Castration-resistant Prostate Cancer Pts Research Articles

1391P Tumor-first mutation-specific risk approach to trigger germline testing in castration-resistant prostate cancer

The prevalence of hereditary prostate cancer (PCa) in the Netherlands appears lower than previously reported, and routine germline testing is not advocated as standard of care. Current referral strategies are based on a positive family history (FH) for high-risk penetrating cancer predisposition genes, on presence of metastatic disease (DISCOVER-study), or on a tumor-first approach in patients (pts) with castration-resistant PCa (CRPC) with cascade germline testing in those with an alteration in predefined genes. Here we compare referral based on FH with the tumor-first approach. The PROMPT trial (NCT04746300) prospectively studies the impact of routine molecular tumor profiling with broad next-generation sequencing (NGS) in recently diagnosed CRPC pts. All results were discussed within the Radboudumc Molecular Tumor Board to guide precision medicine and for germline testing by geneticists per protocol. FH was taken at screening. The presence of familial and hereditary PCa by Dutch criteria for included pts was retrospectively assessed. High-risk homologous recombination deficiency (HRD) genes studied were BRCA1, BRCA2 and PALB2. Data on ATM and CHEK2 (lower-risk) will also be presented. In the 307 evaluable pts at least one pathogenic HRD alteration was found in 24 pts (8%), in BRCA1 (n=1), BRCA2 (n=21) and PALB2 (n=2) respectively. 17 pts (6%) were referred for germline testing; in 11 pts a germline variant was found. In 7/11 families the genetic predisposition was unknown, with pts not fulfilling Dutch referral criteria. FH was reported in 305 pts. Based on FH 53 pts would have been eligible for referral to clinical genetics and germline testing. In these pts, 48 pts did not have a pathogenic aberration in BRCA1/BRCA2 or PALB2 in tumor DNA. Based on reported FH, 18% of the pts would meet the Dutch criteria for genetic testing. In the majority of them the chance of a germline mutation is estimated to be low based on tumor test results, and 7 families with a germline mutation would have been missed. A tumor-first approach for high risk genes led to referral of 6%, with a germline variant in 53% of pts. Routine tumor-first DNA testing in CRPC efficiently identifies pts eligible for germline testing.

Abstract CT006: Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects

Abstract Introduction: ATR kinase is a critical component of DDR machinery and is activated by DNA damage or replication stress. Elimusertib is a selective ATR inhibitor with promising antitumor activity in pts with advanced solid tumors with ataxia telangiectasia mutated (ATM) protein loss and/or ATM putative deleterious alterations (Yap et al. Cancer Discov 2021). We report here the safety and efficacy of elimusertib in expansion cohorts of pts with a range of cancer types and DDR deficiencies and/or ATM loss. We also explored an alternative dose schedule in pts with ATM aberrations. Methods: Pts with advanced solid tumors resistant or refractory to standard treatment were screened for pathogenic DDR defects by next-generation sequencing or ATM protein loss by immunohistochemistry (IHC) analysis of baseline tumor tissue. Pts were assigned to cohorts: colorectal cancer (CRC); castration-resistant prostate cancer (CRPC); HER2− breast cancer (BC); gynecologic (GYN, mainly ovarian and endometrial); and advanced cancers with ATM IHC loss. Pts were treated with elimusertib 40 mg twice daily (BID) 3 days on/4 days off (3 on/4 off). A schedule of 3 on/11 off was also explored by dose escalation in pts with ATM loss or inactivating mutation. Results: 143 pts received ≥1 dose of elimusertib 40 mg BID 3 on/4 off, including 24 CRC, 19 CRPC, 19 BC, 45 GYN, and 36 ATM loss. 56% of pts had ≥4 prior therapy lines. Drug-related grade 3 and 4 treatment-emergent adverse events (TEAEs) were observed in 69% and 15% of pts, respectively, mainly anemia, leukopenia/neutropenia, and thrombocytopenia leading to dose modification but not withdrawal. 32 pts were treated 3 on/11 off with doses from 60 to 120 mg BID. Compared with 3 on/4 off, drug-related grade ≥3 hematologic TEAEs and dose modifications improved at lower doses, with 80 mg 3 on/11 off determined as the recommended dose. In pts receiving elimusertib 3 on/4 off, 5 RECIST partial responses were observed: 1 in ovarian (BRCA1 heterozygous mutation), 1 in BC (BRCA2 mutation), and 3 in ATM IHC loss: 2 CRPC pts both with ATM mutations (1 heterozygous, 1 homozygous), including 1 with FANCA mutation; 1 esophageal with ATM mutation. In pts with ATM IHC loss, objective response rate (ORR) was 9% and disease control rate (DCR) was 65%. A similar ORR was seen on 3 on/11 off in pts with ATM aberrations. In GYN pts, ORR was 2.3% and DCR was 73%. Conclusions: Elimusertib monotherapy demonstrated clinical activity in pts with DDR defects. Overall safety was manageable and hematologic toxicity improved on the 3 on/11 off schedule. Further biomarker analysis is underway to identify potential gene signatures associated with response. Clinical development of elimusertib in combination with checkpoint inhibitors and chemotherapy is ongoing (NCT04095273, NCT04514497). Citation Format: Timothy A. Yap, David S. Tan, Anastasios Stathis, Geoffrey I. Shapiro, Satoru Iwasa, Markus Joerger, Jingsong Zhang, Ruth Plummer, Michael Sawyer, Aaron C. Tan, Vincent Castonguay, Nashat Gabrail, Nobuaki Matsubara, Gary Wilkinson, Matthias Ludwig, Yinghui Zhou, Claudia Merz, Joseph Hreiki, Neelesh Sharma, Johan deBono. Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT006.

First results of the PROMPT trial: Precision oncology allocation in patients with early castration-resistant prostate cancer following routine molecular profiling.

