic assisted laparoscopic radical prostatectomy using the da Vinci SP robotic platform for same-day surgery. MethodsExtraperitoneal single-port robotic prostatectomy (ESRP) using the da Vinci SP platform was performed on 60 patients with clinically localized prostate cancer and no prior definitive therapy. An enhanced recovery protocol was used in the perioperative period and minimal to no opiates were used in these patients. Preoperative, perioperative, and postoperative data were collected in a prospectively maintained institutional review board approved database and evaluated in a retrospective fashion. ResultsMean operative time was 198 minutes and mean estimated blood loss was 179 mL. No patients required blood transfusion and there were no intraoperative complications. Pain at discharge was 0-1 in 37% of patients. Forty-five patients (75%) were discharged home the day of surgery, including patients with all surgical start times. When excluding patients that were planned for an overnight stay preoperatively or patients whose surgery finished after 6 PM, 88% of patients were discharged home the day of surgery and 96% were discharged within 24 hours of surgery. Median length of stay was 4.2 hours. Fourty-eight percent of patients required 0-1 pads at 30 days postoperatively in patients with 30 day follow data (n = 58) and 76% of patients reported requiring 0-1 pads per day by 90 days postoperatively (n = 37). ConclusionESRP using the da Vinci SP platform can be performed safely and reproducibly as a same-day outpatient surgery with minimal to no opiate use, excellent pain control, and acceptable short term functional and oncological outcomes.

Time from definitive therapy to onset of metastatic disease predicts outcomes in men with metastatic hormone sensitive prostate cancer

PurposeContemporary treatment for metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) plus abiraterone or docetaxel. While these intensified regimens have improved efficacy, they are also associated with increased cost and toxicities. Not all men with mHSPC may be candidates for these intensified regimens, yet there are no clinical models or biomarkers used to optimize treatment selection. Herein, we hypothesized that longer time from prior definitive therapy (DT), either radical prostatectomy, definitive radiotherapy, or both, to onset of metastatic disease is associated with improved survival outcomes in men with newly diagnosed mHSPC. MethodsThis multicenter retrospective study included men initiating systemic therapy with ADT for new mHSPC. Kaplan-Meier and COX proportional hazard models assessed time to metastatic castration-resistant prostate cancer (mCRPC) and overall survival (OS) by receipt of prior DT. ResultsOf the 253 men with new mHSPC, 115 (45%) had received prior DT. In a multivariate analysis, increasing years from DT to the start of ADT was an independent predictor of time to mCRPC (per year: hazard ratio 0.91 95% confidence interval 0.84–0.99, P = 0.020) and improved OS (per year: hazard ratio 0.87, 95% confidence interval 0.74–0.99, P = 0.0025) in patients with new mHSPC, and may assist with risk stratification in these patients at time of mHSPC. ConclusionTime from DT to start of ADT is an independent predictor of time to mCRPC and OS in men with new mHSPC, and may assist with risk stratification of these patients for systemic therapy selection.

Prostate-Specific Membrane Antigen Positron Emission Tomography–Computed Tomography for Prostate Cancer: Distribution of Disease and Implications for Radiation Therapy Planning

To explore the prostate-specific membrane antigen (PSMA)-avid distribution of prostate cancer (PC) on positron emission tomography (PET), both at the time of initial diagnosis and at the time of relapse after definitive local treatment. A total of 179 PSMA PET scans in patients with nil or ≤3 lesions on conventional imaging were retrospectively categorized into 3 subgroups: group A, high-risk PC with no prior definitive therapy (n=34); group B, prior prostatectomy (n=75); and group C, prior radiation therapy (n=70). The numbers and locations of the PSMA-avid lesions were mapped. The PSMA-positive lesions were identified subjectively by a nuclear medicine physician on the basis of clinical experience and taking into account the recent literature and artefacts. A total of 893 PSMA-avid lesions were identified; at least 1 lesion was detected in 80% of all scans. A high detection rate was present even at very low serum PSA levels (eg, at PSA ≤0.20ng/mL in group B, the detection rate was 46%). Thirty-eight percent of studies revealed extrapelvic disease (41%, 31%, and 46% in groups A, B, and C, respectively). Almost one-third of all studies showed only oligometastases (24%, 36%, and 31% in groups A, B, and C, respectively). A large proportion of these (40%) were a solitary lesion. Prostate-specific membrane antigen PET demonstrated a large number of otherwise unknown metastatic lesions. Therefore we recommend PSMA PET for more accurate assessment of disease burden in initial staging of high-risk PC, as well as for restaging in patients with prostate-specific antigen relapse after primary therapies. Furthermore, a high proportion of oligometastases on PSMA PET provides a prime opportunity to investigate the role of targeted local therapies for oligometastatic PCs.

