PSA Response Research Articles

PSMA PET findings in patients with undetectable PSA more than 3 years after docetaxel for metastatic castration-sensitive prostate cancer (mCSPC).

e17046 Background: Multiple treatment options combined with androgen deprivation therapy (ADT) provide a survival advantage in mCSPC. In this prospective study, mCSPC patients were treated with docetaxel and Prostvac, a therapeutic cancer vaccine. Since initiation of the study, a phase 3 trial of Prostvac did not show independent clinical activity in metastatic castration-resistant prostate cancer. Still, this study offers a chance to evaluate responses to docetaxel-based therapy in mCSPC. More specifically, with FDA approval of prostate-specific membrane antigen (PSMA) PET imaging in just the last year, there is a paucity of data regarding the use of this scan in long-term responders to therapies for mCSPC. Methods: Eligible patients included those with mCSPC and ECOG PS of ≤ 2. As per the CHAARTED regimen, patients started docetaxel within 4 months of initiating ADT with a plan to receive 75mg/m2 for 6 cycles. Patients were randomized to receive Prostvac prior to, concurrent with, or after docetaxel. Restaging was done annually with CT and Tc99 bone scan. The study was powered to evaluate immune responses, which is being reported separately. For this analysis, patients were evaluated as one group. Ten patients are in follow up with continued PSA values of ≤ 0.2 ng/mL and 7/10 were evaluated with 18F-DCFPyL PSMA PET. Results: Seventy-three patients enrolled. Median age was 63 years with a range of 41-86 years. Race distribution was 71.6% White, 20.3% Black, 4.1% other, and 4.1% unknown. Gleason 6, 7, and 8 to 10 was 4.1%, 21.6%, and 68.9% of patients, respectively, with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Low-volume disease represented 41.1% of patients and high-volume was 58.9%. After 2 years from the start of ADT, 22% of patients had PSA values of ≤ 0.2 ng/mL. This included 37% of the low-volume group and 12% of the high-volume group. Three years from starting ADT, 14% of patients had PSA values ≤ 0.2 ng/mL (20% of the low-volume group, 9% of the high-volume group). Of the 7 patients who remain in follow-up with PSA values ≤ 0.2 ng/mL and who were evaluated with PSMA PET, median time from start of ADT was 4 years with a range of 3.5-6 years. These patients either had no evidence of disease or minimal residual findings on CT/Tc99 bone scan. Four of the 7 patients still had residual areas of uptake on PSMA PET. Conclusions: Patients treated with docetaxel for mCSPC have the potential for long-term clinical responses. In these long-term responders, despite prolonged PSA response and minimal findings on conventional CT and Tc99 scans, more than half of patients still had findings on PSMA PET imaging. Further studies are required to better understand the clinical implications of these findings and the role of PSMA PET in mCSPC. Clinical trial information: NCT02649855.

Olaparib for Chinese metastatic castration-resistant prostate cancer: A real-world study of efficacy and gene predictive analysis.

To evaluate the real-world effectiveness and gene predictive analysis of olaparib in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC), amulticenter, retrospective, real-world study was conducted by involving Chinese patients with mCRPC from December 2017 to June 2021. Homologous Recombination repair (HRR)gene mutation (HRRm) status was identified using targeted next-generation sequencing (NGS). The primary endpoint includes prostate-specific antigen (PSA) response rate (PSA50). Secondary end points include PSA progression-free survival (PSA-PFS), exploratory endpoints include PSA50, and PSA-PFS in HRRm-negative patients with variants of unknown significance (VUS). Survival rates were analyzed using Kaplan-Meier (KM) plot. A total of 39 eligible patients with a median age of 65 (interquartile range [IQR]: 59.5-69.5) years were included in the study. Overall, 40% (12/30) of the patients with mCRPC achieved PSA50 and the median PSA-PFS was 3.1months (95% Confidence interval [CI]: 2.4-7). Furthermore, higher PSA50 rate and longer PSA-PFS were observed in HRRm-positive patients (PSA50: 50% [7/14]; median PSA-PFS: 5.3months, 95% CI: 3.73-10). Among the HRRm-positive patients, those harboring the BRCA2 aberrations experienced best clinical efficacy (PSA50: 55.5% [5/9] and median PSA-PFS [95% CI]: 9.5months [4.3, NA]). Clinical benefit was also observed in HRRm-negative patients (PSA50: 31.3% [5/16]; median PSA-PFS [95% CI]:2.05months [1.5,8]), wherein most patients with a PSA50 response were carrying VUS (PSA50: 50% [4/8]; median PSA-PFS [95% CI]: 2.75months [1.27, NA]). In one patients with mutation in the ATR gene, the PSA level decreased by 62%. Olaparib improved PSA response and prolonged PSA-PFS in Chinese mCRPC patients especially in those carrying HRR mutation. Among the HRR genes, patients with BRCA2 mutation showed the best clinical benefit. Besides, some patients carrying VUS on HRR gene and other DNA damage response (DDR) gene mutations also showed response to olaparib treatment, indicating that the clinical benefits observed in HRR-negative group were driven by VUS and other DDR gene mutation. However, this should be further explored in the future, and more molecular functional studies are needed to reclassify VUS for better clinical treatment decision-making and management of mCRPC.

Outcome of 177 Lu-PSMA Radionuclide Treatment in Advanced Prostate Cancer and Its Association With Clinical Parameters : A Single-Center Experience.

