Prostate-specific Antigen Reduction Research Articles

620P MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors: Preliminary results of phase I cohort expansion

MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody. B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Phase I dose escalation was completed with two dose-limiting toxicities: one neutropenia grade 4 and one grade 3 fatigue of 72 hrs. There was 1 confirmed partial response in a melanoma patient, and 5/9 patients with 50% prostate-specific antigen (PSA) reduction in metastatic castration resistant prostate cancer (mCRPC). The cohort expansion characterizes safety and preliminary efficacy with the recommended phase II dose of 3 mg/kg IV every 3 weeks. Patients with advanced mCRPC, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), and melanoma are eligible for enrollment. Response is evaluated per RECIST v1.1 for all participants. mCRPC tumor response and PSA are evaluated using Prostate Cancer Working Group 2 criteria. The cohort expansion enrolled and dosed 49/80 patients as of May 3, 2021. mCRPC n=26/40, NSCLC, n=16/20, and TNBC n=7/20. At least 1 treatment emergent adverse event occurred in 43 patients (87.7%); the most common (≥10%) were neutropenia/neutrophil count decreased, fatigue, asthenia, palmar plantar erythrodysesthesia, and headache. Febrile neutropenia was not reported. Of 13 mCRPC patients with measurable disease, six were not yet evaluable, and seven had first 9-week imaging. Of the seven, four had reductions in target lesion sums of 13%, 21%, 27%, and 35% (unconfirmed partial response); 12 of the 13 remain on treatment. There are 11/22 evaluable patients with ≥50% PSA reduction. Results to date have demonstrated a manageable safety profile with evidence of clinical activity by PSA and tumor responses in mCRPC. Enrollment is ongoing in advanced mCRPC, NSCLC, TNBC, SCCHN, and melanoma. Updated data will be provided.

PD34-06 SERUM TESTOSTERONE AS A PREDICTIVE BIOMARKER FOR PSA RESPONSE: RESULTS FROM A RANDOMISED TRIAL COMPARING ENZALUTAMIDE WITH ABIRATERONE ACETATE PLUS PREDNISONE

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III (PD34)1 Sep 2021PD34-06 SERUM TESTOSTERONE AS A PREDICTIVE BIOMARKER FOR PSA RESPONSE: RESULTS FROM A RANDOMISED TRIAL COMPARING ENZALUTAMIDE WITH ABIRATERONE ACETATE PLUS PREDNISONE Klara Kvorning Ternov, Jens Sønksen, Mikkel Fode, Henriette Lindberg, Rasmus Bisbjerg, Ganesh Palapattu, and Peter Busch Østergren Klara Kvorning TernovKlara Kvorning Ternov More articles by this author , Jens SønksenJens Sønksen More articles by this author , Mikkel FodeMikkel Fode More articles by this author , Henriette LindbergHenriette Lindberg More articles by this author , Rasmus BisbjergRasmus Bisbjerg More articles by this author , Ganesh PalapattuGanesh Palapattu More articles by this author , and Peter Busch ØstergrenPeter Busch Østergren More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002038.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Baseline serum testosterone has been suggested to be a predictive biomarker of patient important outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). Herein, we investigate the prostate-specific antigen (PSA) treatment response based on baseline testosterone levels in men treated first-line with enzalutamide (ENZ) or abiraterone acetate plus prednisone (AAP) for mCRPC. METHODS: We randomised (1:1) men to ENZ (160 mg/day) or AAP (1000 mg abiraterone acetate and 10 mg prednisone/day) groups, in this investigator-initiated phase IV trial. Eligible patients had progressive metastatic prostate cancer despite castrate levels of testosterone (<1.7nmol/L). The purpose of this trial was to compare side-effects between ENZ and AAP. In this exploratory analysis, patients were grouped according to baseline testosterone levels above the mean or less than or equal to the mean. PSA progression-free survival (PFS) was analysed with Kaplan-Meier and with univariate and multivariable (including treatment, testosterone and PSA) cox regression analyses. PSA response rates (≥50% reduction in PSA) were compared between testosterone groups with Chi-Square test for the entire cohort and treatment subgroups. Serum testosterone was measured by the gold standard assay liquid chromatography–tandem mass spectrometry. RESULTS: 166 patients (82 treated with ENZ and 84 with AAP) were included in the analyses. The mean baseline testosterone was 0.35nmol/L (10ng/dL). Median follow-up was 22.3 months. Men with baseline testosterone above the mean value had longer PSA PFS (16.6 vs. 9.9 months, hazard ratio 0.59, 95% confidence interval 0.41; 0.85, p=0.005). No interaction was found between treatment subgroups in PSA PFS (p=0.635). The PSA response rate was greater in those with higher testosterone compared with those with lower testosterone overall (91% vs 74%, p=0.007). This difference was only statistically significant in the AAP treatment subgroup (table 1). CONCLUSIONS: Baseline serum testosterone seems to be predictive of PSA response in men with mCRPC treated with ENZ or AAP and may be useful for risk stratification of men with mCRPC. Source of Funding: Herlev and Gentofte Hospital, Herlev, Denmark © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e584-e585 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Klara Kvorning Ternov More articles by this author Jens Sønksen More articles by this author Mikkel Fode More articles by this author Henriette Lindberg More articles by this author Rasmus Bisbjerg More articles by this author Ganesh Palapattu More articles by this author Peter Busch Østergren More articles by this author Expand All Advertisement Loading ...