40 Background: Castration-resistant prostate cancer (CRPC) comprises distinct molecular actionable subtypes. Radboudumc, a tertiary referral center for PCa, hosts a Molecular Tumor Board (MTB), and frequently sees CRPC patients (pts) for referral for genetic testing. In the period 2017-2020, almost 50% of heavily pre-treated CRPC pts received a recommendation for a genetically matched therapy (GMT). In 2020 we initiated the PROMPT trial (NCT04746300) to prospectively study the impact of routine early molecular characterization in CRPC. Increased GMT utilization of targeted- and immunotherapy may improve outcome and quality of life of pts with metastatic CRPC, and lead to lower medical resource utilization (MRU). Here we report on first results from our observational trial. Methods: Within the PROMPT trial, prior to receiving first- or second line standard of care CRPC therapy, up to 300 pts were offered molecular tumor characterization with the TruSightOncology 500 panel (TSO500). Formalin-fixed paraffin-embedded prostate or metastatic tissue biopsies were used, preferably newly obtained. To assess both mutations and copy number alterations, the TSO500 required a minimal tumor cell percentage (TC%) of 30%. Results were discussed within the Radboudumc MTB for GMT recommendation. Actionable targets were defined per Precision Medicine Working group criteria and, when druggable, within the Drug Rediscovery Protocol trial (NCT02925234). All pts with tumor mutations carrying with a risk for cancer predisposition were referred for genetic counselling. Follow-up with patient-reported outcomes (EORTC QLQ-C30, EQ5D, BPI & EPIC-26 questionnaires) and MRU was conducted every 3 months until withdrawal or death. Results: From February 2020 until October 2021 we included 284 consecutive CRPC pts with a median age of 70 years (range 46-86) with a median follow-up of 6.8 months. Newly obtained biopsies and archival material was used in 131 and 126 pts, respectively. Median TC% was 60% (range: 20-90%). TSO500 results could be reported in 254 (89%) cases, with at least one putative clinically relevant aberration in 188 evaluable pts (74%). In 100 pts (39,4%) ≥ 1 druggable target was found. Most common actionable alterations were in PTEN (19%), BRCA2 (9%) or in mismatch-repair genes or resulting in high tumor mutational burden (5%). Out of the 100 druggable pts, 31 pts (31%) initiated a form of GMT, 4 pts (4%; 2 BRCA2, 2 PTEN) died prior to receiving GMT, in 65 pts (65%) GMT is pending as they receive standard of care. Conclusions: Routine molecular profiling early in the CRPC setting is feasible in a tertiary referral center with a MTB and high volume of CRPC pts. Almost 40% CRPC pts harbored an actionable target with 31% of these pts already allocated to a GMT. Failure rates of NGS were low at 11%.

Phase II Evaluation Of Stereotactic Ablative Radiotherapy (SABR) in 11C-Choline PET/CT (Cho-PET)-Identified Oligometastatic Castration-Resistant Prostate Cancer (CRPC)

Outcomes for metastatic castration-resistant prostate cancer (CRPC) remain poor. We prospectively sought to improve clinical outcomes in a subgroup of CRPC patients (pts) with oligometastases identified by 11C-Choline (Cho)-PET and treated with stereotactic ablative radiotherapy (SABR). This is a single arm, single institution Phase II study which enrolled 94 pts from Aug 2016-Dec 2019; 4 pts voluntarily withdrew and 1 pt had only 1 month follow up. Nine pts who received 8 Gy in 1 were also included in survival analysis. Eligibility included ECOG 0-2, pathologically proven prostate cancer, ≤ 3 metastases identified on Cho-PET, testosterone < 50 ng/dL on androgen deprivation therapy, and life expectancy > 6 months. Primary endpoints were 2-year overall survival (OS) and 1-year PSA-progression (Prostate Cancer Working Group criteria). Secondary endpoints included 1-year SABR-treated metastasis failure (MF) and 6-month rates of grade ≥ 3 adverse events (AEs) per CTCAE V4.0. Peripheral blood samples were collected for exploratory immunologic biomarker analyses. 89 pts are included in this analysis, and median age was 71 years. 58 pts had one lesion, 23 pts two lesions, and 8 pts three lesions. Prior to SABR (n = 80), 61%, 52%, and 20% had progressed on second-line chemotherapy, abiraterone, or enzalutamide, respectively; 38% progressed on both chemotherapy and next generation androgen axis inhibitors. Median PSA at SABR was 0.7 (IQR 0.25, 3.1), and 64% had PSA < 2 ng/mL. Mode dose and fractionation was 20 Gy and 1. At median follow-up of 23 months, median OS was 29 mos. 1- and 2-year OS was 96% (95% CI: 91-100) and 80% (70-92), respectively, for all and also for SABR pts. The cumulative incidence of PSA progression was 58% (48-71) and 76% (67-88), and MF was 12% (6-24) and 18% (11-32) at 1-and 2-years, respectively, for SABR pts. No grade ≥ 3 AEs were noted. Grade 2 AEs included fatigue (1%), fracture (3%), and flare-up pain (8%) in SABR pts. We observed an estimated 2-year OS of 80% in heavily-treated CRPC pts after metastasis-directed therapy to Cho-PET-defined oligometastatic sites with no grade ≥ 3 AEs. Approximately 20% of pts did not have a change or additional systemic therapy following SABR. These results are favorable compared to historical series and support the study of Cho-PET and SABR in CRPC pts in Phase III trials.

Use of plasma androgen receptor (AR) testing to optimize docetaxel chemotherapy in castration-resistant prostate cancer (CRPC): A multicenter biomarker study.

