Prostate Cancer Working Group Research Articles

Same-day post-therapy imaging with a new generation whole-body digital SPECT/CT in assessing treatment response to [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer.

Lutetium-177 [177Lu]Lu-PSMA-617 radioligand therapy (RLT) represents a significant advancement for metastatic castration-resistant prostate cancer (mCRPC), demonstrating improvements in radiographic progression free survival (rPFS) and overall survival (OS) with a low rate of associated side effects. Currently, most post-therapy SPECT/CT is conducted at 24h after infusion. This study examines the clinical utility of a next-generation multi-detector Cadmium-Zinc-Telluride (CZT) SPECT/CT system (StarGuide) in same-day post-infusion assessment and early treatment response to [177Lu]Lu-PSMA-617. In this retrospective study, 68 men with progressive mCRPC treated with [177Lu]Lu-PSMA-617 at our center from June 2022 to June 2023 were evaluated. Digital whole-body SPECT/CT imaging was performed after [177Lu]Lu-PSMA-617infusion (mean ± SD: 1.8 ± 0.6h, range 1.1-4.9h). Quantitative analysis of [177Lu]Lu-PSMA-617 positive lesions was performed in patients who underwent at least 2 post-therapy SPECT/CT, using liver parenchyma uptake as reference. Metrics including [177Lu]Lu-PSMA-617 positive total tumor volume (Lu-TTV), SUVmax and SUVmean were calculated. These quantitative metrics on post-infusion SPECT/CT images after cycles 1, 2 and 3 were correlated with overall survival (OS), prostate specific antigen-progression free survival (PSA-PFS) as defined by prostate cancer working group 3 (PCWG3), and PSA decrease over 50% (PSA50) response rates. 56 patients (means age 76.2 ± 8.1 years, range: 60-93) who underwent at least 2 post-therapy SPECT/CT were included in the image analysis. The whole-body SPECT/CT scans (~ 12min per scan) were well tolerated, with 221 same-day scans performed (89%). At a median of 10-months follow-up, 33 (58.9%) patients achieved PSA50 after [177Lu]Lu-PSMA-617 treatment and median PSA-PFS was 5.0 months (range: 1.0-15 months) while median OS was not reached. Quantitative analysis of SPECT/CT images showed that 37 patients (66%) had > 30% reduction in Lu-TTV, associated with significantly improved overall survival (median not reached vs. 6 months, P = 0.008) and PSA-PFS (median 6 months vs. 1 months, P < 0.001). However, changes in SUVmax or SUVmean did not correlate with PSA-PFS or OS. We successfully implemented same-day post-therapy SPECT/CT after [177Lu]Lu-PSMA-617 infusions. Quantitation of 1-2h post-therapy SPECT/CT images is a promising method for assessing treatment response. However, the approach is currently limited by its suboptimal detection of small tumor lesions and the necessity of incorporating a third-cycle SPECT/CT to mitigate the effects of any potential treatment-related flare-up. Further investigation in a larger patient cohort and prospective validation is essential to confirm these findings and to explore the role of SPECT/CT as a potential adjunct to PSMA PET/CT in managing mCRPC.

Do Subgroup Evaluations Provide Additional Contributions to Biochemical Recurrence in Grade Group 4 and 5 Patients? A Multicenter Study by the Turkish Urooncology Association Prostate Cancer Working Group

Do Subgroup Evaluations Provide Additional Contributions to Biochemical Recurrence in Grade Group 4 and 5 Patients? A Multicenter Study by the Turkish Urooncology Association Prostate Cancer Working Group

Prognostic Performance of RECIP 1.0 Based on [18F]PSMA-1007 PET in Prostate Cancer Patients Treated with [177Lu]Lu-PSMA I&T.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.

Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study

BackgroundThe European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. ObjectiveTo assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. Design, setting, and participantsWe conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. Outcome measurements and statistical analysisBaseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. Results and limitationsA prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). Conclusions177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. Patient summary177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

Abstract CT121: ARX517, an anti-PSMA ADC targeting mCRPC resistant or refractory to standard therapies: A phase 1 dose escalation and dose expansion study (ARX517-2011, NCT04662580)

Abstract Background: Targeted therapies against prostate-specific membrane antigen (PSMA) have exhibited promising antitumor activity in prostate cancer. With the FDA’s approval of (177) Lu-PSMA-617, PSMA has been validated as a target to treat metastatic castration-resistant prostate cancer (mCRPC). ARX517 is an antibody-drug conjugates (ADC) composed of a fully humanized anti-PSMA mAb site-specifically conjugated to AS269, a potent tubulin inhibitor, yielding a drug-to-antibody (DAR) ratio of 2. After binding to PSMA on the surface of cancer cells, ARX517 is internalized and delivers a cytotoxic payload which inhibits tubulin polymerization and induces cellular apoptosis. ARX517’s site-specific linkage, stable conjugation chemistry, and non-cleavable linker exhibit a homogenous drug-antibody-ratio, mAb-like biophysical properties, and exceptional stability. Therefore, ARX517 promotes highly specific tumor cell apoptosis with minimal off-target bystander activity. Trial Design: The Phase 1 study’s dose escalation and dose expansion evaluates the safety, pharmacokinetics, and preliminary evidence of anti-tumor activity of ARX517 in adults with mCRPC. Patients must have mCRPC which is resistant or refractory to standard therapies, including androgen receptor signaling inhibitors, and show disease progression by Prostate Cancer Working Group 3 (PCWG3) criteria. All patients must have adequate organ function and brain metastases must be radiographically stable. Ascending dose levels of ARX517 administered as a single agent will use an i3+3 design in the dose escalation phase. During the dose expansion phase, ARX517 will be administered at the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD). Exploratory pharmacodynamic assessment includes PSMA-PET/CT imaging. The total number of subjects is dependent on the number of ascending doses and cohort size before dose expansion. Status: ARX517-2011 began enrolling patients in July 2021. With no dose limiting toxicities through dose level 6 (2.0 mg/kg Q3W), dose escalation remains ongoing. As of January 2023, the APEX-01 study is currently enrolling in cohort 7 (2.4 mg/kg) of dose-escalation. Dose expansion will start after RP2D or MTD. Citation Format: John Shen, Richard Pachynski, Luke Nordquist, Nabil Adra, Mehmet Bilen, Rahul Aggarwal, Zachary Reichert, Michael Schweizer, Dong Xu, Manan Patel, Jin Zhang, Wenge Shi, Darryl Z. L'Heureux, Scott Tagawa. ARX517, an anti-PSMA ADC targeting mCRPC resistant or refractory to standard therapies: A phase 1 dose escalation and dose expansion study (ARX517-2011, NCT04662580) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT121.

Guidelines for Evaluating Treatment Response Based on Bone Scan for Metastatic Castration-Resistant Prostate Cancer: Prostate Cancer Clinical Trial Working Group 3 Recommendations

In prostate cancer, the bone is the most common site of metastasis, and it is essential to evaluate metastatic bone lesions to assess the tumor burden and treatment response. Castration-resistant prostate cancer refers to the state wherein the cancer continues to progress despite a significant reduction of the sex hormone level and is associated with frequent distant metastasis. The Prostate Cancer Working Group 3 (PCWG3) released guidelines that aimed to standardize the assessment of treatment effects in castration-resistant prostate cancer using bone scintigraphy. However, these guidelines can be challenging to comprehend and implement in practical settings. The purpose of this review was to provide an overview of a specific image acquisition method and treatment response assessment for bone scintigraphy-based evaluation of bone lesions in metastatic castration-resistant prostate cancer, in accordance with the PCWG3 guidelines.

Factores pronósticos de eficacia y seguridad que afectan a la supervivencia global de los pacientes con cáncer de próstata metastásico sometidos a tratamiento con [177Lu]Lu-PSMA-617: estudio en un único centro