1632P At home androgen deprivation therapy for patients with prostate cancer during the COVID-19 pandemic. One center experience

COVID-19 pandemic created major challenges in cancer care. Studies have shown increased risk for COVID-19 infectivity, severe disease and death in patients with cancer. Cancer centers worldwide adapted by modifying and often delaying treatment to minimize contact with patients. To provide safe and uninterrupted care for patients, a home care program was created for patients with prostate cancer at Acad. F. Todua Medical center. Men with locally advanced or metastatic prostate cancer (MPC) receiving androgen deprivation therapy (ADT) were enrolled. Patients and their caretakers were instructed on gonadotropin-releasing hormone (GnRH) subcutaneous injections (SQ) for home administration. Monthly at home laboratory testing and virtual consultations with medical oncologists every 1-3 months were arranged. A total of 52 patients were enrolled during the period of March 2020 – March 2021. All men were White and had ECOG 0/1. The mean age was 71 [±6.3 y] years. Sixteen (31%) patients had stage IIIB PC and 36 (69%) patients had stage IV disease. Stage IIIB patients were receiving adjuvant ADT with SQ Goserelin Acetate 10,8mg every 8 weeks and bicalutamide 50mg daily for two weeks after definitive local treatment. Thirty-one (86%) patients had hormone sensitive metastatic PC and were receiving SQ Goserelin Acetate 10.8mg (28) every 8 weeks or SQ Leuprolide Acetate 22,5mg every 8 weeks (3) with 2 weeks of Bicalutamide 50mg daily. Five (14%) patients had castration resistant (CR) PC and were receiving SQ Goserelin Acetate 10,8mg every 8 weeks with Enzalutamide 160mg daily. Thirty-three (63%) patients had Gleason’s score of 8/9. All patients were compliant with home injections, laboratory tests and virtual physician visits. Thirty-nine (75%) patients administered injections by themselves. Forty-two (80%) patients had PSA reduction >50%. Ten (20%) patients had disease progression and required clinic visits for investigations. Median time to progression was 12 months. Only 1 (2%) patient acquired COVID-19 infection, was hospitalized and died of respiratory failure. At home ADT with appropriate patient/caregiver education and close follow up may be safe for patients with PC during the COVID-19 pandemic.

Enzalutamide in patients with castration-resistant prostate cancer: retrospective, multicenter, real life study.

BACKGROUND Metastatic castration-resistant prostate cancer (mCRPC) is the final stage of pCa history and represents a clinically relevant phenotype with an elevated burden of mortality. The aim of the present study was to evaluate the efficacy and safety of enzalutamide in a real-life setting in mCRPC patients. METHODS Data about all mCRPC patients treated with enzalutamide from September 2017 to September 2018 were collected. Demographics, comorbidities, clinical parameters, outcomes, toxicity, overall survival and progression free survival were analyzed. RESULTS Overall, 158 patients were enrolled. Mean age was 75.8 (±8.7) years with a baseline median PSA of 16.5 (IQR 7.4-47.8) ng/mL. The median follow-up lasted 7.7 (IQR 4-14.1) months. Of all the 10.1% of patients reported grade 3-4 adverse events. 43.7% of patients experienced a progression. Overall, the 6 and 12 months PFS rates were 69.5% (95% CI: 61.7-78.3%) and the 45.6% (95% CI: 36.5-57.1%); a median baseline PSA>16 ng/mL (HR:2.0, 95% CI: 1.2-3.3, P<0.005), the use of opioid (HR: 3.1, 95% CI: 1.9-5.0, P<0.001), a previous treatment (abiraterone, docetaxel or abiraterone + docetaxel) were significantly associated with higher rates of cancer progression. Conversely, a brief pain questionnaire of 0-1 (HR: 0.4, 95% CI: 0.2-0.7, P<0.001), a 12 weeks 50% PSA reduction (HR: 0.4, 95% CI: 0.2-0.8, P<0.006) and a longer time to mCRPC (HR: 0.4, 95% CI: 0.3-0.7, P<0.002) were related to lower cancer progression rates. CONCLUSIONS Our data shows an effective and safe profile of enzalutamide in a real world perspective in patients with mcRPC.

MP09-11 GREENLIGHT LASER PROSTATECTOMY: ARE OUTCOMES SUSTAINABLE AFTER A DECADE OF SURGERY? A SINGLE CENTER EXPERIENCE WITH UP TO 15 YEARS' FOLLOW-UP

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Surgical Therapy & New Technology II (MP09)1 Sep 2021MP09-11 GREENLIGHT LASER PROSTATECTOMY: ARE OUTCOMES SUSTAINABLE AFTER A DECADE OF SURGERY? A SINGLE CENTER EXPERIENCE WITH UP TO 15 YEARS' FOLLOW-UP Ahmed Ibrahim, Nawar Touma, Ahmad M. AlShammari, Serge Carrier, and Mélanie Aubé-Peterkin Ahmed IbrahimAhmed Ibrahim More articles by this author , Nawar ToumaNawar Touma More articles by this author , Ahmad M. AlShammariAhmad M. AlShammari More articles by this author , Serge CarrierSerge Carrier More articles by this author , and Mélanie Aubé-PeterkinMélanie Aubé-Peterkin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001982.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Since its introduction in 2005, GreenLight laser has been widely adopted as a convenient source of energy for surgical treatment of benign prostatic hyperplasia (BPH). However, there is paucity in the literature quantifying long-term outcomes (>10 years) of GreenLight laser prostatectomy. Herein, we report our single-center experience with long-term outcomes over a period of 15 years. METHODS: Between 2005 and 2020, a prospectively maintained database for patients undergoing GreenLight photovaporization of the prostate (PVP) for symptomatic BPH was reviewed. Three Generations of Green Light Laser were used over this time period. Patients with ≥10-years follow-up were included. Demographic and perioperative data were collected together with the International Prostate Symptoms Score (IPSS), Quality of Life (QoL), peak flow rate (Qmax), post-void residual urine (PVR), and PSA changes. In addition, perioperative and late adverse events were recorded. RESULTS: After a mean follow-up of 12.1 years (10-15 years), 124 patients were included with a mean age of 73.9 (range: 54- 85) years and a mean preoperative prostate size of 72.4±15.3mL. Demographic and perioperative data are presented in Table 1. Blood transfusion rate was 2.4%. Development of bladder neck contracture and urethral stricture were encountered in 7 (5.6%) and 9 (4.3%) of patients. 6 (4.8%) patients required repeat surgery for adenoma regrowth. Additionally, there were significant reductions in mean IPSS, QoL and PVR (60.4% and 65%, and 72.6%, respectively) (p <0.001). Likewise, there was a significant increase in Qmax (8.2 to 17.7 ml/s, p <0.001) with PSA reduction by 64.2 % compared to its baseline value. CONCLUSIONS: Our long-term functional outcomes support the durability of the GreenLight laser prostatectomy with acceptable long-term adverse events after a decade of surgery. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e163-e164 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ahmed Ibrahim More articles by this author Nawar Touma More articles by this author Ahmad M. AlShammari More articles by this author Serge Carrier More articles by this author Mélanie Aubé-Peterkin More articles by this author Expand All Advertisement Loading ...