5546 Background: Plasma AR status has been identified as a potential biomarker of response in CRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR in the overall management of CRPC patients (pts) receiving docetaxel at different dose due to the toxicity profiles and physician-patient preferences is unknown. Methods: This was a multi-institution study of associations between baseline plasma AR-copy-number status assessed by droplet digital PCR and outcome in 325 CRPC pts. Between September 2011 and July 2019 pts started treatment with docetaxel administered at standard regimen 75mg/m2 every three weeks or adapted regimen (75-80% of standard recommended dose or 30mg/m2 weekly administration) at the discretion of the treating physician. Patients were assigned randomly into 2 sets with a ratio 2:1 to either training (n=217) and internal validation (n=108) cohorts. Results: In our study, adapted regimen of docetaxel was administered in 68 (31.3%) and 35 (32.4%) of training and validation cohorts, respectively. Based on plasma AR status, 67 (30.9%) and 39 (36.1%) validation and training set pts were classified as AR gain, respectively. In men treated with standard docetaxel regimen, no difference in progression-free/overall survival (PFS/OS) was seen between plasma AR normal and gain in both cohorts. In patients treated with adapted docetaxel regimen, we observed a significantly shorter median PFS (3.9 vs. 6.4 months, HR 4.77, 95%CI 1.48-3.80, p=0.0003) and median OS (11.2 vs . 20.4 months, HR 2.87, 95%CI 1.73-2.13, p=0.0008) in the training cohort. This finding was confirmed in the validation cohort (median PFS: 4.8 vs. 7.4 months, HR 2.54, 95%CI 1.40-4.58, p=0.005, and median OS: 11.8 vs. 26.4 months, HR 5.00, 95%CI 2.59-9.65, p&lt;0.0001). In addition, AR-gained patients were less likely than AR normal to have a PSA decline when receiving an adapted regimen in both cohorts (p=0.010 e p=0.003, respectively). Conclusions: This study suggests that plasma AR may improve clinical decision making in choosing not only between AR-directed therapies and taxanes, but also between adapted and standard regimen of docetaxel in first- and subsequent-therapy lines, providing promising clinical implications to select the proper timing and dose of docetaxel. Prospective trials to validate these findings are warranted.

SLFN11 expression (exp) in castration-resistant prostate cancer (CRPC) patients (pts) to predict response to platinum-based chemotherapy (PLT).

5065 Background: Schlafen family member 11 (SLFN11) sensitizes tumor cells to DNA-damaging agents and has been investigated as a potential predictive biomarker of response to PLT and PARP inhibitors, especially in small cell lung cancer (Lok, CCR 2017; Pietanza, JCO 2018). We aimed to explore the predictive/prognostic role of SLFN11 in PLT-treated CRPC. Methods: We assessed tumor exp of SLFN11 in PLT-treated, metastatic CRPC pts by RNAseq (N=27) and/or CTCs (N=20) (via the Epic Sciences platform). In addition, tumor morphology for neuroendocrine (NE) features and genomic status of select genes (ie, AR, TP53, RB1, BRCA2, BRCA1, ATM) by whole exome sequencing were evaluated. Statistical comparisons used Cox regression analysis and Kaplan Meier method for the association with overall/radiographic progression free survival (OS/rPFS). A dose response curve with PLT was performed in patient-derived organoids using Cell Title Glo according to the manufacturer’s protocol. Results: 41 CRPC (including 20 CRPC-NE) treated with PLT monotherapy (N=3) or PLT combination therapy (N=38) between August 2013 and December 2017 were evaluated. Median age was 67.1 years (range 51-91). Median number of prior therapies was 2 (range 1-7). A longer median rPFS was observed in all SLFN11+ pts treated with PLT (regardless of histology, RB1, TP53, PTEN, or DNA repair status) compared to SLFN11- [5.2 vs 2.3 months, HR 3.5, 95%CI 1.6-7.7, P&lt;0.0001]. No association was reported for OS. On multivariable analysis (Table), SLFN11 was an independent factor associated with rPFS. Organoids derived from patient tumors expressing SLFN11 showed sensitivity to PLT in vitro. Conclusions: SLFN11 exp identifies both CRPC and CRPC-NE pts with a better response to PLT. Patient-derived organoids expressing SLFN11 confirmed increased sensitivity to PLT. Larger prospective evaluation of therapy decisions based on SLFN11 exp is now required. [Table: see text]

A phase II, open-label, multi-arm study of TAS-115 for castration-resistant prostate cancer patients with bone metastases.

164 Background: TAS-115, a novel multi-kinase (eg, MET, VEGFR) inhibitor has also shown to inhibits Feline McDonough Sarcoma oncogene (FMS) kinase, Anti-tumor activity against bone metastases was observed in the preclinical and phase1 study. In this phase 2 study, the efficacy and safety of TAS-115 were evaluated in castration-resistant prostate cancer (CRPC) patients (pts) with bone metastases. Methods: This was a phase 2, open-label, multi-arm study for CRPC pts with bone metastases to evaluate the clinical anti-tumor activity of TAS-115. Pts who had visceral metastases were ineligible for this study. TAS-115 was given orally, once daily, and schedule of 5 days on/2 days off each week was repeated. This study had 2 cohorts (A and B). In cohort A, TAS-115 ranging from 200 to 400 mg/day with abiraterone acetate was given to pts prior to docetaxel. In cohort B, CRPC pts who had symptomatic bone metastases, post or unfit to docetaxel, were randomized in a 1:1 to 400 or 600 mg/day of TAS-115. The primary endpoint was bone scan index (BSI) response rate at week 12, defined as ≥ 30% decrease of BSI from baseline. BSI is a quantitative assessment of bone scan data calculated by software (BONE NAVI). Results: From Nov 2016 to Jul 2018, a total of 50 pts received TAS-115 (24 pts in cohort A and 26 pts in cohort B). BSI response rate at week 12 and best BSI response was 20.8 % and 37.5% in cohort A, and 15.4 % and 19.2% in cohort B, respectively. Any reduction of BSI was observed in 70.8% of cohort A and 61.5% of cohort B. In cohort B, pain was assessed using the Brief Pain Inventory short form and improvement was observed in 61.5% of pts. Furthermore, the reduction of bone-turnover marker (BAP, P1NP, NTx and TRACP-5b) were observed in both cohorts, but not PSA response. The major (≥ 10%) Grade 3/4 treatment-related adverse drug reactions were hypophosphataemia (21%) in cohort A, and anemia (23%), hypophosphataemia (12%) and neutrophil count decreased (12%) in cohort B. Conclusions: Preliminary anti-tumor activity to bone lesion and improved pain were observed in CRPC pts with bone metastases, and safety of TAS-115 was acceptable. TAS-115 could be a novel therapeutic agent with a favorable safety profile for CRPC with bone metastases. Clinical trial information: JapicCTI-163448.

Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).

195 Background: A small proportion of metastatic PC exhibit outlier somatic mutation rates. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing of 1047 plasma cell-free DNA samples and calculated somatic mutation burden. HM samples and available matched archival tissue were additionally subjected to whole exome sequencing. Trinucleotide mutational signatures and microsatellite instability (MSI) were determined via nonnegative matrix factorization and mSINGS, respectively. We evaluated PSA decline ≥50% from baseline (PSA50), time from androgen deprivation therapy (ADT) to castration-resistant prostate cancer (CRPC), median duration of 1st line CRPC therapy (1L CRPCT) and median OS (time from CRPC to death). The control cohort consisted of 199 CRPC pts treated with 1L abiraterone + prednisone (ABI+P) or enzalutamide (ENZ). Results: 671 samples from 434 pts had ctDNA% &gt; 2 and were evaluable. The median mutation rate was 2.59/Mb (range, 0.9 – 155.6/Mb). 32 samples from 24 pts had &gt; 11/Mb and fell above the 95th percentile for mutational burden. 10/24 pts had biallelic loss of mismatch repair (MMR) genes MSH2/6, and a further 5 pts without confirmed MMR defects had enrichment of trinucleotide signatures associated with MMR and/or were MSI high by mSINGS. The remaining 9 pts had either BRCA2 mutations or Kataegis (localized hypermutation). Clinical data was available for 10/15 MMR defective pts. Median age was 73.6 y. At diagnosis, 70% had Gleason score ≥8, 50% with M1 disease, median PSA was 22.8 (6.8 – 820). PSA50 with ADT (n = 8) or ADT + docetaxel (n = 2) was 100% in the castration sensitive setting. 5 pts had ENZ, 4 ABI + P, and 1 cabazitaxel in 1L CRPCT. Comparing the MMR defective with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9 – 11.4) vs. 18.2 m (95% CI 15.1 – 21.3), p = 0.001; 1L CRPCT duration was 3.9 m (95% CI 1.3 – 6.5) vs. 8.4 m (95% CI 7.2 – 9.6), p = &lt; 0.001; median OS was 13.1 m (95% CI 0.33 – 25.9) vs. 40.1 m (95% CI 32.4 – 47.8), p &lt; 0.001. Conclusions: HM and MMR defects can be identified in a liquid biopsy. Although these pts can have poor outcomes with standard therapy, ctDNA may help selection for immunotherapy.

A retrospective observational study assessing bone metastases (mets) detection and management of patients (pts) with castration-resistant prostate cancer (CRPC) in Canada.

161 Background: Canadian Urological Association guidelines outline the scheduling of imaging modalities based on prostate-specific antigen doubling time (PSADT) to screen for mets in pts with nonmetastatic (M0) CRPC and to manage pts with metastatic (M1) CRPC. Data describing guideline adoption and real-world timing of bone scans and treatment patterns in Canadian CRPC pts are limited. Methods: A retrospective chart review conducted at 13 Canadian urology practices included pts with CRPC (PSA ≥2 ng/mL despite androgen deprivation therapy) sequentially identified in reverse chronological order starting July 30, 2015. Pts had no mets at CRPC diagnosis (index date). Data were abstracted from the index date to the chart review date. Coprimary objectives were to describe CRPC management in terms of timing of the 1st and repeat bone scans in M0 and treatment patterns when pts became metastatic. Secondary objectives described nonbone imaging. Results: 232 pts enrolled. Over the observation period 109 remained nonmetastatic (M0 cohort); 123 developed mets (M1 cohort). Median index PSADT was ~1.5x greater for the M0 cohort than the M1 cohort. 68 pts (71.6%) in M0 and 117 pts (95.1%) in M1 had ≥1 bone scan. Median (95% CI) months from CRPC diagnosis to 1st bone scan was 7.5 (5.6–9.6) for pts in M1 and 15.7 (10.0–23.0) for pts in M0. Median (95% CI) months from identification of mets to start of treatment for the M1 cohort was 3.2 (2.3–5.7). The most common therapies were abiraterone (55%) and enzalutamide (42%), with respective median (95% CI) durations of 12.7 (8.7–23.3) and 15.7 months (10.4–NE). 25% of pts received a bone-targeted agent. Conclusions: In CRPC, time to first bone scan was shorter for pts who subsequently developed mets or had rapid PSADT. Abiraterone and enzalutamide were the most common therapies in pts with mets. [Table: see text]

Treatment patterns for metastatic hormone-sensitive prostate cancer (mHSPC) progressing after up-front docetaxel in combination with androgen deprivation therapy (D-ADT).