This study was set out to analyze the efficacy and safety of 177 Lu-PSMA-617 (LuPSMA) treatment in metastatic castration-resistant prostate cancer (mCRPC) patients. Progressive mCRPC patients who received at least 1 cycle of LuPSMA therapy were evaluated retrospectively. Demographic, clinic, and histopathological data were documented. Treatment efficacy was determined based on biochemical response criteria (Prostate Cancer Clinical Trial Working Group 3), and toxicity rates were defined based on CTCAE v4.03. The prognostic significance of laboratory/clinical data and 68 Ga-PSMA PET/CT quantitative results were analyzed using SPSS Version 24.0. One hundred patients (median prostate-specific antigen [PSA] level, 75.7 ng/mL) who met the eligibility criteria were identified. The median number of cycles received per patient was 3 (range, 1-9). After the first cycles of LuPSMA, biochemical partial response, biochemical stable disease, and biochemical progressive disease were observed in 31%, 36%, and 33% of patients, respectively. Any PSA decline was determined in 60% of patients. After the fourth cycle of treatment, biochemical partial response, biochemical stable disease, and biochemical progressive disease were defined in 48%, 26%, and 26% of patients, respectively. The median overall survival (OS) from the first cycle of LuPSMA was 14 months. Patients who had any PSA response after the first cycle had significantly longer OS than nonresponders (median OS: 17 vs 9 months; P ≤ 0.001). Total PSMA-derived tumor volume ( P = 0.004), total PSMA activity per lesion ( P = 0.01), PSA ( P = 0.007), alkaline phosphatase ( P = 0.002), lactate dehydrogenase ( P < 0.001), and hemoglobin ( P < 0.001) were significant prognostic factors for OS in univariate Cox regression analysis. LuPSMA therapy is a favorable treatment for mCRPC with remarkable therapeutic efficacy and low toxicity rates, even in progressive disease under standard therapies. Baseline PSMA-based tumor burden, PSA, alkaline phosphatase, lactate dehydrogenase, and hemoglobin were significant predictors of OS and can be useful for selection of the best candidate for LuPSMA therapy.

Time to castration-resistant prostate cancer and prostate cancer death according to PSA response in men with non-metastatic prostate cancer treated with gonadotropin releasing hormone agonists

Objectives: To predict castration-resistant prostate cancer (CRPC) and prostate cancer (Pca) death by use of clinical variables at Pca diagnosis and PSA levels after start of gonadotropin-releasing hormone agonists (GnRH) in men with non-metastatic castration sensitive prostate cancer (nmCSPC). Materials and Methods: PSA values for 1603 men with nmCSPC in the National Prostate Cancer Register of Sweden who received GnRH as primary treatment were retrieved from Uppsala-Örebro PSA Cohort and Stockholm PSA and Biopsy Register. All men had measured PSA before (pre-GnRH PSA) and 3–6 months after (post-GnRH PSA) date of start of GnRH. Unadjusted and adjusted Cox models were used to predict CRPC by PSA levels. PSA levels and ISUP grade were used to construct a risk score to stratify men by tertiles according to risk of CRPC and Pca death. Results: 788 (49%) men reached CRPC and 456 (28%) died of Pca during follow-up. Post-GnRH PSA predicted CRPC regardless of pre-GnRH PSA. CRPC risk increased with higher post-GnRH PSA, HR 4.7 (95% CI: 3.4–6.7) for PSA > 16 ng/mL vs 0–0.25 ng/mL and with ISUP grade, HR 3.7 (95%: 2.5–5.4) for ISUP 5 vs ISUP 1. Risk of Pca death in men above top vs bellow bottom tertile of post-GnRH PSA and ISUP grade was HR 4.1 (95% CI: 3.0–5.5). Conclusion: A risk score based on post-GnRH PSA and ISUP grade could be used for early identification of a target group for future clinical trials on additional therapy to GnRH.

Homologous Recombination Repair Gene Variants and Outcomes Among Patients With Prostate Cancer Treated With Poly (ADP-ribose) Polymerase Inhibitors.

Poly ADP-ribose polymerase inhibitors (PARPi) are used for patients with advanced prostate cancer bearing alterations in homologous recombination repair (HRR) genes. We sought to characterize HRR gene variants and describe real-world outcomes for patients on PARPi. The US Department of Veterans Affairs' National Precision Oncology Program's database was reviewed to identify patients who underwent somatic DNA sequencing and were prescribed a PARPi before May 15, 2020. Somatic and germline variants within HRR genes were reported, and pathogenicity was reviewed via OncoKB. In patients treated with PARPi for > 4 weeks, the rate of those achieving a 30% decrease in prostate-specific antigen (PSA30) and composite progression-free survival (PFS) were compared between patients bearing pathogenic variants of BRCA2 and patients without these variants using Mann-Whitney and log-rank tests, respectively. Forty-eight patients bearing 67 total HRR gene variants were prescribed PARPi for prostate cancer. Twenty-one patients (43.8%) were found to have at least one pathogenic HRR gene variant. Eight (16.6%) were referred to genetic counseling, and five (10.4%) were ultimately confirmed with germline variants. The median PFS was 4.0 months, and PSA30 was 25.6% (11 of 43) for all 43 evaluable patients. Patients with pathogenic BRCA2 variants (n = 13) had higher PSA30 (69.2% v 4.0%; P < .001) and longer PFS (7.2 v 2.8 months; P = .0291) than those without. In a real-world setting, heavily pretreated patients with prostate cancer and pathogenic BRCA2 variants have a significant PSA response rate and a PFS > 7 months with PARPi. This work emphasizes the importance of determining pathogenicity and origin of HRR alterations to better inform clinical treatment decisions and highlights the need for provider education and other decision support tools.