MP01-13 GREENLIGHT (532 nm) LASER TRANSURETHRAL PROSTATECTOMY FOR TREATMENT OF BENIGN PROSTATE OBSTRUCTION USING XPS-180 WATT SYSTEM, DOES IT PASS THE TEST OF TIME?

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Surgical Therapy & New Technology I (MP01)1 Sep 2021MP01-13 GREENLIGHT (532 nm) LASER TRANSURETHRAL PROSTATECTOMY FOR TREATMENT OF BENIGN PROSTATE OBSTRUCTION USING XPS-180 WATT SYSTEM, DOES IT PASS THE TEST OF TIME? Fady Ghobrial, Mahmoud Laymon, Mohamed Soltan, Ahmed Abolazm, Nasr El-Tabey, and Ahmed Elshal Fady GhobrialFady Ghobrial More articles by this author , Mahmoud LaymonMahmoud Laymon More articles by this author , Mohamed SoltanMohamed Soltan More articles by this author , Ahmed AbolazmAhmed Abolazm More articles by this author , Nasr El-TabeyNasr El-Tabey More articles by this author , and Ahmed ElshalAhmed Elshal More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001962.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To evaluate efficacy and durability of greenlight laser (XPS-180watt) based prostatectomy for treatment of benign prostatic obstruction (BPO). The need for medical and or surgical retreatment for recurring or residual BPO as well as their predictors will be assessed. METHODS: After IRB approval, a prospectively maintained database was established for patients with BPO for whom greenlight laser photoselective vaporization (PVP) and vapoenucleation (PVEP) of the prostate were carried out between August 2014 to March 2018. Patients’ perioperative data and urinary functional outcome parameters and postoperative complications were depicted. The need for retreatment was assessed and its predictors retreatment were evaluated. RESULTS: This study included 248 patients, 157 (63.3%) and 91(36.7%) patients underwent PVP and PVEP with mean prostate volume (60±18 and 100±22 ml) respectively. Mean ±SD follow up duration was 62±9 months. At last point follow up, mean ±SD percentage of improvement in IPSS was 61±28 and 78±20 p=0.03, median (range) percentage of improvement in Q max was 119(-13-549) and 123(-13-649) % p=0.2 and median (range) percentage of PSA reduction was 63(-172-99) and 65(-75-97) % p=0.7 for PVP and PVEP groups respectively. Overall retreatment rate (medical and surgical) was 23% (57 patients), 38 (24.2%) after PVP and 19 (20.9%) after PVEP, p=0.5. The need surgical retreatment was statistically significant more after PVP (table 1). Median (range) time to event (defined as medical or surgical re-intervention) was 20 (1-60) for all cases, 3.5 (0-42) and 30 (18-60) months p= 0.7 for PVP and PVEP groups respectively. On multivariate analysis, only percent reduction of one-year post-operative PSA was a significant predictor of need for retreatment (surgical/ medical) of recurring or residual BPO (P 0.021, 95% CI 0.018-0.024). The cutoff point was 64.2% (58.2% sensitivity, 73.4% specificity, AUC 0.647, 95% CI 0.52-0.76) above it there is less probability for having BPO retreatment. CONCLUSIONS: Greenlight laser prostatectomy using XPS-180Watt is an effective and versatile tool in treating BPO. Durability of the outcome is predictable with more postoperative PSA reduction. Source of Funding: No funding © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e5-e6 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fady Ghobrial More articles by this author Mahmoud Laymon More articles by this author Mohamed Soltan More articles by this author Ahmed Abolazm More articles by this author Nasr El-Tabey More articles by this author Ahmed Elshal More articles by this author Expand All Advertisement Loading ...

PD44-11 THERAPEUTIC POTENTIAL OF NITRIC OXIDE AGAINST NEUROENDOCRINE PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (PD44)1 Sep 2021PD44-11 THERAPEUTIC POTENTIAL OF NITRIC OXIDE AGAINST NEUROENDOCRINE PROSTATE CANCER Fabio Frech, Omar Rosete, Khushi Shah, Fakiha Firdaus, Joshua Hare, Ranjith Ramasamy, and Himanshu Arora Fabio FrechFabio Frech More articles by this author , Omar RoseteOmar Rosete More articles by this author , Khushi ShahKhushi Shah More articles by this author , Fakiha FirdausFakiha Firdaus More articles by this author , Joshua HareJoshua Hare More articles by this author , Ranjith RamasamyRanjith Ramasamy More articles by this author , and Himanshu AroraHimanshu Arora More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002058.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. The underlying mechanisms and effective therapies against NEPC are largely underexplored. We showed that S-nitrosoglutathione (GSNO), an NO donor, reduced CRPC tumor burden by targeting the tumor microenvironment (TME). In the present study, we evaluated the impact of increased nitric oxide on NEPC reduction. We hypothesized that increased nitric oxide reduces NEPC tumor burden by suppressing NEPC TME. METHODS: Cell proliferation assay (MTT) was performed using H660 cells (NEPC cells) in the presence of increasing concentration of GSNO (from 0, 5, 10, 25, 50, 100, 200, and 500 uM respectively). Expression of neuroendocrine and proliferative markers (chromogranin A, synaptophysin, and pERK) was checked at RNA and protein levels after treating H660 cells with increasing concentrations of GSNO (from 0, 25, 50, 100, 200, and 500uM respectively). For in-vivo experiments, castrated SCID mice were grafted with H660 cells (3 million) to generate NEPC murine models. Once tumors became palpable, the animals were divided into two groups. Group 1 received vehicle control and group 2 received GSNO treatment at the dosage of 10 mg/kg/day intraperitoneally (IP). Treatment was performed daily for two weeks and tumor growth was monitored until tumor reached 1000 mm3 size. Subsequently, tumors and blood were extracted; proteins were harvested from the tumors to study the expression of neuroendocrine markers and markers of cancer progression. Animal experiments were carried out in compliance with the Institutional Animal Care and Use Committee of University of Miami. Molecular analyses were performed using standard procedures. GraphPad Prism (GraphPad Software) was used for statistical analysis. All data were presented as the means±SEM. The statistical significance between two groups was estimated by unpaired two-tailed t test. RESULTS: Cell proliferation assay showed that increase NO levels suppresses H660 cell proliferation with increasing doses. In-vivo results showed that treatment with GSNO in castrated SCID mice treated with H660 cells showed a significant decrease (p<0.05) in tumor volume compared to the mice which received PBS. Proteins from the tumors showed that GSNO induces a reduction in chromogranin A and synaptophysin (neuroendocrine markers) compared to control. Moreover, immunohistochemistry results showed a significant reduction in synaptophysin, PSA and CD206 levels. CONCLUSIONS: This study shows that GSNO decreases NEPC tumor volume and H660 cell proliferation. GSNO is known to reduce tumor burden in CRPC through interaction with the TME. Further studies investigating the mechanism of effect of nitric oxide in NEPC through the targeting of the TME are in process. Source of Funding: Clinician Scientist Development award from American Cancer Society to RR and Research Scholar Award from American Urological Association to HA © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e741-e741 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fabio Frech More articles by this author Omar Rosete More articles by this author Khushi Shah More articles by this author Fakiha Firdaus More articles by this author Joshua Hare More articles by this author Ranjith Ramasamy More articles by this author Himanshu Arora More articles by this author Expand All Advertisement Loading ...