BackgroundDetermining the efficacy, safety, and prognostic factors affecting overall survival (OS) among metastatic prostate cancer patients undergoing PSMA-targeted radioligand therapy (PRLT). MethodIn this retrospective study, from November 2016 and December 2019, 43 heavily pretreated (90.7% on 1st line androgen deprivation therapy (ADT), 53.5% on 2nd line ADT, 58.1% on docetaxel) metastatic prostate cancer patients with median age of 71 years (range: 51-88 years) were enrolled. Treatment cycles were repeated every 8 weeks (range: 6-12 weeks). To evaluate the biochemical response after each cycle, prostate specific antigen (PSA) levels were measured and analyzed according to the Prostate Cancer Working Group 3 (PCWG3) criteria cutoffs. Possible adverse events after therapy were retrospectively classified according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. Kaplan-Meier and multivariable Cox proportional hazard regression analyses were used to identify factors associated with OS. ResultsA total of 112 cycles of PRLT with a median of 3 cycles (range: 1-6) and median administered activity per cycle of 6.29 GBq (range: 4.45-7.7 GBq) were used. PSA decline was observed in 65.1% of patients, and best PSA decline of ≥50% and ≥90% were achieved in 39.5% and 23.3% of patients, respectively. Major (grade III) anemia and thrombocytopenia occurred in 11.6% and 7% of patients, respectively. Median OS and median PSA progression-free survival were 52 and 20 weeks, respectively. In univariate analysis, baseline hemoglobin <11.2 g/dL, baseline platelets count ≥327,000/μL, PSA decline <20.94% after first cycle of therapy, Eastern Cooperative Oncology Group (ECOG) >2, baseline PSA ≥115 ng/ml, cumulative dose of 177Lu-PSMA <12.95 GBq, initial alkaline phosphatase ≥196.5 U/L, initial lactate dehydrogenase ≥380 U/L and superscan pattern in bone scintigraphy were associated with worse OS. In multivariable Cox regression analysis, higher baseline platelet count, lower baseline hemoglobin, superscan pattern, and lower cumulative dose of 177Lu-PSMA remained significant predictors of poor OS. ConclusionPRLT with 177Lu-PSMA is well-tolerated and effective in metastatic prostate cancer patients who have no other treatment options available. The novel prognostic markers found in this study (high platelet count, superscan pattern) were associated with poor overall survival.

Automated Bone Scan Index to Optimize Prostate Cancer Working Group Radiographic Progression Criteria for Men With Metastatic Castration-Resistant Prostate Cancer.

Radiographic progression-free survival (rPFS) by Prostate Cancer Working Group (PCWG) criteria is a radiographic endpoint. The automated bone scan index (aBSI) quantifies osseous disease burden on bone scintigraphy as a percentage of total skeletal weight. Using the aBSI, we sought to quantify increase in tumor burden represented by PCWG progression criteria, and to determine the interval increase that best associates with overall survival (OS). Retrospective analysis of trials using androgen receptor axis-targeted drugs for metastatic castration resistant prostate cancer patients (mCRPC). aBSI increase in bone disease was assessed from baseline scan to time-to-progression (per PCWG criteria). Threshold for time to aBSI increase were explored and the association between each time-to-threshold and OS was computed. A total of 169 mCPRC patients had bone scans available for aBSI analysis. Of these, 90 (53%) had progression in bone meeting PCWG criteria. Total aBSI increase in patients meeting PCWG criteria was 1.22 (interquartile range [IQR]: 0.65-2.49), with a median relative increase of 109% (IQR: 40%-377%). Median aBSI at baseline was 3.1 (IQR: 1.3-7.1). The best association between OS and time-to-progression occurred with an absolute increase in aBSI equal to 0.6 (Kendall's tau 0.52). An absolute increase of 0.6 or more in aBSI from the first follow-up scan results in the highest association with OS in patients with mCRPC. The rPFS by PCWG, identified progression at nearly twice this tumor burden, suggesting that aBSI may be used to further develop the PCWG criteria without degrading its association with OS.

Activation of the AKT pathway and outcomes in patients (pts) treated with or without ipatasertib (ipat) in metastatic castration-resistant prostate cancer (mCRPC): Next-generation sequencing (NGS) data from the phase III IPATential150 trial.