Cribriform pattern disease over-represented in pelvic lymph node metastases identified on 68GA PSMA-PET/CT.

ObjectivesTo determine whether any specific histologic subtype of prostate cancer was preferentially represented in pelvic lymph node metastases identified on 68GA‐PSMA‐PET/CT.Subjects and MethodsA consecutive series of 66 men with biochemical recurrent prostate cancer was evaluated with 68GA‐PSMA‐PET/CT. Where disease was confined to pelvic lymph nodes, patients were offered salvage extended pelvic lymph node dissection. Twenty patients ultimately proceeded to extended bilateral template pelvic lymph node dissection. Lymph node positivity and the histologic subtype of apparent cancer were assessed, as was PSA response to this intervention.ResultsMean PSA at time of PSMA scanning for patients undergoing lymphadenectomy was 2.49 (n = 20, range 0.21–12.0). In 16 of 20 patients, there was evidence of metastatic cribriform pattern prostate cancer in excised nodes (100% cribriform pattern in 11/16). Only four of 20 patients had no evidence of this histologic subtype of disease. PSA response was not related to the presence or proportional amount of cribriform pattern disease identified.ConclusionsCribriform pattern adenocarcinoma appears to be the histologic subtype preferentially identified in pelvic lymph nodes on 68GA‐PSMA‐PET/CT. The use of PSMA‐PET may be particularly valuable in staging of primary or biochemically recurrent prostate cancer in patients with cribriform pattern disease detected on initial biopsy or radical prostatectomy. Further research is required to further confirm the observed association.

LHRH sparing therapy in patients with chemotherapy-naïve, mCRPC treated with abiraterone acetate plus prednisone: results of the randomized phase II SPARE trial

BackgroundAlthough the benefit of androgen deprivation therapy (ADT) continuation in metastatic castration-resistant prostate cancer (mCRPC) remains controversial, clinical evidence is lacking. Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone, suggesting that continuation of ADT in the treatment of mCRPC may not be necessary.MethodsIn this exploratory phase 2 study, mCRPC patients were randomized with a 1:1 ratio to receive either continued ADT plus AA + P (Arm A) or AA + P alone (Arm B). The primary endpoint was the rate of radiographic progression-free survival (rPFS) at month 12. Secondary endpoints included PSA-response rate, objective response, time to PSA progression and safety.ResultsA total of 68 patients were equally randomized between the two study arms. Median testosterone-levels remained below castrate-levels throughout treatment in all patients. According to the intention-to-treat analysis the rPFS rate was 0.84 in Arm A and 0.89 in Arm B. Moderate and severe treatment-emergent adverse events were reported for 72% of the patients in Arm A and for 85% of the patients in Arm B.ConclusionsAA + P treatment without ADT may be effective in mCRPC patients and ADT may not be necessary in patients receiving AA + P.

Evaluation of maintenance of the common androgen deprivation therapy with the new antiandrogen therapy in patients with castration-resistant prostate cancer: a systematic review

Advanced prostate cancer does not respond to traditional androgen deprivation therapy (ADT) at some point in the treatment. The development of new hormonal agents demonstrated clear efficacy and changed the treatment scenario. To evaluate the use of new antiandrogens alone versus their use in combination with maintenance ADT in patients with advanced castration-resistant prostate cancer. A literature systematic review of randomized clinical trials, cohorts, and real-life studies including patients who received the new antiandrogens with or without ADT due to histologic confirmed advanced castration-resistant prostate adenocarcinoma was carried out. 2181 articles were identified and three studies were included with a total of 246 patients. Two studies were randomized clinical trials, and the third was a retrospective study, which showed similar results for both arms, in relation to PSA response, radiological progression-free survival, and testosterone levels, in addition to cost analysis with savings avoided in the ADT maintenance-free arm. Despite the positive data, it is still not possible to categorically state whether there is a statistical benefit in suspending the ADT during the use of new antiandrogens, due to the heterogeneity of the studies. The literature is limited on the issue. Available data are still immature with no clear benefit of the use of newer antiandrogens alone in the setting of advanced castration-resistant prostate cancer.

Hematologic toxicity profile and efficacy of [225Ac]Ac-PSMA-617 α-radioligand therapy of patients with extensive skeletal metastases of castration-resistant prostate cancer.