Outcome of 177Lu-PSMA-617 Radioligand Therapy in Chemo-Refractory Patients with Metastatic Castration-Resistant Early-Onset Prostate Cancer.

Simple SummaryThe risk of prostate cancer development, the second most commonly occurring cancer in men overall, increases strongly with age. About 10% of patients, however, are diagnosed with early-onset prostate cancer (age at diagnosis: ≤55 years). This is considered to be a distinct clinical and pathological phenotype with a poor prognosis. Generally, prostate cancer cells express high quantities of prostate-specific membrane antigen (PSMA) on their surface. Radioligand therapy is a type of treatment, which, among other available agents, uses the beta-emitting radionuclide 177Lutetium (177Lu) and a PSMA-targeting ligand termed PSMA-617 for internal irradiation of metastatic prostate cancer cells. The aim of our retrospective study was to assess the efficacy and safety of radioligand therapy with 177Lu-PSMA-617 in early-onset metastasized castration-resistant prostate cancer patients refractory to chemotherapy. Special emphasis was placed on the patients’ response to the treatment and survival. The study provides support for the expected shorter survival compared to heterogenous patient groups.The aim of this retrospective study was to assess the outcome of patients with metastasized castration-resistant early-onset prostate cancer refractory to chemotherapy receiving radioligand therapy with 177Lutetium-PSMA-617 (LuPSMA-RLT). Twenty-five patients of ≤55 years of age at prostate cancer diagnosis, treated with a median of four (IQR 2–6) cycles (mean of 7.7 ± 1.4 GBq per cycle) every 6–8 weeks, were analyzed. Survival outcome was calculated based on the Kaplan–Meier method. The median progression-free survival (PFS) was 3.8 months (95% CI 2.3–5.3), and overall survival (OS) was 8.5 months (95% CI 6.2–10.8). An initial PSA reduction (≥ 50%) was observed in 9/25 (36%) of patients without being significantly associated with OS (p = 0.601). PSA response (PSA decline ≥50% at 12 weeks) was observed in 12/25 (48%) of patients and significantly associated with longer OS (16.0 months, 95% CI 7.4–24.6 vs. 4.0 months, 95% CI 1.1–6.9, p = 0.002). Imaging-based response using 68Ga-PSMA-11-PET/CT after two to three cycles was seen in 11/25 (44%). Additionally, responders had a significantly longer median PFS (8.7 months, 95% CI 1.3–16.1 vs. 1.9 months, 95% CI 1.7–2.2, p < 0.001) and OS (16.0 months, 95% CI 7.6–24.4 vs. 4.0 months, 95% CI 0.9–7.1; p = 0.002). Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade ≥ 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade ≥ 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline ≥ 1) in 8/17 (47%) of patients. Compared to previous reports, radioligand therapy with 177Lu-PSMA-617 in metastasized castration-resistant early-onset prostate cancer patients refractory to chemotherapy yields similar response rates with a comparable safety profile, but is associated with shorter survival.

High Tumor Burden Predicts Poor Response to Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients

Simple SummarySeveral available medications are involved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). In this Taiwanese mCRPC cohort receiving enzalutamide patients with high tumor burden (HTB) were defined as those with either appendicular bony metastasis or visceral metastasis. A high tumor burden reduced the PSA response rate, radiological response rate, and progression-free survival duration. In addition, patients’ comorbidities and laboratory data—such as ALP, LDH, ALT, and hemoglobin—were correlated with the treatment efficacy of enzalutamide. Our study revealed a tumor burden before the use of enzalutamide was associated with treatment outcomes. The physician can use this information to estimate the response rate of enzalutamide and help formulate a personalized treatment plan for mCRPC patients.To assess the predictive value of tumor burden on the biochemical response, and radiological response in Taiwanese metastatic castration-resistant prostate cancer (mCRPC) patients receiving enzalutamide. The mCRPC patients treated with enzalutamide were recruited from three hospitals. High tumor burden (HTB) was classified as metastases at either appendicular bone or visceral organ. Good prostate-specific antigen (PSA) response was defined as PSA reduction of 80%. In this cohort, there were 104 (54.2%) HTB patients and 88 (45.8%) with low tumor burden (LTB). Compared to LTB patients, fewer HTB patients had good PSA response (odds ratio: 0.43, range: 0.22–0.87, p = 0.019) and fewer radiological response (complete and partial remission) (odds ratio: 0.78, range: 0.36–1.68, p = 0.52) to enzalutamide. The disease control rate which also contained stable disease, was still lower in HTB (76.0%) than LTB group (92.9%, OR: 0.24, range: 0.07–0.77, p = 0.016) in the multivariable model. In addition, HTB patients had significantly shorter progression–free survival duration than did LTB patients (median: 8.3 vs. 21.6 months, log-rank test p = 0.003) in the univariable analysis. The tumor burden before the use of enzalutamide was associated with treatment outcomes. HTB reduced PSA response rate, radiological response rate and progression-free survival duration.

Prognostic significance of third-line treatment for patients with metastatic castration-resistant prostate cancer: comparative assessments between cabazitaxel and other agents.