305 Background: D-ADT increases overall survival (OS) in men with mHSPC. All patients (pts) however progress and develop castration-resistant prostate cancer (CRPC). Little is known about response to subsequent therapy and outcomes in this setting. Methods: Retrospective analysis of consecutive mHSPC pts treated with ≥3 cycles of D-ADT at Cleveland Clinic and University of Wisconsin-Madison. We aimed to describe baseline, progression characteristics, treatment choices, sequence and outcome of subsequent therapy. Results: A total of 146 mHSPC pts were treated with D-ADT (6% 1-2 cycles; 94% ≥3 cycles). Final analysis included 136 pts, median age 65 (range 35-86), 65% GS≥8, 79% high-volume disease. Median number of D cycles was 6 (1-6). PSA declined to “0” at 12 and 24 months in 32% and 25% of pts, respectively. Median time to CRPC (biochemical, clinical or radiographic) was 19.6 months (95% CI, 16.6-22.6). 57 pts (42%) received ≥1 subsequent treatment after CRPC [46 hormonal therapy (HT) (21 abiraterone acetate, 19 enzalutamide, 6 ASN-001); 4 Sipuleucel-T; 4 radium-223, 5 chemotherapy (2 carboplatin-based, 2 cabazitaxel, 1 D); 3 temsirolimus/bevacizumab]. Treatment response was independent from time to CRPC (≥12 months, p = 0.264). Pts receiving HT as the first subsequent treatment had a median rPFS of 13.3 months (95% CI, 10.1-16.5) compared with 3.1 months (95% CI, 0-15.8) for non-HT (p = 0.332). Treatment choice was independent of GS (p = 0.513), visceral disease (p = 0.374) and time to CRPC (p = 0.500). Most CRPC pts treated with ≥2 lines of therapy received one HT (n = 21) followed by a different HT (43%), chemo (38%), radium-223 (14%) or olaparib (10%). 57% of pts were alive at 2 years. Longer OS correlated with time to CRPC (p = 0.010) and first subsequent treatment with HT (p = 0.009) but not with visceral disease (p = 0.258), GS (p = 0.599) or sequence of therapies received (HT/HT vs HT/non-HT, p = 0.836). Conclusions: Prior D-ADT did not preclude subsequent treatment response in CRPC pts, independent of time to CRPC. The choice of first-line treatment for CRPC may impact survival in favor of those who start HT.

Prognostic impact of DNA repair germline variants in hormone sensitive prostate cancer stage.

262 Background: Inherited and somatic aberrations in DNA repair genes in castrate resistant prostate cancer (CRPC) are associated with poor prognosis, but respond well to poly ADP ribose polymerase (PARP) inhibitors. We evaluated the prevalence and prognostic impact of harboring germline DNA repair variants in hormone sensitive prostate cancer (HSPC). Methods: Germline DNA from buffy coat was sequenced on HiSeq4000 with a median coverage of 200X for DNA repair variants in 20 genes in HSPC and CRPC patients (pts) enrolled in a hospital registry. Pts were divided into two groups; Group A: pts enrolled at the time of CRPC stage; Group B: treatment naïve HSPC stage pts. The primary endpoints were to determine any impact of harboring DNA repair variants on time to progression from HSPC to CRPC and, from CRPC to death. Group A pts were retrospectively analyzed for time to progression from HSPC to CRPC while Group B patients were followed prospectively for outcomes. Statistical analysis included Cox proportional hazard models and Wilcoxon Rank sum test with significance at p≤0.05. Results: In Group A, 51/562 CRPC pts (9.07%) had variants in the 20 genes (most frequently in BRCA2; n = 15). 44/51 pts with variants and 399/511 without variants had died. Median time of progression from HSPC to CRPC with/without variants was 22.1 vs. 25.1 months (mths); p-value = 0.679. Median time from CRPC to death with/without variants was 32.2 Vs. 27.7 mths (p = 0.6). In HSPC Group B, 14/100 pts were identified with germline variants in ATM (n = 5), CHEK2 (n = 3), BRCA1 (n = 2), BRCA2 (n = 2), RAD50 (n = 1), and MSH2 (n = 1). 31/100 have died and median time to progression from HSPC to CRPC with/without variants was 15.6 vs.11.8 mths, p-value = 0.76. Conclusions: Pts with germline DNA repair variants detected in HSPC stage were not associated with poor prognosis. Presence of additional somatic DNA repair gene aberrations in cell-free DNA, not investigated in this cohort may add to the prevalence of DNA repair gene variations in HSPC and together impact prognosis adversely so as to provide a rationale for PARP inhibitor therapy in select HSPC stage pts.

Post marketing surveillance study of cabazitaxel (CBZ) in Japanese patients with castration resistant prostate cancer (CRPC) in real world settings.

290 Background: The study evaluated safety and efficacy of CBZ in Japanese patients (pts) with CRPC in real world settings. Methods: This prospective, observational study targeted all CRPC pts receiving CBZ in daily practice between September 2014 and June 2015. Observation period was 1 year after first dose of CBZ given. Adverse drug reactions (ADRs) were evaluated for safety by CTCAE 4.0. Overall survival (OS), time to treatment failure (TTF) and prostate specific antigen (PSA) response rate (≥30% PSA decrease) were the efficacy endpoints. Two groups, those given 25mg/m2 of CBZ as initial dose (C25) and those given 20mg/m2 of CBZ (C20), were comparatively analyzed. This study was supported by Sanofi. Results: Of 662 enrolled pts with CRPC treated with CBZ, 660 pts were analyzed. ADRs occurred in 511 pts (77.4%). Most frequent all grade ADRs were neutropenia (49.2%), febrile neutropenia (18.0%) and anemia (14.2%). Median OS and TTF were 319 and 116 days, respectively. Of 540 PSA evaluable pts, 158 (29.3%) achieved PSA response. Populations for post hoc analysis were 159 pts for C25 and 190 pts for C20. Patient characteristics were similar C25 and C20 groups. Statistical significant differences were observed between C25 and C20 groups for OS (Hazzard Ratio [HR] = 0.71) and TTF (HR = 0.78) in favor of C25 group. Initial dose of CBZ remained as the independent prognostic factor for OS and TTF in univariate and multivariate analysis. There was no significant difference for PSA response rate. ≥ Grade 3 ADRs with C25 and C20 occurred in 129 pts (81.1%) and 116 pts (61.1%), respectively. Conclusions: Safety profile of CBZ was generally consistent with clinical studies conducted before approval in Japan. Although there are some limitations of studies done in real world settings, there were significant differences for OS and TTF between C25 and C20. Less ADRs occurred with C20. [Table: see text]

LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.