Actinium-225-labeled prostate-specific membrane antigen ([225Ac]Ac-PSMA-617) is safe and effective in the treatment of metastatic castration-resistant prostate cancer (mCRPC). No study has specifically assessed its safety in patients with extensive skeletal metastases of mCRPC. We aimed to investigate the hematologic toxicity and efficacy of [225Ac]Ac-PSMA-617 therapy in patients with extensive skeletal metastases of mCRPC. We retrospectively reviewed the medical record of patients treated with [225Ac]Ac-PSMA-617 for mCRPC. We included patients with a superscan pattern of skeletal metastases and those with 20 or more multifocal sites of skeletal metastases on baseline [68Ga]Ga-PSMA-11 PET/CT. We reviewed the levels of hemoglobin, white blood cell (WBC), and platelet prior to each cycle of treatment and determined the presence of impaired bone marrow function at baseline and the grade of toxicity in the hematologic parameters induced by treatment. We evaluated the predictors of hematologic toxicity using binary logistic regression analysis. We also determined the presence of renal dysfunction before or during treatment. We assessed response to treatment using prostate-specific antigen response and the progression-free survival (PFS) and overall survival (OS). A total of 106 patients were included. Skeletal metastasis was in the superscan pattern in 34 patients (32.1%) and multifocal in 72 patients (67.9%). The median treatment cycle was 4 (range = 1-9). Ninety-eight patients (92.5%) had abnormal baseline hematologic parameters. One patient had grade 4 thrombocytopenia. Grade 3 anemia, leukopenia, and thrombocytopenia were seen in 1 (0.9%), 3 (2.8%), and 2 (1.9%) patients, respectively. Age, the number of treatment cycles, and the presence of renal dysfunction were significant predictors of hematologic toxicity. Eighty-five patients (80.2%) achieved PSA response. The median PFS and OS of the study population were 14:00 (95%CI: 8.15-19.86) months and 15.0 (95%CI: 12.8-17.2) months, respectively. [225Ac]Ac-PSMA-617 induces a good anti-tumor effect in about 80% of patients with extensive skeletal metastases of mCRPC with a rare incidence of severe hematologic toxicity. Age, number of treatment cycles, and the presence of renal dysfunction were significant risk factors for hematologic toxicity of [225Ac]Ac-PSMA-617 therapy.

Molecular and Clinical Characterization of Patients With Metastatic Castration Resistant Prostate Cancer Achieving Deep Responses to Bipolar Androgen Therapy.

Bipolar androgen therapy (BAT) is an emerging treatment strategy for men with metastatic castration resistant prostate cancer (mCRPC) whereby serum testosterone is cycled from supraphysiologic to near-castrate levels each month. BAT has been shown to induce clinical responses in a significant proportion of patients, some of which are extreme. We explored the clinical and molecular characteristics of patients with mCRPC who achieved deep responses to BAT. We conducted a retrospective analysis of patients with mCRPC treated with BAT at Johns Hopkins. We identified 22 of 114 (19%) patients with mCRPC who achieved ≥70% PSA reductions upon treatment with BAT. All patients were treated using 400 mg testosterone cypionate intramuscularly every 28 days, together with continuous LHRH agonist therapy. Clinical-grade DNA sequencing was obtained using commercially available assays. Somatic next-generation sequencing was obtained for 15 of 22 (68%) patients. Of these 15 extreme PSA responders with sequencing data available, All 15 of 15 (100%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene. Among the subset of patients with measureable disease (N=15), 10 patients (67%) achieved an objective response including one patient with a complete response. The median radiographic progression-free survival of these deep PSA responders was 11.3 months (95% CI, 7.9-25.0 months). We observed an enrichment of TP53 and HRD mutations in mCRPC patients with extreme PSA responses to BAT, with durability lasting about a year. These data support the hypothesis that BAT may most benefit patients with DNA repair-deficient mCRPC. Further studies of BAT in biomarker-selected mCRPC populations (ie, TP53/HRD-mutated) are warranted.

CGE22-098: Correlation Between Trough Level of Abiraterone Acetate and PSA Response in Metastatic Hormone Sensitive Prostate Cancer

CGE22-098: Correlation Between Trough Level of Abiraterone Acetate and PSA Response in Metastatic Hormone Sensitive Prostate Cancer

Prognostic nutritional index is an independent prognostic factor for treatment response, survival and drug choice in metastatic castration-resistant prostate cancer treated with abiraterone acetate or enzalutamide

PurposeWe designed this study to identify the prognostic value of baseline prognostic nutritional index (PNI) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide. Methods101 mCRPC patients were included. PNI was calculated using formula 10 x serum albumin value (gr/dL) + 0.005 × total lymphocyte count (per mm3). ROC analysis was used for determining prognostic PNI value. ResultsThe statistically significant cut-off value for PNI was 46.62. Initial PSA response and PSA kinetics (early PSA response and 30 %–50%–90% PSA response at any time) were much better in PNI > 46.62 group than the PNI ≤ 46.62 group (p < 0.01). In multivariate analysis, baseline PNI level >46.62 was an independent predictor of PSA-PFS (HR: 0.42, p < 0.01), radiologic PFS (HR: 0.53, p < 0.01), and OS (HR: 0.42, p < 0.01). In the PNI ≤ 46.62 group, median OS was 7.4 months (95% CI: 4.1–10.7) for the abiraterone acetate subgroup vs. 17.6 months (95% CI: 10.1–25.1) for enzalutamide subgroups (p < 0.01). ConclusionPNI is a useful, independent prognostic marker for mCRPC patients treated with either abiraterone acetate or enzalutamide. Using pre-treatment PNI may help clinicians in the prediction of survival and decision making based on abiraterone acetate or enzalutamide.