Cabazitaxel has played an important role in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC); however, several types of sequential therapy against mCRPC have been performed in routine clinical practice. The objective of this study was to investigate the impact of third-line treatment on prognostic outcomes of mCRPC patients. This study retrospectively analyzed the clinical outcomes of 166 patients who received 3 agents following the diagnosis of mCRPC, consisting of 81 sequentially treated with either abiraterone or enzalutamide and then docetaxel, followed by third-line cabazitaxel (group A) and 85 treated with 3 agents, including abiraterone, enzalutamide, and docetaxel (group B). There were no significant differences in major characteristics at the introduction of the third-line agent between these 2 groups. The proportion of patients with prostate-specific antigen (PSA) reduction > 50% by cabazitaxel in group A was significantly greater than that by either third-line agent in group B. Both PSA progression-free survival (PFS) and overall survival (OS) following third-line therapy in group A were significantly longer than those in group B. Furthermore, OS after the diagnosis of mCRPC in group A was significantly longer than that in group B. Multivariate analysis identified independent predictors of favorable prognostic outcomes after third-line therapy as follows: high-performance status (PS), low PSA level and third-line cabazitaxel for PSA PFS, and high PS, low lactate dehydrogenase level and third-line cabazitaxel for OS. The introduction of cabazitaxel as a third-line agent could markedly improve the prognostic outcomes of mCRPC patients.

Are all procedures for benign prostatic hyperplasia created equal? A systematic review on post-procedural PSA dynamics and its correlation with relief of bladder outlet obstruction.

To evaluate and provide a comprehensive literature review of Prostate specific antigen (PSA) dynamics after various surgical procedures for benign prostatic hyperplasia (BPH). A thorough PubMed database search was performed over last 30years including terms "PSA" and various surgical procedures for BPH. PSA nadir after various procedure was evaluated. The post-operative improvement in International Prostate Symptom Score, maximum void rates and post-void residue after surgeries were recorded. An indirect correlation was made between PSA nadir and outcome of various BPH surgical procedures. Enucleation procedures like simple prostatectomy and endoscopic enucleation of prostate (EEP) produced maximum drop in PSA level after surgery and were associated with the highest improvement in post-operative parameters. The PSA nadir following resection techniques like transurethral resection of prostate and Holmium laser resection of prostate and vaporization technique was variable and less robust when compared to EEP. Newer techniques like Aquablation, Rezum, Urolift, Prostate artery embolization and Temporary implantable nitinol devices (iTIND) produce relatively less reduction in PSA and lesser percentile improvement in post-operative parameters. Various surgical procedures for BPH result in varying PSA nadirs level. Enucleation procedures and simple prostatectomy produce the most drastic and sustained decrease in PSA. There is a possible indirect evidence suggesting that the level of PSA nadir corresponds closely with the degree of post-operative improvement and durability of the procedure. Establishing the new PSA nadir at 3-6months after the procedure is recommended as a part of routine surveillance for prostate cancer in eligible patients.

Development and internal validation of multivariable prediction models for biochemical failure after MRI-guided focal salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer

Background and purposeMagnetic resonance-guided focal salvage high-dose-rate brachytherapy (FS-HDR-BT) for radiorecurrent prostate cancer (PCa) shows low toxicity rates. However, biochemical failure (BF) after treatment occurs frequently. We developed two prediction models for BF (Phoenix definition) with the aim of enhancing patient counselling before FS-HDR-BT and during follow-up. Materials and methodsA prospective cohort of 150 radiorecurrent PCa patients treated with FS-HDR-BT between 2013 and 2020 was used for model development and internal validation. Multivariable Cox Proportional Hazards regression was applied. For model 1, only pre-salvage variables were included as candidate predictors. For model 2, additional (post-)salvage characteristics were tested. After calibration, nomograms and webtools were constructed. Finally, three risk groups were identified. ResultsSixty-one patients (41%) experienced BF. At baseline (model 1), age, gross tumour volume, pre-salvage PSA, and pre-salvage PSA doubling time (PSADT) were predictive of BF. During follow-up (model 2), age, pre-salvage PSA and PSADT, seminal vesicle involvement, post-salvage time to PSA nadir, and percentage PSA reduction were predictive of BF. The adjusted C-statistics were 0.73 (95% CI: 0.66–0.81) and 0.84 (95% CI: 0.78–0.90), respectively, with acceptable calibration. Estimated 2-year biochemical disease-free survival for the low-, intermediate-, and high-risk groups were 84%, 70%, and 31% (model 1), and 100%, 71%, and 5% (model 2). ConclusionTwo models are provided for prediction of BF in patients with radiorecurrent PCa treated with FS-HDR-BT. Based on pre- and post-salvage characteristics, we are able to identify patients with a high risk of BF. These findings can aid patient counselling for FS-HDR-BT.

P1056 - The percentage of prostate-specific antigen reduction after high-intensity focused ultrasound for primary localized prostate cancer as a predictive parameter for treatment failure: A validation study

P1056 - The percentage of prostate-specific antigen reduction after high-intensity focused ultrasound for primary localized prostate cancer as a predictive parameter for treatment failure: A validation study

Effect of immunotherapy on survival outcomes in prostate cancer: Systematic review and meta-analysis.

e17030 Background: Prostate cancer is one of the leading cancers in men with an estimated 191,930 new cases in 2020 in the USA alone. Treatment options for metastatic castration resistant prostate cancer (mCRPC) have evolved in recent years. Immunotherapy involving vaccines like sipuleucel-T, PROSTVAC and immune checkpoint inhibitors have been evaluated in these patients. We present a systematic review and meta-analysis of the randomized controlled trials (RCTs) testing the effect of immunotherapy in mCRPC. Methods: A systematic search was performed using PubMed, Embase and the Cochrane library without language limitations from inception to January 3, 2021. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), prostate specific antigen (PSA) reduction ≥ 50% and incidence of grade 3-4 adverse events. The analysis of OS, PFS was done using random effects hazard ratio (HR) by generic inverse variance method and analysis of PSA reduction ≥ 50% and grade 3-4 adverse events was done using random effects risk ratio (RR) by the Mantel-Haenszel method. Results: 12 RCTs comprising 4109 patients were included in the analysis. There was a statistically significant improvement in OS (HR 0.89; 95% CI (0.81, 0.97)) and PFS (HR 0.83; 95% CI (0.76, 0.92)) in the immunotherapy arm compared to placebo or standard treatment arms with moderate quality of evidence. Patients in the immunotherapy group had significant reduction in PSA ≥ 50% (RR 1.71; 95% CI (1.09, 2.68)) but also had statistically significant increased risk of grade 3-4 adverse events (RR (1.25; 95% CI (1.02, 1.54)) when compared to placebo and the standard treatment group. Subgroup analysis showed that the use of vaccine therapy in prostate cancer leads to significant improvement in OS (HR 0.83; 95% CI (0.74, 0.93)) and PFS (HR 0.80; 95% CI (0.67, 0.95)) compared to placebo and standard treatment. The use of immune checkpoint inhibitors was not associated with statistically significant improvement in OS (HR 0.98; 95% CI (0.88, 1.09)) but is associated with improvement in PFS (HR 0.87; 95%CI (0.81, 0.94)). Conclusions: This meta-analysis showed that immunotherapy led to significant improvement in OS, PFS and PSA reduction of ≥ 50%. However, there is an increased incidence of grade 3-4 adverse events with the use of immunotherapy when compared to other standard therapies and placebo. The improvement in overall survival is limited to the use of vaccine therapy and not to immune checkpoint inhibitors. Careful use of selective forms of immunotherapy in mCRPC can lead to greater improvement in survival.