LBA3 Background: Pts with newly diagnosed mHNPC, particularly with high-risk characteristics, have a poor prognosis. ADT+docetaxel showed improved outcomes in mHNPC, but many pts are not candidates for docetaxel and may benefit from alternative therapy. AA+P is indicated for metastatic castration-resistant prostate cancer pts. LATITUDE evaluates clinical benefit of early intervention with AA+P added to ADT in newly diagnosed, high-risk mHNPC pts. Methods: 1199 pts with newly diagnosed (≤ 3 mos prior to randomization) mHNPC (ECOG PS 0-2) with ≥ 2 of 3 risk factors (Gleason ≥ 8, ≥ 3 bone lesions, measurable visceral metastases) were randomized 1:1 to ADT+AA (1 g QD) + P (5 mg QD) or ADT+PBOs of AA and P. Co-primary end points were overall survival (OS) and radiographic progression-free survival (rPFS). One rPFS (~565 events), 2 interim, and 1 final OS analyses (~426, ~554, and ~852 events) were planned. Results: At this first interim analysis (median follow-up of 30.4 mos; 406 deaths [48%]; 593 rPFS events), OS, rPFS, and all secondary end points significantly favored ADT+AA+P (Table). The IDMC unanimously recommended unblinding the study and crossing pts to ADT+AA+P. Grade 3/4 adverse events (ADT+AA+P vs ADT+PBOs) (%): hypertension (20.3 vs 10.0); hypokalemia (10.4 vs 1.3); increased ALT (5.5 vs 1.3) or AST (4.4 vs 1.5). Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC. Clinical trial information: NCT01715285. [Table: see text]

Trop-2 expression on treatment resistant cancer cells in castrate-resistant prostate cancer (CRPC) as a predictive biomarker for targeted therapy.

5045 Background: Trophoblastic cell-surface antigen (Trop-2) is a transmembrane glycoprotein that is highly expressed in many solid tumors. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate of an anti-Trop-2 humanized antibody with SN-38. Early clinical trials have shown high response rates in a broad range of diseases including triple negative breast and urothelial cancers. We evaluated Trop-2 expression in tumor biopsies and circulating tumor cells (CTCs) from men with mCRPC (metastatic castrate-resistant prostate cancer). Methods: Trop-2 expression was evaluated from mCRPC biopsies from patients (Pts) treated with abiraterone acetate (AA) on the PROMOTE clinical trial, CTCs from a separate cohort treated with either enzalutamide or AA. Trop-2 CTCs were compared with EpCAM captured CTCs using a microscale technology termed the VERSA (Vertical Exclusion-based Rare Sample Analysis) platform to compare protein and gene expression signatures of resistance to these agents. Results: RNA sequencing identified Trop-2 gene expression in &gt; 70% of metastatic biopsies. The AR splice variant V7 was found in 48 biopsies that also expressed Trop-2. Trop-2 expression was not altered by treatment with AA at 12 weeks. The number of CTCs captured from 25 pts with Trop-2 or EpCAM were closely correlated (R2= 0.84). Gene expression analysis showed similar patterns of expression for the TROP-2 and EPCAM captured cells. AR splice variant expression (AR-V7, AR-V9) in Trop-2 and EpCAM CTCs was detected in 33% of patients. Expression of neuroendocrine markers was identified in 40% of Trop-2 CTCs. Conclusions: Trop-2 is frequently expressed in mCRPC and co-expressed in tumors that express AR splice variants. Trop-2 CTCs are detected in CRPC pts previously treated with AA or Enzalutamide that also express multiple AR splice variants and neuroendocrine markers. The results support Trop-2 expression as predictive biomarker of sensitivity to targeted therapies tumors resistant to AA or Enzalutamide. Men with mCRPC are being enrolled on a Phase I trial with IMMU-132, and multi-site Phase II clinical trial in men who have progressed on AA or Enzalutamide is being finalized.

Sipuleucel-T (sip-T) induced lytic CD8+ T cell responses to target antigens in men with hormone-sensitive and castration-resistant prostate cancer (CRPC).

162 Background: Sip-T is an FDA-approved immunotherapy for patients (pts) with asymptomatic or minimally symptomatic metastatic CRPC. Sip-T is manufactured from autologous peripheral blood mononuclear cells cultured with the immunogen PA2024, a fusion antigen of prostatic acid phosphatase (PAP) conjugated to granulocyte macrophage colony-stimulating factor. After sip-T, antibody and T cell responses to PA2024 and/or PAP correlate with improved survival. To further elucidate the mechanism of sip-T–induced immune responses, we evaluated the proliferative and lytic ability of PA2024- and PAP-specific CD8+ T cells. Methods: Mononuclear blood cells were labeled with the membrane dye carboxyfluorescein succinimidyl ester (CFSE) and cultured with PA2024 or PAP. In vitro proliferative and lytic CD8+ (cytotoxic T lymphocyte [CTL]) T cell responses to these antigens were evaluated by flow cytometry. For proliferation, progressive dilution of CFSE was measured. For CTL activity, the loss of intracellular granzyme B (GzB), indicating exocytosis of this apoptosis-mediating enzyme, was assessed. Samples were from 2 sip-T clinical trials STAND (NCT01431391) and STRIDE (NCT01981122), hormone-sensitive and CRPC pts, respectively. Results: Six wk after sip-T administration, CD8+ PAP- and PA2024-specific responses were observed (n=14 pts assessed). The magnitude of PA2024-specific CD8+ proliferative responses was greater than that for PAP-specific responses. CD8+ T cells from a subset of pts who exhibited PA2024- and/or PAP-specific proliferative responses were assessed for lytic ability. After in vitro antigen stimulation, CTL activity in all evaluated samples (n=14, PA2024; n=13, PAP) was demonstrated by a significant decrease (p&lt;0.05) in intracellular GzB relative to a no-antigen control. Conclusions: Sip-T induced CD8+ CTL proliferation against the target antigens PAP and PA2024. Moreover, antigen-specific CTL activity provides the first direct evidence that sip-T can induce tumor cell lysis. These antigen-specific CD8+ lytic abilities were observed within 6 wk following sip-T, suggesting rapidly generated immune responses. Clinical trial information: NCT01431391; NCT01981122.