MRI-defined treatment margins, urinary toxicity, and PSA response in LDR prostate brachytherapy

Implant quality metrics as measured by D90 and V100 do not address the adequacy of periprostatic margins. Relative margin deficiencies may relate to efficacy and margin excesses to post-implant toxicity. Our purpose is to determine MRI-defined treatment margins on prostate achieved with LDR brachytherapy. Post implant CT and MR images from 487 consecutive patients who received LDR brachytherapy from 2010 to 14 were co-registered. Four prostate quadrants were defined; anterior-superior (AS), posterior-superior (PS), anterior-inferior (AI), posterior-inferior (PI). Dosimetric variables were measured for prostate, and for each quadrant with a 0-, 2-, 3-, and 5-mm margin, as well as for the membranous urethra defined on MRI. Prostate D90 (no margin) was associated with D90 to the volume enclosed by 2 mm, 3 mm and 5 mm margins (R2 = 0.9 - 1.0) with an average 7.1% decrease in dose per mm of margin. Mean D90 for PS, AI and PI quadrants were > 110% of prescription dose for margins of 2-, 3-, and 5-mm. AS quadrant mean D90s were generally lower (83.2% for 2 mm, 76.4% for 3 mm and 62.2% for 5 mm). Urethral strictures (n = 9) were associated with higher doses in the AI quadrant, and higher membranous urethral V125 (51 vs. 32%, p 0.013) and V150 (34.5 vs. 17.6%, p 0.01). Using MR-CT post implant dosimetry, margin coverage up to 5 mm was excellent with less margin coverage in the AS quadrant. Late ≥ grade 2 toxicity and urinary strictures are more likely to occur with relative margin excess in the anterior-inferior quadrant and higher doses caudal to the prostate apex. Within this analysis, there was no relationship between treatment margins, and PSA outcome.

PSMA PET and FDG PET as predictors of response and prognosis in a randomized phase 2 trial of 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic, castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603).

10 Background: The TheraP trial showed that LuPSMA improved PSA≥50% response rate (PSA50-RR), PSA-PFS, and radiographic PFS (rPFS) compared with cabazitaxel in mCRPC progressing after docetaxel. Study inclusion required high PSMA uptake (SUVmax≥20) and no lesions that were FDG+ and PSMA-. Here we report on PSMA PET and FDG PET as potential predictive and prognostic biomarkers. Methods: We prospectively analysed semi-automated quantitative PET parameters in centrally- collected 68Ga-PSMA-11 PET and 18F-FDG PET in 200 eligible men. SUVmean ≥10 on PSMA PET was evaluated as a predictive biomarker for response to Lu-PSMA vs cabazitaxel. Metabolic tumor volume (MTV) ≥200mL on FDG PET was tested as a prognostic biomarker accounting for the randomly assigned treatment. Quantitative PET cut-offs were pre-specified from prior research (PMID:32140802). Responses were defined according to PSA50-RR (primary endpoint), PSA-PFS and rPFS. Binary and PFS endpoints were analyzed using logistic and Cox regression, respectively. Results: Very high PSMA uptake on PSMA PET (SUVmean≥10) was seen in 35/99 (35%) assigned LuPSMA and 30/101 (30%) assigned cabazitaxel. The odds of a response to LuPSMA vs. cabazitaxel were significantly higher for men with SUVmean≥10 (OR 12.2, 95%CI 3.4-59 vs. 2.2, 95%CI 1.1-4.5; p = 0.03). In men with SUVmean≥10, the PSA50-RR for LuPSMA vs. cabazitaxel were 32/35 (91%) vs. 14/30 (47%). In men with PSMA SUVmean &lt; 10, the PSA50-RR were 33/64 (52%) vs. 23/71 (32%). High-volume metabolic disease on FDG PET (MTV ≥200mL) was seen in 30/99 (30%) assigned LuPSMA and 30/101 (30%) assigned cabazitaxel. The PSA50-RR in these men was 17/30 (57%) for LuPSMA vs. 6/30 (20%) for cabazitaxel. In comparison, the PSA50-RR for men with MTV &lt; 200mL on FDG PET was 48/69 (70%) for LuPSMA vs. 31/71 (44%) for cabazitaxel. After accounting for treatment, the odds of a PSA50-response was lower among men with high MTV (OR 0.44; p = 0.01). The HR for PSA-PFS for LuPSMA vs cabazitaxel was 0.45 (95%CI 0.25-0.80) for SUVmean≥10 vs. 0.77 (95%CI 0.53-1.12) for SUVmean &lt; 10 (p = 0.2). Findings were similar for rPFS. The HRs for high MTV on FDG PET adjusted for treatment were 1.44 (95%CI 1.03-2.02) for PSA-PFS (p = 0.03); and 1.79 (95%CI 1.28-2.52) for rPFS (p &lt; 0.001). Conclusions: In men with mCRPC, PSMA SUVmean≥10 was predictive of a higher likelihood of favourable response to LuPSMA than cabazitaxel, whilst a high volume of disease on FDG PET was associated with a worse prognosis regardless of randomly assigned treatment. Clinical trial information: NCT03392428.

Phase 2 trial of immunotherapy in tumors with CDK12 inactivation (IMPACT): Results from cohort A of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) receiving dual immune checkpoint inhibition (ICI).