Biomarker analysis of phase (Ph) IB trial of radium-223 (Rad) and niraparib (Nira) in patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) (NiraRad).

5036 Background: Rad is an alpha particle emitter that causes DNA double strand breaks and has been FDA-approved for use in mCRPC pts with bone metastases. PARP-1 activity critically supports androgen receptor (AR) activity in mCRPC and potentiates AR-dependent DNA damage response pathways that promote prostate cancer cell survival. Nira is a potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in mCRPC. We previously reported the safety of targeting the PARP-1/AR axis with Nira in combination with Rad. Herein we describe the results of an exploratory biomarker analysis. Methods: The primary objective of NiraRad is to determine the optimum Ph II dose of Nira plus Rad (55 kBq/kg of body weight IV every 4 weeks (wks) x 6) in pts with and without prior chemotherapy (docetaxel). Pts were enrolled to one of three dose levels of Nira (100, 200, or 300 mg PO daily). All cohorts were combined for exploratory biomarker analysis using Nanostring PanCancer Driver and Immune Pathways panels and the nSolver Advanced analysis module was performed on blood obtained from 23 pts at baseline, cycle (C) 1 day (D) 15, and C3D15. A favorable response was defined as any PSA reduction at week 12 or treatment (tx) duration &gt; 18 wks, the median time on tx in the cohort of pts analyzed. A threshold of &gt; 2 fold (X) differentially expressed genes was used. Results: Of the 23 pts with biomarker data, 7 (30%) experienced PSA reductions and 11 (48%) received tx for &gt; 18 wks, 6 of which also had PSA reductions. Exploratory analysis revealed that the PI3K/Ras, MAPK, and transcriptional misregulation pathways were differentially regulated in pts who had favorable responses. The top downregulated gene, PAX5, which has been shown to promote prostate cancer growth, was decreased at C1D15 (2.7X, p &lt; 0.01) and C3D15 (4.8X, p &lt; 0.001) in pts with tx duration &gt; 18 wks and at baseline in pts who had PSA reductions (3.1X, p &lt; 0.05). Immune pathways analysis suggested downregulation of immunosuppressive B-cell (plasma cell) and upregulation of NK and T cell pathways in pts with tx duration &gt; 18 wks. Conclusions: Previously Nira and Rad have been shown to have acceptable tolerability in mCRPC pts. This exploratory analysis suggests potential response biomarkers that warrant further investigation. Managed by: the Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Pharmaceuticals and Bayer Healthcare Pharmaceuticals, Inc. Clinical trial information: NCT03076203.

Real-world outcomes among prostate cancer patients with BRCA2 gene variants compared to variants in other homologous DNA repair genes.

e17033 Background: PARP inhibitors (PARPis) were approved by the FDA for the treatment of advanced prostate cancer (PC) among patients (pts) harboring mutations in genes responsible for homologous DNA repair. Increasing evidence has suggested that pts with BRCA2 gene alterations may derive the most benefit from these drugs. Study objectives were to evaluate real-world treatment outcomes among Veterans prescribed PARPis for PC and to compare outcomes between pts with BRCA2 gene variants and those with variants in other homologous DNA repair genes. Methods: The U.S. Department of Veterans Affairs (VA) National Precision Oncology Program database was reviewed to identify PC pts who successfully underwent tumor DNA sequencing and were prescribed olaparib, rucaparib, niraparib or talazaporib prior to FDA approval for PARPi use in PC (May 15, 2020). Only pts who received a PARPi for &gt; 4 weeks were included in outcome assessments The VA’s Corporate Data Warehouse was reviewed to obtain clinical and disease characteristics, laboratory and imaging reports, and treatments administered. Assessed outcomes included PSA30, defined as the percentage of pts achieving 30% reduction in prostate-specific antigen (PSA) level, and composite progression-free survival (PFS), which included time to radiographic progression per RECIST criteria, discontinuation of therapy, and/or death. Pts who discontinued therapy due to toxicity were censored for PFS analyses. PSA30 and PFS were compared between pts bearing BRCA2 gene variants and those with variants in other homologous DNA repair genes using t-testing and log-rank testing, respectively. Results: 48 pts were prescribed a PARPi for PC; 43 (89.6%) received therapy for &gt; 4 weeks. BRCA2 gene variants (43.8%) were most commonly observed followed by ATM (23.0%) and BRCA1 (16.7%). Forty-two pts (87.5%) received prior systemic therapy beyond androgen deprivation. Forty (83.3%) pts received olaparib, 6 (12.5%) received rucaparib, and 2 (4.2%) received both. Eleven (22.9%) discontinued therapy due to toxicity, with anemia being most common toxicity. Of the 43 pts treated for &gt; 4 weeks, pts with BRCA2 variants had a higher rate of PSA30 than those without (47.9% vs. 4.5%; p = 0.004). The median PFS for all pts was 4.0 months. Pts with BRCA2 gene variants had longer PFS than those without BRCA2 gene variants (7.2 vs 3.3 months; p = 0.037). Pts with BRCA2 gene variants also had longer PFS than those with BRCA1 variants (7.2 vs 3.3, p = 0.031). No difference was observed in PFS between those with BRCA2 variants and those with ATM variants ( p = 0.51). Conclusions: Approximately one-quarter of PC pts with variants in homologous DNA repair genes treated with PARPis achieve a 30% reduction in PSA, and the median PFS is 4 months. Pts harboring BRCA2 gene variants have a significantly higher rate of PSA30 and a longer PFS than those with variants in other homologous DNA repair genes.