Validation of the total illness burden index for prostate cancer (TIBI-CaP) in men with castration-resistant prostate cancer (CRPC): Data from TRUMPET.

256 Background: The TRUMPET registry is a prospective, observational cohort study of patients (pts) with CRPC designed to evaluate treatment patterns and health-related quality of life (HRQoL) outcomes associated with CRPC and its management in a real-world setting. Comorbidities may influence how physicians approach CRPC treatment; therefore, evaluation of comorbidity presence and severity is important. The TIBI-CaP questionnaire measures comorbidity, with the aim of this analysis to validate TIBI-CaP in CRPC. Methods: Data were collected from 302 enrolled CRPC pts treated in academic and community-based sites under routine care. Baseline data collected included clinical history and self-reported demographics, comorbidities, and HRQoL. TIBI-CaP scores were analyzed based on correlation analysis and analysis of variance (ANOVA). Estimated correlations were used to verify the association of TIBI-CaP scores to scores on the SF-12v2 and FACT-P questionnaires. ANOVA models were run with SF-12v2 and FACT-P as response and quartile ranges for TIBI-CaP scores as predictor. Results: Mean age was 73.7 years. 84.7% were white; 13.9% were black. 87.8% had M1 CRPC at study entry. Mean (SD) TIBI-CaP score was 5.3 (2.72) [range 0-13], with 42.4% of CRPC pts presenting with moderate/severe comorbidity burden (higher scores). TIBI-CaP scores had statistically significant (p value &lt; 0.0002) negative correlations with all SF-12v2 composite and domain scores. Correlation estimates for physical condition and mental condition scores were -0.46 and -0.23, respectively. TIBI-CaP scores also had statistically significant (p value &lt; 0.02) negative correlations with FACT-P total scores and all subscales. FACT-P total scores had a -0.44 correlation estimate. F-tests showed significant differences across the four quartiles of TIBI-CaP scores and SF-12v2 and FACT-P (all p values &lt; 0.05). Conclusions: At baseline, TIBI-CaP scores were negatively correlated with CRPC pts baseline functional status as measured by the SF-12v2 and FACT-P questionnaires. TIBI-CaP was strongly associated with HRQoL physical subscales. This analysis demonstrates validity of TIBI-CaP in CRPC pts.

Radium-223 with concomitant bone-targeting agents in metastatic castration-resistant prostate cancer (CRPC) patients treated in an international early access program (EAP)

Background: The bone-targeting agents (BTAs) denosumab and bisphosphonates (BPs) are widely used in the supportive care of patients (pts) with CRPC and bone metastases. We present data on pts treated with radium-223 dichloride (Ra-223) with or without a concomitant BTA in an international EAP.Methods: This was a prospective single-arm phase IIIb study of CRPC pts with symptomatic or asymptomatic bone metastases (no visceral disease) recruited from 14 countries. Pts received Ra-223 55 kBq/kg (iv injection) every 4 weeks for 6 cycles. Co-primary endpoints were safety and overall survival (OS). Exploratory analyses investigated the effects of concomitant denosumab (no BPs) or BPs (no denosumab) on OS and symptomatic skeletal events (SSE). Results: 696 pts received at least one Ra-223 cycle. Of those, 127 (18%) pts were treated with concomitant denosumab (no BPs) and 435 (63%) without any concomitant BTAs. Key baseline characteristics are reported in pts treated with Ra-223 with or without a concomitant BTA (Table). Median OS (mOS) and median time to first SSE (mSSE) were longer in pts treated with Ra-223 and denosumab versus pts without a concomitant BTA (Table). While key baseline characteristics in pts treated with Ra-223 and denosumab were similar to pts treated with Ra-223 and BPs, adding BPs to Ra-223 did not appear to improve mOS. However, mSSE was prolonged in pts receiving Ra-223 and BPs versus pts who received Ra-223 without a concomitant BTA (Table). Conclusions: In this EAP, pts treated with Ra-223 and a concomitant BTA appeared to have longer time to first SSE than those treated without a concomitant BTA. However, improvement in OS was observed with denosumab but not with BPs. Prospective randomized controlled studies are required to confirm the benefit of this specific treatment combination in metastatic CRPC.Table: B7DenosumabBPsNo denosumab/ no BPsN = 127N = 125N = 435Baseline characteristicsECOG PS, n (%)058 (46%)55 (44%)144 (33%)155 (43%)54 (43%)234 (54%)≥214 (11%)16 (13%)57 (13%)Pain, n (%)123122413Mild75 (61%)72 (59%)218 (53%)Moderate-severe19 (15%)24 (20%)113 (27%)None29 (24%)26 (21%)82 (20%)ALP (U/L), n127125433Median121.0137.0168.0PSA (µg/L), n127124433Median91.2118.5174.6Efficacy outcomeOverall survivalMedian, monthsNR12.713.495% CINA10.9–NA11.7–NAHazard ratio (95% CI)0.630 (0.431– 0.922)0.846 (0.584– 1.226)-Time to first SSEMedian, months17.0NR15.895% CI17.0–17.5NA10.9–19.1Hazard ratio (95% CI)0.761 (0.493– 1.173)0.498 (0.294– 0.845)-NR/A = not reached/available. Open table in a new tab NR/A = not reached/available.

Imaging response during therapy with radium-223 (Ra-223) for castration-resistant prostate cancer (CRPC) with bone metastases (BM): A multicenter analysis.