103 Background: Prostate cancer with CDK12 inactivation represents a distinct subtype in mCRPC, tumors are characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens and increased tumor T cell infiltration. Retrospective experiences with ICI in CDK12 inactivation CRPC pts reported PSA and radiographic responses. We conducted a prospective multi-site clinical trial of ipilimumab and nivolumab in CDK12 inactivation or mutated cancers. Herein, we report our findings in the completed cohort A of men with mCPRC. Methods: Eligible pts had mCRPC (ongoing androgen deprivation therapy with serum testosterone £ 50 ng/dL) and putative CDK12 inactivation of function aberrations on any commercial or institutional CLIA/CAP approved next generation sequencing assay. Archival tumor tissue was requested for correlative biomarker analysis. Pts received nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was PSA response, defined as a greater than or equal to 50% decline in PSA from baseline. Secondary endpoints included safety/toxicity, secondary efficacy measures including QoL and overall survival. Exploratory objectives included baseline tumor whole exome analysis and changes in circulating immune profiles with therapy. Results: As of data cut-off in Aug 2021, 28 mCRPC pts enrolled in Cohort A; median ECOG PS was 1 (0-2 range), 22/28 had Gleason 8-10 cancer, mean baseline PSA at study entry was 231 ng/dL, all pts had received ≥1 prior oral androgen signaling inhibitor and ≥1 cytotoxic chemotherapy. Unconfirmed PSA ≥30% decline was seen in 6/28 pts (21.4%) and PSA ≥50% decline in 4/28 pts (14.2%). Grade ≥3 possible/probable/definite adverse events were noted in 7/28 (25%) and SAEs in 10/28 pts (35.7%). Six pts (21.4%) experienced a rapid PSA increase by ≥ 10-fold over baseline. Conclusions: Combination immunotherapy was reasonably tolerated in this heavily pre-treated population and was associated with unconfirmed PSA responses in a subset of pts. Ongoing correlative analyses could explain responses mechanistically. Enrollment in Cohort B of non-prostate cancers and Cohort C of nivolumab monotherapy in prostate cancer are still ongoing. Clinical trial information: NCT03570619.

Serial stereotactic body radiation therapy for oligometastatic prostate cancer (PCa) detected by positron emission tomography (PET) imaging.

109 Background: Radiopharmaceuticals, including Ga-68-prostate specific membrane antigen (PSMA)-11, F-18-fluciclovine, and choline C-11, are increasingly used to stage and inform therapies for PCa. Stereotactic body radiation therapy (SBRT) to PET-detected oligometastatic PCa has been shown to improve progression free survival (PFS) compared to observation. However, for men who subsequently develop oligorecurrent disease, outcomes following second SBRT are unknown. Methods: A retrospective, single-center, cohort study was conducted. Pts were identified through electronic health records. Inclusion criteria included pts with oligometastatic (1-5 lesions) PCa detected on PSMA, fluciclovine, or choline C-11 PET who underwent 2 consecutive courses of SBRT to tracer-avid oligometastatic disease between 7/2013 and 7/2021. Exclusion criteria included presence of visceral metastases and pure small cell neuroendocrine PCa. Data on stage, tracer type, concurrent systemic therapy, and prostate-specific antigen (PSA) responses for first SBRT (SBRT1) and second SBRT (SBRT2) were collected. Outcomes included PSA decline of ≥50% (PSA50), ≥90% (PSA90), and PSA-PFS. SBRT2 outcomes were compared based on change of concurrent systemic therapy with SBRT2 (e.g., addition of abiraterone or anti-androgen withdrawal) and PSA50 to SBRT1 using Fisher’s exact text and Wilcoxon rank sum test, respectively. Results: A total of 12 pts met eligibility criteria. At SBRT1, 10 (83%) pts had hormone-sensitive PCa (HSPC) and 2 (17%) had castration-resistant PCa (CRPC). For PET tracers, 7 (58%) used PSMA, 4 (33%) fluciclovine, and 1 (8%) choline. After SBRT1, 12 pts (100%) had a PSA decline, 8 (67%) had a PSA50 response, and 6 (50%) a PSA90 response. Median PSA PFS after SBRT1 was 30mo (95%CI 9-65mo). Six (50%) SBRT1 pts had a concurrent change in systemic therapy. At SBRT2, 8 (67%) pts had HSPC and 4 (33%) had CRPC; 7 (58%) used PSMA and 5 (42%) fluciclovine. After SBRT2, 12 (100%) pts had a PSA decline, 8 (67%) had a PSA50 response, and 8 (67%) a PSA90 response. After SBRT2, median PSA PFS was 23mo (95%CI 12-35mo). Among 7 pts who had a concurrent change in systemic therapy with SBRT2, all (100%) had a PSA50 response; among 5 who did not (4 of whom did not receive any systemic therapy), 1 (20%) had a PSA50 response (P=0.01). Among 8 pts who had a PSA50 response to SBRT1, 7 (88%) had one to SBRT2; among 4 who did not have a PSA50 response to SBRT1, 1 (25%) had one to SBRT2 (P=0.01). No complications related to SBRT were documented. Conclusions: Serial SBRT for oligometastatic PCa detected on fluciclovine, PSMA, or choline PET is feasible and can achieve PSA declines independent of systemic therapy. PSA responses were greater when systemic therapy was changed. This preliminary evidence of benefit, based on PSA responses and PSA PFS, provides rationale for larger, prospective studies of serial SBRT for oligometastatic PCa.

Quantitative assessment of PSMA imaging before and after 177Lu-PSMA-617 treatment in a Ph I/II trial.