5056 Background: Ipat + abiraterone (abi) significantly reduced the risk of radiographic disease progression vs placebo (pbo) + abi in pts with mCRPC and PTEN loss tumors by immunohistochemistry (IHC; HR, 0.77; 95% CI: 0.61, 0.98; P=0.034) but not in ITT pts (HR, 0.84; 95% CI: 0.71, 0.99; P=0.043; Sweeney Lancet 2021). A greater risk reduction was seen in pts with PTEN loss by NGS (HR, 0.65; 95% CI: 0.45, 0.95). We describe the efficacy and safety of pbo + abi vs ipat + abi at the second interim analysis (IA) of overall survival (OS) and explore the impact of AKT pathway alterations. Methods: Pts with mCRPC were randomized 1:1 to ipat (400 mg/d) + abi (1000 mg/d) + prednisone (5 mg bid) or pbo + abi + prednisone. Coprimary endpoints were investigator-assessed radiographic progression-free survival by Prostate Cancer Working Group 3 (PCWG3) criteria in pts with PTEN loss tumors by IHC (PTEN loss in ≥50% of tumor cells) and in ITT pts. Secondary endpoints in both populations included OS, objective response rate (ORR) per RECIST 1.1 and PCWG3 and time to pain progression (TPP). Ad hoc analyses assessed pts with PIK3CA/ AKT1/ PTEN alterations by NGS vs wildtype (WT). Results: Median follow-up was 31 mo (cutoff: 2021 Sept 30). In PTEN loss by IHC pts, median OS was 35.8 mo (n=261) with pbo + abi and 36.8 mo (n=260) with ipat + abi (HR: 0.95; 95% CI: 0.74, 1.21; P=0.665); in ITT pts, median OS was 36.7 mo (n=554) with pbo + abi and 40.3 mo (n=547) with ipat + abi (HR: 0.90; 95% CI: 0.76, 1.07). With longer follow-up, the safety profile was consistent with that of the primary analysis. In the full NGS evaluable population (n=743), ipat + abi was associated with better outcomes in pts with PIK3CA/ AKT1/ PTEN alterations (Table). Among pts with PTEN loss tumors by NGS (205 of the evaluable 518 pts), median OS was 29.8 mo (n=102) with pbo + abi and 35.8 mo (n=103) with ipat + abi (unstratified HR: 0.82; 95% CI: 0.56, 1.19). Conclusions: At the second IA, no significant improvement in OS was observed with ipat + abi in pts with PTEN loss by IHC. Exploratory analyses in pts with PIK3CA/ AKT1/ PTEN alterations by NGS suggest that these patients have poorer prognosis but may derive greater benefit from ipat + abi. Clinical trial information: NCT03072238. [Table: see text]

Correlation Between Imaging-Based Intermediate Endpoints and Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer: Analysis of 28 Randomized Trials Using the Prostate Cancer Clinical Trials Working Group (PCWG2) Criteria in 16,511 Patients.

Radiographic progression-free survival (rPFS) based on Prostate Cancer Working Group 2 (PCWG2) has been increasingly used as a meaningful imaging-based intermediate endpoint (IBIE) for overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). In randomized phase III trials, rPFS showed good correlation with OS at the individual trial level. We aimed to assess the correlation between the hazard ratios (HR) of IBIE and OS among PCWG2-based randomized trials. PubMed and EMBASE databases were systematically searched for randomized trials evaluating systemic treatments on mCRPC using PCWG2 up to April 15, 2020. Hazard ratios for OS and IBIEs were extracted and their correlation was assessed using weighted linear regression. Subgroup analyses were performed according to various clinical settings: prior chemotherapy, drug category, type of IBIE (rPFS vs. composite IBIE, latter defined as progression by imaging and one or a combination of PSA, pain, skeletal-related events, and performance status), and publication year. Twenty-eight phase II-III randomized trials (16,511 patients) were included. Correlation between OS and IBIE was good (R2=0.57, 95% confidence interval [CI], 0.35-0.78). Trials using rPFS showed substantially higher correlation than those using a composite IBIE (R2=0.58, 95% CI, 0.32-0.82 vs. 0.00, 95% CI, -0.01 to 0.01). Correlations between OS and IBIE in other subgroups were at least moderate in nearly all subgroups (R2=0.32-0.91). IBIEs in the era of PCWG2 correlate well with OS in randomized trials for systemic drugs in patients with mCRPC. PCWG2-based rPFS should be used instead of a composite IBIE that includes PSA and other clinical variables.

Imaging response assessment for oncology: An algorithmic approach

Treatment response assessment by imaging plays a vital role in evaluating changes in solid tumors during oncology therapeutic clinical trials. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is the reference standard imaging response criteria and provides details regarding image acquisition, image interpretation and categorical response classification. While RECIST 1.1 is applied for the majority of clinical trials in solid tumors, other criteria and modifications have been introduced when RECIST 1.1 outcomes may be incomplete. Available criteria beyond RECIST 1.1 can be explored in an algorithmic fashion dependent on imaging modality, tumor type and method of treatment. Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) is available for use with PET/CT. Modifications to RECIST 1.1 can be tumor specific, including mRECIST for hepatocellular carcinoma and mesothelioma. Choi criteria for gastrointestinal stromal tumors incorporate tumor density with alterations to categorical response thresholds. Prostate Cancer Working Group 3 (PCWG3) imaging criteria combine RECIST 1.1 findings with those of bone scans. In addition, multiple response criteria have been created to address atypical imaging responses in immunotherapy.