5057Background: Ra-223 is an alpha emitter that selectively targets BM. Ra-223 is an approved treatment option for CRPC patients (pts) based on a significant improvement in overall survival. The pivotal phase III ALSYMPCA trial did not mandate monitoring of antitumor activity by imaging. We aimed to describe the imaging response in pts treated with Ra-223. Methods: Retrospective evaluation of computed tomography (CT) and bone scintigraphy (BS) of consecutive CRPC pts treated with Ra-223. All patients had scans done at baseline. Patients were treated with Ra-223 in 8 centers across 3 countries. Therapy consisted of standard Ra-223 administration (50 kBq q4 weeks for up to 6 injections). Results: A total of 127 pts were included (median age 72), of which 68% (n = 86) were treated with Ra-223 post docetaxel chemotherapy. A total of 20% (n = 26) of patients received concomitant abiraterone or enzalutamide. 52% (n = 66) patients completed the planned 6 injections. Clinical benefit (improvement of skeletal pain...

AR-V7 and efficacy of abiraterone (Abi) and enzalutamide (Enza) in castration-resistant prostate cancer (CRPC): Expanded analysis of the Johns Hopkins cohort.

5012Background: We previously reported an association between ARV7 detection and poor outcomes with Abi/Enza in 62 CRPC pts (NEJM 2014). Here, we expand our analysis to 202 pts, and also report the...

PD32-05 PHASE I CLINICAL STUDY ON THE COMBINATION THERAPY OF CHP-NY-ESO-1 CANCER VACCINE AND MIS416 FOR THE TREATMENT OF PATIENTS WITH NY-ESO-1 EXPRESSING REFRACTORY UROTHELIAL CANCER OR CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2016PD32-05 PHASE I CLINICAL STUDY ON THE COMBINATION THERAPY OF CHP-NY-ESO-1 CANCER VACCINE AND MIS416 FOR THE TREATMENT OF PATIENTS WITH NY-ESO-1 EXPRESSING REFRACTORY UROTHELIAL CANCER OR CASTRATION-RESISTANT PROSTATE CANCER Takeshi Sasaki, Mikiya Ishihara, Hideki Kanda, Yasuhide Hori, Norihito Soga, Naozumi Harada, Yoshihiro Miyahara, Shinichi Kageyama, Hiroshi Shiku, and Yoshiki Sugimura Takeshi SasakiTakeshi Sasaki More articles by this author , Mikiya IshiharaMikiya Ishihara More articles by this author , Hideki KandaHideki Kanda More articles by this author , Yasuhide HoriYasuhide Hori More articles by this author , Norihito SogaNorihito Soga More articles by this author , Naozumi HaradaNaozumi Harada More articles by this author , Yoshihiro MiyaharaYoshihiro Miyahara More articles by this author , Shinichi KageyamaShinichi Kageyama More articles by this author , Hiroshi ShikuHiroshi Shiku More articles by this author , and Yoshiki SugimuraYoshiki Sugimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.681AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES NY-ESO-1 antigen is a cancer-testis antigen that is exclusively expressed in several types of cancer, aside from expression in the normal testis and placenta. This antigen is considered an ideal target for cancer immunotherapy. Cholesteryl pullulan (CHP) is a novel antigen delivery system. Complexes of CHP and NY-ESO-1 antigen (CHP-NY-ESO-1) present multiple epitope peptides to both the MHC class I and class II pathways. MIS416 is a non-toxic microparticle adjuvant that activates immune responses via NOD-2 and TLR9 pathways. Vaccination studies in mice had demonstrated that CHP-NY-ESO-1 with MIS416 enhanced anti-tumor efficacy. This study evaluated the safety, tolerability, and clinical efficacy of CHP-NY-ESO-1 with adjuvant MIS416 in NY-ESO-1-expressing patients (pts) with refractory urothelial cancer (UC) or castration-resistant prostate cancer (CRPC) (Clinical trial registration number, UMIN000005246). METHODS Archival or newly obtained tumor samples from pts were screened for NY-ESO-1 expression using immunohistochemistry and RT-PCR. Eligible pts were those with NY-ESO-1 expression in ≥1% of tumor cells and/or ≥NY-ESO-1 1 copy/GADPH 104 copy. Pts received CHP-NY-ESO-1/MIS416 100 μg/200 μg, 200 μg/200 μg, 200 μg/400 μg, or 200 μg/600 μg every 2 wk 6 doses followed by every 4 wks vaccination until disease progression or unacceptable toxicity was observed. Response was assessed at 12 wks by CT and bone scan per RECIST v1.1 and serum PSA levels. The primary endpoints were safety and tolerability, and the secondary endpoints were clinical efficacy and quality of life. RESULTS A total of 16 pts were enrolled (4 pts with UC and 12 pts with CRPC). Median age was 74 y (range, 48-84). All pts had prior therapies (chemotherapy, radiation, and/or surgery). Five were repeatedly vaccinated with 100 µg (median 4.5 [1-7] doses) and 10 pts with 200 μg (6 [3-37] doses) of CHP-NY-ESO-1. Ten pts (63%) received ≥6 doses. One pt remains on therapy. G1-2 drug-related adverse event (AE) was observed in all pts, most commonly injection site reaction (n = 16), malaise (n = 3), sinus tachycardia (n = 3), and hyperkalemia (n = 3). Grade 3 drug-related AEs were observed in 5 pts (31%), hypertension (n = 3) and anorexia (n = 1). No G4 drug-related AEs were observed. All pts with refractory UC had PD <6 doses. In CRPC pts, 4 pts (48%) had SD, 7 pts (58%) had PD, and one pt had N/A. No significant difference was seen in QLQ-C30 symptom score during treatment. CONCLUSIONS CHP-NY-ESO-1 with adjuvant MIS416 demonstrates acceptable safety and tolerability in refractory UC and CRPC pts with promising anti-tumor efficacy in CRPC pts. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e762 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Takeshi Sasaki More articles by this author Mikiya Ishihara More articles by this author Hideki Kanda More articles by this author Yasuhide Hori More articles by this author Norihito Soga More articles by this author Naozumi Harada More articles by this author Yoshihiro Miyahara More articles by this author Shinichi Kageyama More articles by this author Hiroshi Shiku More articles by this author Yoshiki Sugimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...