37 Background: We have previously reported a dose-intense single-cycle of 177Lu-PSMA-617 was effective in pretreated patients with mCRPC without requiring PSMA-positive imaging for enrollment. Prior post-hoc analyses of these data using approximate quantification of exclusively the most PSMA-positive disease sites have demonstrated associations between PSA response and PFS with pre-treatment 68Ga-PSMA11-PET signal. Greater sophistication in pre- and post-treatment evaluation of PSMA-expression in tumor and normal organs may allow for better patient selection and prediction of toxicities. Methods: A total of 50 patients were treated on a phase I/II study of fractionated-dose (D1, 15) 177Lu-617-PSMA. Quantification using artificial intelligence (AI) were used to measure pre- and post-treatment PSMA signal intensity. Scoring cutoffs with confidence intervals around scan variation were empirically established from a subset of test/re-test of subjects within 24h without intervening therapy. A variety of measurements were performed including SUVmean across all detectable tumor lesions, volume of lesions, and SUVtotal (Total + Volume), as well as select normal organs and changes after treatment. Associations with survival were tested via Cox proportional hazard models in univariate analyses and associations with adverse events (AEs) and PSA responses were via assessed via Wilcoxon rank sum tests. Results: 13 subjects were selected to complete AI-based quantification and associated survival analyses. Among these, 10 (77%) experienced any PSA decline, with 8 (62%) with PSA50 and 3 (23%)with PSA90. Median overall survival (OS) was 17.0 mos (10, NA) via Kaplan-Meier estimates. In univariate analysis, pretreatment SUVmean was associated with improved PFS (HR 0.66, 95% CI 0.49-0.90, p = 0.009) and OS (HR 0.81, 95% CI 0.65-1.00, p = 0.048). The metrics most strongly associated with PSA50 were pretreatment SUVmean (median [IQR]: 7.66 [6.52, 10.54] v 3.50 [3.02, 3.56], p = 0.019) and SUV Total (14982 [11110, 20595] v 1303 [576, 1512], p = 0.019), and change in Volume (-27 [-44, -20] v 145 [38, 154], p = 0.006) and SUVtotal (-57 [-67, -35] v 132 [9, 269], p = 0.030). Subjects with xerostomia had higher salivary gland SUVmax (pretreatment and change in after treatment). Those with pain flare had lower pretreatment SUV scores (Mean, Max, Total) in unaffected portions of bony skeleton. Conclusions: Sophisticated AI-based quantification analysis of PSMA expression on pre- and post-treatment 68Ga-PSMA11-PETs demonstrate associations with treatment efficacy (PSA response, OS), and associations between patient experience (AEs) and PSMA expression in non-tumor tissues. Expansion of this algorithm to a larger patient cohort may improve our ability to anticipate toxicity by body-wide PSMA detection and predict treatment response. Clinical trial information: NCT03042468.

Assessment of patient-reported outcomes (PROs) and longer-term adverse events (AEs) in phase I study of 225Ac-J591-PSMA for metastatic castration-resistant prostate cancer (mCRPC).

77 Background: Prostate Specific Membrane Antigen (PSMA) is a conserved cell surface protein in PC and is used for targeted imaging and therapeutics. Antibodies circulate longer than small molecules and are less likely to reach luminal PSMA on normal organs. Here we report PROs and longer-term AEs from the dose-escalation and expansion cohorts of a first-in-human study of combined monoclonal antibody and potent alpha emitter (225Ac-J591). Methods: Eligible subjects with mCPRC were administered 225Ac-J591. Initial to maximum doses were 13.3 to 93.3 KBq/kg). AEs are reporting using CTCAE v5 and PROs, including pain (BPI-SF) and quality of life (QOL, FACT-P), and associations with PSA response were also examined. Results: A total of 32 subjects (one enrolled in both dose-escalation and expansion) were treated with a single dose of 225Ac-J591 across 7 dose levels with expansion at the level (93.3 KBq/kg, n = 16). Median age 69.5 (52-89) and PSA 149.1 (4.8-7168.4). All subjects had at least 1 AE of any grade. Most common were fatigue (31/32, 1 Gr &gt; 2), anorexia (25/32, all Gr 1-2), and thrombocytopenia (25/32, 3 Gr 3, 2 Gr 4). Xerostomia was observed in 14/32 subjects (all Gr 1), 7 of whom had prior 177Lu-PSMA. Pain flare was reported in 43% (17/32) subjects (11 Gr 1, 6 Gr 2). 19 had evaluable PROs at baseline and efficacy visit (week 12). Pain severity (p = 0.8) and interference from pain (p = 0.4) were unchanged from baseline to 12 weeks, yet better PSA response (by percent) was associated with reduced pain severity (r = 0.7, p = 0.0023). Despite at least one AE in each subject, total FACT-P was not significantly changed after treatment (p = 0.2), but emotional well-being declined over time (15 [10.0, 18.0] v 10.0 [7.5, 13.0], p = 0.011). Reduction in median emotional well-being reached clinically important score differences. When stratified by AE, subjects with xerostomia had lower FACT-P total scores, but no difference was observed between those with and without pain. PSA response was not associated with change in QOL or subscales. Conclusions: Pain and quality of life in subjects with mCRPC did not change, on average, from baseline to 12 weeks after treatment with 225Ac-J591. This is despite preliminary evidence of clinical efficacy being accompanied by frequent, treatment emergent AEs. A promising trend toward improved pain in those with PSA response warrants further analysis. Small numbers limited statistical power for testing other subgroup associations. Additional correlations with pretreatment sites of disease, performance status, and adverse event distribution are ongoing. Assessment of changes in PROs in the follow up studies [NCT04506567] are underway. Clinical trial information: NCT03276572.

A randomized mCRPC phase 2b study of the BET bromodomain inhibitor (BETi) zen-3694 and enzalutamide vesus enzalutamide.