CheckMate 9KD cohort A1 final analysis: Nivolumab (NIVO) + rucaparib for post-chemotherapy (CT) metastatic castration-resistant prostate cancer (mCRPC).

5044 Background: CheckMate 9KD is a phase 2 trial of NIVO (anti-PD-1) combined with either rucaparib, docetaxel, or enzalutamide for mCRPC. PARP inhibitors, like rucaparib, increase cellular DNA damage, particularly in tumors with DNA repair defects, leading to genomic instability and cell death. This DNA damage promotes immune priming and adaptive PD-L1 upregulation. Consequently, dual PD-(L)1 and PARP inhibition is a plausible therapeutic strategy for mCRPC. We report final results for cohort A1 (NIVO + rucaparib for post-CT mCRPC) of CheckMate 9KD. Methods: Cohort A1 enrolled patients (pts) with post-CT mCRPC (1–2 prior taxane regimens), ongoing ADT, ≤ 2 prior novel hormonal therapies (abiraterone, enzalutamide, etc) for mCRPC, and no prior PARP inhibitor treatment. Pts received NIVO 480 mg Q4W + rucaparib 600 mg BID until disease progression/unacceptable toxicity (NIVO dosing limited to 2 yrs). Coprimary endpoints: objective response rate (ORR) per PCWG3 criteria and prostate-specific antigen response rate (PSA-RR; ≥ 50% PSA reduction) in all treated pts and pts with homologous recombination deficiency positive (HRD+) tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Of 88 treated pts, median age 66 yrs (range, 46–85), 34.1% had visceral metastases and 65.9% had measurable disease. Median follow-up was 11.9 mo. Pts had a median of 4.5 NIVO doses and 3.8 mo of rucaparib. The table summarizes primary and key secondary efficacy results, and shows better outcomes for HRD+ vs HRD–/not evaluable (NE) tumors. In pts with BRCA2 mutations, confirmed ORR was 37.5% (3/8 pts) and confirmed PSA-RR was 45.5% (5/11 pts). Any-grade treatment-related AEs (TRAEs) occurred in 93.2% of pts, most commonly nausea (40.9%) and fatigue (33.0%). Grade ≥ 3 TRAEs occurred in 54.5% of pts, most commonly anemia (20.5%) and neutropenia (10.2%). TRAEs led to discontinuation in 27.3% of pts. One pt had a stroke, considered related to rucaparib by the investigator, after 28 days on rucaparib and 2 NIVO doses and died 2 months later due to post-thrombolysis hematoma. Conclusions: NIVO + rucaparib is active in pts with HRD+ post-CT mCRPC, although the trial design and short follow-up limit assessment of benefits of the combination vs individual components. Pts with HRD– tumors did not appear to benefit from either drug. No new safety signals were observed with NIVO + rucaparib. Additional biomarker analyses are ongoing. Clinical trial information: NCT03338790. [Table: see text]

A phase 2 study of berzosertib (M6620) in combination with carboplatin compared with docetaxel in combination with carboplatin in metastatic castration-resistant prostate cancer.

5034 Background: Alterations in DNA damage repair (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in responses to carboplatin [carbo], PARP inhibitors and immunotherapeutics. Inhibitors of the ATR kinase, which is involved in the DDR response, have been demonstrated to have synergistic activity with platinum compounds in preclinical models. We therefore conducted a phase 2 study of the ATR inhibitor berzosertib [berzo]+carbo vs. docetaxel [doce]+carbo in mCRPC. Methods: Patients (pts) previously treated with at least one secondary hormonal therapy and taxane underwent mandatory pre-treatment biopsy and were randomized 1:1 to receive Arm A (doce 60 mg/m2 day 1 + carbo AUC 4 day 1) or Arm B (berzo 90 mg/m2 days 2,9 + carbo AUC 5 day 1) every 21 days. Pts randomized to Arm A who were not candidates for doce received carbo AUC 5 monotherapy. Stratification factors were 1) prior PARP inhibitor (yes vs. no) and 2) evaluable disease by RECIST 1.1 (yes vs. no). Pts on Arm A crossed over to Arm B (berzo+carbo) at the earlier of PSA or radiographic progression. The primary endpoint was overall response rate (ORR; PSA reduction by ≥ 50% or radiographic response by RECIST 1.1). Secondary endpoints included time to PSA progression, radiographic PFS (rPFS), PFS by PCWG3 criteria, and adverse events (AEs) in each arm. Planned enrollment was 136 pts (for 130 to be treated), with interim analysis for futility after 65 pts were treated. Results: 73 pts were randomized between 6/2019 and 7/2020; 34 pts were treated on Arm A (26 carbo+doce; 8 carbo alone) and 31 on Arm B. Median number of prior systemic therapies (excluding ADT, 5α-reductase inhibitors, 1st generation antiandrogens) was 4 (range 2-8). Median treatment duration was 3 cycles, and 4 pts in each arm discontinued for AEs. Grade 3 or higher treatment-related AEs (TrAE) were seen in 13(38%) pts in Arm A and 21(68%) in Arm B. Pts in Arm B had greater frequency of grade 3-4 thrombocytopenia (8[26%] vs. 3[9%]). 1 pt in Arm B had grade 5 sepsis attributed to study treatment. ORR was 15% in Arm A (5/34; 5/26[19%] in pts who received carbo+doce) and 0% in Arm B (0/31). 14 pts in Arm A crossed over, with no subsequent responses seen. Median rPFS was 2.1(95% CI:2.0,3.2) mo in Arm A and 2.4(1.9,4.2) mo in Arm B. At planned interim analysis, trial enrollment and crossover to Arm B were halted due to futility. Conclusions: Carbo+berzo led to fewer overall responses and a higher rate of grade 3 or higher TrAEs compared to carbo+doce. All responses seen were in pts who received carbo+doce despite requirement for prior progression on taxane, suggesting that this combination is favored over carbo+berzo or carbo monotherapy in a heavily pre-treated biomarker-unselected population. Extensive genetic and molecular studies for DDR assessment from tissue and cfDNA are in progress. Clinical trial information: NCT03517969.