Association of time from definitive therapy (DT) to start of androgen deprivation therapy (ADT) for metastatic disease and survival outcomes in men with new metastatic hormone-sensitive prostate cancer (mHSPC).

265 Background: Few objective criteria are considered for risk stratification for treatment decision making in men with new mHSPC. Time between DT for localized disease, and start of ADT for new mHSPC may predict response to ADT, and prognosticate outcomes in this setting. Methods: In this multicenter study, men with newly diagnosed mHSPC with prior history of definite therapy for localized prostate cancer were included. Kaplan-Meier and Cox proportional hazard methods assessed time to castration resistance (CRPC) and overall survival (OS) from initiation of ADT, and correlated with the time elapsed from DT to initiation of ADT for new mHSPC. Results: A total of 112 men with new mHSPC initiating ADT, with prior definitive therapy were eligible (all median: age 68 yrs, Gleason score 7, PSA 14 ng/ml, ECOG 0, median time from DT to start of ADT for new mHSPC 54 months). In the univariate analysis, time from DT to start of ADT of &lt; 60 months vs ≥ 60 months significantly correlated with duration of response to ADT and outcomes (Table). After adjustment for Gleason score and log PSA, time from DT to start of ADT for new mHSPC (&lt;60 vs ≥60 months) remained an independent and a significant predictor of time to CRPC (HR 1.92 95% CI 1.02-3.90, p=0.044), and showed trends towards predicting OS (HR 1.77 95% CI 0.60-6.19, p=0.33). Conclusions: Time from DT for localized prostate cancer to initiation of ADT for new mHSPC independently predicts response to ADT, and may aid in risk stratification for treatment decision making in men with new mHSPC. These hypothesis-generating data require validation in a larger cohort. [Table: see text]

PET of Glucose Metabolism and Cellular Proliferation in Prostate Cancer.

Imaging of the Warburg effect, which is the principal but not the sole cause for enhanced glucose metabolism in tumors, with PET and 18F-FDG has become the mainstay for the imaging evaluation of several cancers. Despite the seemingly prevalent notion that 18F-FDG PET may not be useful in prostate cancer, relatively limited evidence suggests that this imaging modality can be useful for the evaluation of the extent of metastatic disease and the assessment of the therapy response and prognosis in men with castration-resistant prostate cancer. Incidental high focal 18F-FDG uptake in the prostate gland, although generally rare, may also indicate occult prostate cancer that may need to be further scrutinized. In general, 18F-FDG PET is not useful for initial staging and is of limited utility in the clinical setting of biochemical failure after prior definitive therapy for primary cancer. Although more experience is needed, it appears that the imaging of cellular proliferation with PET and 3'-deoxy-3'-18F-fluorothymidine or 2'-18F-fluoro-5-methyl-1-β-d-arabinofuranosyluracil may also allow for targeted biopsy and localization for focal therapy of aggressive prostate tumors as well as assessment of the therapy response to various standard and novel treatment regimens in patients with metastatic disease.

Impact of prior definitive therapy on survival outcomes in men with new hormone-sensitive metastatic prostate cancer (mHSPC).

Impact of prior definitive therapy on survival outcomes in men with new hormone-sensitive metastatic prostate cancer (mHSPC).

Impact of prior definitive therapy on survival outcomes in men with new hormone sensitive metastatic prostate cancer (mHSPC).

269 Background: In mHSPC, treating the primary tumor may have a biologic effect on the metastatic sites, and definitive therapy in this setting has been hypothesized to delay disease progression and even death. Outcomes with prior definitive therapy in this setting have not been reported. Methods: In this multicenter study, men with new mHSPC, starting androgen deprivation therapy (ADT) were included. Index date was the day of starting ADT. Kaplan-Meier and Cox proportional hazard methods assessed time to castrate resistance (CRPC) and overall survival (OS) in those with or without prior definitive therapy. Variables significant at P &lt; 0.05 were included in the final models. Results: A total of 235 men with mHSPC were included (median age ~ 67 yrs). Prior definitive therapy was performed in 64 men (27%). Results are presented in the table. Conclusions: Definitive treatment was associated with improved time to CRPC and OS in univariate analysis; however, when combined with other prognostic factors the significance was not maintained. Analysis of a larger data set is warranted to fully assess the role of prior definitive therapy in mHSPC. [Table: see text]