TPS201 Background: Androgen receptor signaling inhibitors (ARSI), such as enzalutamide (Enza), and abiraterone (Abi), are standard therapies for metastatic hormone-sensitive and metastatic castration-resistant prostate cancer (mHSPC, mCRPC). Patients who respond to the initial ARSI are frequently prescribed a second ARSI upon progression. However, a suboptimal response to first line ARSI, including the ̃ 20% treated with an ARSI for mHSPC who progress within 12 months of treatment initiation, may enrich for cancers harboring AR-independent mechanisms of resistance including treatment-emergent neuroendocrine prostate cancer (t-NEPC). Recently, BETi have been shown pre-clinically to block the neuroendocrine prostate cancer lineage plasticity program through modulating E2F1, a transcription factor involved in stemness and cell differentiation. Prior results from a mCRPC Ph. 1b/2a trial of ZEN-3694+ Enza support this notion, as lower AR transcriptional activity in baseline tumor biopsies was associated with longer radiographic progression-free survival (rPFS). Additionally, mCRPC patients who were primary refractory to first-line abiraterone had prolonged rPFS with ZEN-3694 + Enza, suggesting that the patients with primary resistance may benefit from the combination. To test this hypothesis, a Ph. 2b randomized trial has been initiated, enriching for mCRPC with suboptimal response to first-line ARSI. Methods: This is a multi-national, open-label, randomized, two cohort, Ph. 2b study of ZEN-3694 + Enza vs. Enza in mCRPC patients who have progressed on Abi (NCT04986423). Cohort A (N = 150): Patients with poor response to Abi defined either as progression in &lt; 12 months or failure to achieve PSA nadir of 0.2 ng/mL while taking Abi in HSPC setting, or progression in &lt; 6 months and/or failure to achieve a PSA50 response while taking Abi in the CRPC setting. Cohort B (N = 50): Patients who responded to Abi, defined as &gt; 12 months duration without progression while on Abi in the HSPC setting and achieving a nadir PSA &lt; 0.2 ng/mL, or &gt; 6 months duration without progression while on Abi in the CRPC setting and confirmed PSA50 response. The primary endpoint is radiographic progression-free survival (rPFS) by blinded independent central review (BICR) in Cohort A evaluated by PCWG3. Key secondary endpoints include rPFS by BICR for Cohorts A + B, PFS by investigator assessment, overall survival, PSA50 response rate, objective response rate by RECIST 1.1, and patient-reported health status and quality of life, evaluated in Cohorts A, and Cohorts A + B together. The trial, conducted in collaboration with Newsoara is expected to enroll 200 participants, and the first patient was dosed in October 2021. Astellas is providing the enzalutamide for this study. Clinical trial information: NCT04986423.

Efficacy and safety of relugolix in black men with advanced prostate cancer: A subgroup analysis from the randomized, phase 3 HERO study versus leuprolide.

105 Background: Prostate cancer disproportionately impacts Black men, with a higher incidence and worse outcomes relative to other races (Siegel DA, MMWR Morb Mortal Wkly Rep. 2020;69:1473). In the international phase 3 HERO study, relugolix, the once-daily oral GnRH receptor antagonist, demonstrated superior continuous suppression of testosterone to castrate levels through week 48 compared to leuprolide (96.7% for relugolix vs. 88.8% of men receiving leuprolide; Shore N, NEJM 2020; 382:2187) in men with advanced prostate cancer (APC). To further characterize the results from this trial in black men a subgroup analysis of HERO was undertaken. Methods: HERO was a phase 3 randomized, open-label, study to evaluate relugolix vs. leuprolide in 930 treated men with APC. The subgroup analyzed included all Black men enrolled in the HERO study. Assessments analyzed included sustained testosterone suppression to castrate levels (&lt;50 ng/dL) from day 29 through 48 weeks, early testosterone suppression to castrate levels (day 4 and day 15), PSA response (&gt;50% decrease) at day 15 with confirmation at day 29, profound castration rate (&lt;20 ng/dL) at day 15, and FSH level at the end of week 24. Results: Of the 930 men (relugolix: 622; leuprolide: 308) randomized and treated in HERO, 30 (4.8%) and 16 (5.2%) Black men were enrolled in the relugolix and leuprolide groups, respectively. Most men in this subgroup were from North America (82.6%) and ≤75 years old (89.1%), with a median age of 66 years. More Black men in the relugolix group had metastatic disease at study entry (30% vs. 25%), prior androgen deprivation therapy (13.3% vs. 6.3%), and prior prostatectomy (53.3% vs. 18.8%). Median PSA (12.8 vs. 16.0 ng/ml) and median testosterone levels (375.2 vs. 419.2 ng/dL) were lower at baseline for relugolix vs leuprolide. Of the Black men who received relugolix, 93.3% (95% confidence interval [CI], 75.9% to 98.3%) maintained castration through 48 weeks, as compared with 93.3% (95% CI, 61.3 to 99.0) of men receiving leuprolide (difference: 0% [95% CI, -15.5% to 15.5]). Testosterone suppression to castrate levels at day 4 (53% vs 0%), castrate levels at day 15 (97% vs 13%), and profound castration rates on day 15 (67% vs 6%) were greater with relugolix vs leuprolide. PSA response at day 15 was 83.3% with relugolix and 6.3% with leuprolide. At the end of week 24, median FSH levels were 1.75 IU/L for relugolix and 3.72 IU/L for leuprolide. Incidence of all grade adverse events were 96.7% vs 87.5% and grade ≥3 adverse events were 16.7% vs 25.0% in the relugolix and leuprolide groups, respectively. Conclusions: In this HERO study subgroup analysis, relugolix was effective and generally well tolerated in a cohort of Black men, consistent with the relugolix results in the overall population. Given the limited size of the subgroup, additional research is warranted in this population. Clinical trial information: NCT03085095.