A phase 1b study of novel immunogenic cell death inducer PT-112 plus PD-L1 inhibitor avelumab in metastatic castrate-resistant prostate cancer (mCRPC) patients.

e17025 Background: PT-112 is a novel pyrophosphate-platinum conjugate that induces immunogenic cell death, reaches highest concentrations in bone (osteotropism), and synergizes with immune checkpoint inhibitors (ICIs) in preclinical models. Phase I studies in solid tumors, as monotherapy and in combination with PD-L1 inhibitor avelumab (“PAVE”), as well as in multiple myeloma as monotherapy have demonstrated that PT-112 is well-tolerated and active. We present updated safety and exploratory efficacy findings in a mCRPC sub-population treated with PAVE, including a cohort of patients at a lower-frequency dosing schedule. Methods: A total of 32 mCRPC patients (pts) received 800 mg of avelumab on days 1 and 15 of a 28-day cycle, of whom 18 received PT-112 on days 1, 8 and 15 at 200mg/m2 (n = 17) or 150 mg/m2 (n = 1); a separate cohort of 14 received PT-112 on days 1 and 15 at 300 mg/m2 (n = 13) or 200mg/m2 (n = 1). Results: Median age was 68 (range 47-87) and number of prior lines of therapy (Tx) was 7 (2-12), including prior platinum-containing therapy in 11 (34%) and ICI Tx in 9 pts (28%). Baseline grade 2 anemia was seen in 7 (22%) pts. The most common treatment-related adverse events (TRAEs) were anemia (47%) and thrombocytopenia (41%); 23 pts (72%) had ≥1 grade 3-4 TRAE, with no cases of bleeding, sepsis, or grade 5 TRAEs. Antitumor effects included 8 (25%) pts with a PSA reduction of ≥50% (PSA50); 5 (16%) were maintained through ≥1 follow-up. Of ten pts with RECIST-measurable disease, 3 had tumor volume reductions, one with a confirmed partial response (PR). Twenty-four (75%) pts experienced a reduction in serum alkaline phosphatase (ALP) (median reduction 15%), and improvement in patient-reported pain and quality of life was observed. For the 13 pts given 300 mg/m2 PT-112 bi-weekly, 7 (54%) had prior platinum-containing Tx and 4 (31%) had baseline grade 2 anemia. The most common TRAEs were anemia (69%) and thrombocytopenia (54%), with 11 (85%) pts having ≥1 grade 3-4 TRAE. Four pts (31%) had PSA50 reductions; 3 (23%) were maintained through ≥1 follow-up. Conclusions: PAVE is safe and generally well tolerated in mCRPC patients at the doses and schedules tested, providing meaningful antitumor effects in heavily pre-treated patients, including tumor volume, PSA and ALP reductions. Reductions in ALP may be indicative of anti-cancer activity at bone sites of disease. Although the sample sizes are small, the frequency of confirmed PSA50 responses and of grade 3-4 TRAEs was slightly higher in the group receiving biweekly 300 mg/m2 PT-112, and higher rates of TRAEs may be explained by higher baseline anemia and/or prior platinum Tx. Further clinical investigation of the combination of PT-112 plus ICIs in a less heavily pre-treated mCRPC population is warranted. A phase 2 study of PT-112 monotherapy in mCRPC is ongoing. Clinical trial information: NCT03409458.

Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC).

5013 Background: HPN424 is a prostate-specific membrane antigen (PSMA)-targeting T cell engager designed to redirect T cells to kill PSMA-expressing prostate cancer cells; engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension and anti-CD3 for T cell engagement. HPN424 is optimized for small size and increased stability compared to other bispecific platforms. Methods: This Ph1/2a study is evaluating HPN424 in mCRPC patients (pts) who have received &gt; 2 prior systemic therapies. Primary endpoints are safety, tolerability and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity and preliminary anti-tumor activity. HPN424 is administered IV once weekly. Tumor assessments include PSA, CT and bone scans every 9-weeks. Results: As of 2/8/21, 80 pts were dosed in 15 cohorts with target doses ranging from 1.3 to 160ng/kg fixed dose, and up to 300ng/kg with step dosing to the target dose after initial priming dose. Pts had received a median of 6 prior systemic regimens, 75% received prior chemotherapy for mCRPC. Median age was 70 (43 – 91). Most common grade &gt; 3 TEAEs were AST increase (18%), anemia (11%) and ALT increase (11%). DLTs include CRS G3 (n = 3), elevated lipase G3 (n = 1) and seizure G3 (n = 1). These events did not limit escalation, MTD has not been reached and escalation continues. All grade CRS occurred in 63% of pts, 4% grade 3 per ASTCT and no Grade 4/5 CRS. CRS G3 events occurred after first administration of target dose (n = 2 fixed dose, n = 1 step dose). Transaminase elevation occurred predominantly during Cycle 1, was transient and had no clinical sequelae. Disease progression was the primary reason for drug discontinuation; 2 pts (3%) discontinued due to TRAE. Reduction in circulating tumor cells (CTC) was seen in 32 of 56 pts (57%) with measurable CTC at baseline. Fifteen of 62 pts (24%) with &gt; 24 weeks follow-up remained on treatment ≥ 24 weeks. Thirteen of 63 pts (21%) with post-baseline levels had PSA declines from baseline, including 3 PSA50, 2 PSA30 responses. In chemo-naïve pts, 5 of 15 (33%) showed PSA declines post-baseline. In the highest fixed dose cohort (160ng/kg) tested to-date, 3 of 7 evaluable pts had PSA declines from baseline and 1 had a confirmed partial response per RECIST. Conclusions: HPN424, a novel half-life extended PSMA-targeting T cell engager, was well tolerated when administered once weekly. AEs were transient, manageable and consistent with class of agent. Grade 3 CRS was observed in 4% of patients, occurring with first administration of target dose. Evidence of antitumor activity included PSA and CTC reductions and treatment duration &gt; 24 weeks in 15/62 pts. Encouraging signals were seen at the highest fixed dose cohort including a confirmed RECIST partial response. NCT03577028 Clinical trial information: NCT03577028.