PD27-05 INTERMITTENT ANDROGEN DEPRIVATION WITH THE GONADOTROPHIN−RELEASING HORMONE ANTAGONIST DEGARELIX

You have accessJournal of UrologyProstate Cancer: Advanced I1 Apr 2014PD27-05 INTERMITTENT ANDROGEN DEPRIVATION WITH THE GONADOTROPHIN−RELEASING HORMONE ANTAGONIST DEGARELIX David Crawford, Neal Shore, Celestia Higano, Anders Neijber, and Vladimir Yankov David CrawfordDavid Crawford More articles by this author , Neal ShoreNeal Shore More articles by this author , Celestia HiganoCelestia Higano More articles by this author , Anders NeijberAnders Neijber More articles by this author , and Vladimir YankovVladimir Yankov More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2104AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Intermittent androgen deprivation (IAD) is proposed as an alternative to continuous androgen deprivation (CAD) in some patients, potentially offering fewer side effects, better quality of life and cost savings. Studies have compared CAD with IAD using luteinizing hormone−releasing hormone agonists. We report the primary endpoint and exploratory analyses of a study of IAD with the gonadotrophin−releasing hormone antagonist degarelix. METHODS Eligible men had rising prostate−specific antigen (PSA) levels after prior definitive therapy and testosterone (T) >150 ng/dL. Men were randomized to intermittent degarelix (DI; n=177), continuous degarelix (DC; n=50) or continuous leuprolide (LC; n=182). Initial treatment was 7 months of degarelix or leuprolide. Patients in the DI arm then entered a 7−month off-treatment period. Men in the DC or LC arm continued on degarelix or leuprolide, respectively. The primary endpoint was the proportion of patients with PSA ≤4.0 ng/mL at 14 months. Non-inferiority required a lower 95% confidence interval bound of greater than -12.5%. RESULTS Despite CAD, 2.4% and 1.3% of patients had PSA >4 ng/mL in the DC and LC arms, respectively, while none of the patients treated with DI had PSA >4 ng/mL at month 14. The lower confidence interval limit for DI vs. CAD (DC and LC arms combined) was -0.19%; therefore non−inferiority was established. During the off treatment period (Months 7–14), 35 (26%) patients in the DI arm had PSA >2 ng/mL and received additional doses of degarelix. In the DI arm, median time to T recovery (T >50 ng/dL) was 112 days (from 28 days after the last degarelix dose) and occurred in 116 (85%) patients within 6 months of discontinuation. Exploratory subanalyses indicated that younger age (<65 years) was predictive for T recovery (p=0.013). Disease stage at enrolment, PSA at baseline and PSA at Month 7 were not indicative of T recovery to >50 ng/dL (p=0.076, 0.506 and 0.384, respectively). Men in the DI arm had significantly improved sexual drive at month 14 compared with CAD patients (p=0.0271). Men with normal sexual drive at baseline had the greatest improvement in the DI arm. Adverse events did not differ significantly between the DI, DC and LC treatment arms. CONCLUSIONS The intermittent use of degarelix is non-inferior to CAD in maintaining PSA suppression when administered in a regimen of 7 months of treatment and a 7−month off−treatment period with treatment restarted for men with PSA >2 ng/mL. Age <65 years was predictive of testosterone recovery. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e766 Advertisement Copyright & Permissions© 2014MetricsAuthor Information David Crawford More articles by this author Neal Shore More articles by this author Celestia Higano More articles by this author Anders Neijber More articles by this author Vladimir Yankov More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Combination immunotherapy with prostatic acid phosphatase pulsed antigen‐presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy

APC8015 (sipuleucel-T) is a cellular prostate cancer vaccine containing autologous antigen-presenting cells (APC) loaded with PA2024, a recombinant prostatic acid phosphatase/granulocyte-macrophage-colony-stimulating factor fusion protein, as the immunogen. Bevacizumab is a recombinant antibody against vascular endothelial growth factor, a proangiogenic protein with inhibitory effects on APC. A clinical trial was conducted to determine the prostate-specific antigen (PSA) and immunomodulatory effects of this combination immunotherapy. Patients with androgen-dependent prostate cancer who had received prior definitive therapy with nonmetastatic, recurrent disease as manifested by a rising PSA of between 0.4 ng/mL and 6.0 ng/mL were enrolled. APC8015 was given intravenously(i.v.) on Weeks 0, 2, and 4. Bevacizumab was given at a dose of 10 mg/kg i.v. on Weeks 0, 2, 4, and every 2 weeks thereafter until toxicity or disease progression. PSA changes were recorded and the PSA doubling time (PSADT) was calculated. Immune response versus PA2024 was measured at baseline and after treatment by T-cell proliferation and interferon-gamma enzyme-linked immunospot (ELISPOT) assays. Twenty-two patients were treated. One patient achieved a > or =50% decrease in PSA. Nine patients exhibited some decrease in PSA from baseline, ranging from 6% to 72%, with the PSA of 3 patients decreasing at least 25%. The median pretreatment PSADT for the 20 evaluable patients was 6.9 months and the median posttreatment PSADT was 12.7 months (P = .01). All patients demonstrated induction of an immune response against PA2024. The combination of APC8015 and bevacizumab induces an immune response and modulates PSA in patients with biochemically recurrent prostate cancer.

Clinical and Immunological Characteristics of Patients With Serologic Progression of Prostate Cancer Achieving Long-Term Disease Control With Granulocyte-Macrophage Colony-Stimulating Factor

We describe the clinical and immunological characteristics of patients with biochemically relapsed prostate cancer who achieved long-term disease control with GM-CSF (Leukine). A total of 30 patients with prostate cancer and nonmetastatic recurrent disease, as manifested by increasing PSA between 0.4 and 6.0 ng/ml after prior definitive therapy, were enrolled in a phase II trial. Patients received 250 microg/m2 GM-CSF daily subcutaneously on days 1 through 14 of a 28-day cycle until PSA or objective progression. The patient and disease characteristics of patients who remained without evidence of disease progression beyond 4 years were examined. Additionally, flow cytometry was performed in peripheral blood to characterize monocyte and dendritic cells. Seven of 29 evaluable patients (24%) remained free of disease progression at a median of 5.1 years (range 4.5 to 5.6 or greater) from the start of GM-CSF therapy. Patients on long-term GM-CSF tended to have lower initial T stage, Gleason score and pretreatment PSA. An increase in the number of circulating monocytes and dendritic cells was observed after 14 days of GM-CSF treatment. These values returned to baseline during the 14-day off period. GM-CSF modulates PSA in androgen dependent, biochemically relapsed cases. A substantial proportion of patients achieve long-term disease control. The clinical characteristics described may help select patients for future clinical trials with GM-CSF or other immunomodulators. Additional investigation is required to define the immunological mechanism of GM-CSF in prostate cancer.

A PROSPECTIVE ANALYSIS OF THE TIME TO NORMALIZATION OF SERUM ANDROGENS FOLLOWING 6 MONTHS OF ANDROGEN DEPRIVATION THERAPY IN PATIENTS ON A RANDOMIZED PHASE III CLINICAL TRIAL USING LIMITED HORMONAL THERAPY

Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent therapy with gonadotropin-releasing hormone agonists (GnRH-A). While these are largely successful in decreasing testosterone (T) and dihydroxytestosterone (DHT) to castrate levels, discontinuation of such therapy often results in continued suppression of androgens for variable periods of time. We present the largest published series of patients evaluating the timing of T and DHT increase after cessation of GnRH therapy. Serial T and DHT measurements were prospectively obtained every 3 months while on GnRH-A then monthly upon discontinuation of GnRH-A. Analysis of time from the second 3-month GnRH-A administration to T and DHT increase was undertaken. A total of 80 evaluable patients had a median time to T 50 ng/dl or greater of 12.9 weeks and a median time to T normalization (212 ng/dl or greater) of 16.6 weeks. Low baseline T was associated with a prolonged time to T 212 ng/dl or greater (p = 0.0086) and a similar trend was seen in patients older than 66 years (p = 0.08). There were 62 evaluable patients with a median of 14.9 weeks to DHT 150 pg/ml or greater. There was no association with Gleason score at diagnosis, on study prostate specific antigen, type of prior definitive therapy, or any prior hormonal therapy and time to increase in circulating androgens. After 6 months of GnRH-A therapy in these patients, DHT and T levels did not return to normal for a median of 14.9 and 16.6 weeks, respectively.