Efficacy, safety and prognostic factors affecting overall survival among metastatic prostate cancer patients undergoing treatment with 177Lu-PSMA-617: A single center study

BackgroundDetermining the efficacy, safety, and prognostic factors affecting overall survival (OS) among metastatic prostate cancer patients undergoing PSMA-targeted radioligand therapy (PRLT). MethodIn this retrospective study, from November 2016 and December 2019, 43 heavily pretreated (90.7% on 1st line androgen deprivation therapy (ADT), 53.5% on 2nd line ADT, 58.1% on docetaxel) metastatic prostate cancer patients with median age of 71 years (range: 51−88 years) were enrolled. Treatment cycles were repeated every 8 weeks (range: 6–12 weeks). To evaluate the biochemical response after each cycle, prostate specific antigen (PSA) levels were measured and analyzed according to the Prostate Cancer Working Group 3 (PCWG3) criteria cutoffs. Possible adverse events after therapy were retrospectively classified according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. Kaplan-Meier and multivariable Cox proportional hazard regression analyses were used to identify factors associated with OS. ResultsA total of 112 cycles of PRLT with a median of 3 cycles (range: 1–6) and median administered activity per cycle of 6.29 GBq (range: 4.45–7.7 GBq) were used. PSA decline was observed in 65.1% of patients, and best PSA decline of ≥50% and ≥90% were achieved in 39.5% and 23.3% of patients, respectively. Major (grade III) anemia and thrombocytopenia occurred in 11.6% and 7% of patients, respectively. Median OS and median PSA progression-free survival were 52 and 20 weeks, respectively. In univariate analysis, baseline hemoglobin <11.2 g/dL, baseline platelets count ≥327,000/μL, PSA decline <20.94% after first cycle of therapy, Eastern Cooperative Oncology Group (ECOG) >2, baseline PSA ≥ 115 ng/mL, cumulative dose of 177Lu-PSMA <12.95 GBq, initial alkaline phosphatase ≥196.5 U/L, initial lactate dehydrogenase ≥380 U/L and superscan pattern in bone scintigraphy were associated with worse OS. In multivariable Cox regression analysis, higher baseline platelet count, lower baseline hemoglobin, superscan pattern, and lower cumulative dose of 177Lu-PSMA remained significant predictors of poor OS. ConclusionPRLT with 177Lu-PSMA is well-tolerated and effective in metastatic prostate cancer patients who have no other treatment options available. The novel prognostic markers found in this study (high platelet count, superscan pattern) were associated with poor overall survival.

Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH).

TPS5087 Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177Lu-PNT2002 (also known as [Lu-177]-PSMA-I&amp;T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526. Clinical trial information: NCT04647526.

Response evaluation of bone metastasis in prostate cancer: Preliminary comparison of computerized bone scan index versus standardized clinical criteria.

The correlation between the computer-assisted bone scan index (BSI) responses versus clinical response classification if bone metastases in prostate cancer patients are not clear. We compared changes in BSI with Prostate Cancer Working Group-3 (PCWG3) and MD Anderson (MDA) criteria. Fifty-six consecutive patients with at least two bone scans (BS) within 12 months were included, who had BS before and after treatment with the same anticancer agent. Progressive disease (PD) by PCWG3 criteria was seen in 28% of the cases (median BSI increased by 1.69 units) versus non-PD in 72% (BSI change -0.13). MDAnderson showed PD in 34% (BSI increase 0.49), 45% stable disease (BSI change 0.00), and 20% partial responses (BSI decrease 1.44). Absolute BSI changes differed significantly among response categories by PCWG3 and MDA criteria (both P<0.0001). Response classification using dichotomized BSI data (>0/≤0 and >0.3/≤0.3 BSI units) showed a significant correlation with PCWG3 and MDA criteria (all P<0.001). Absolute BSI changes and dichotomized BSI correlated to prostate-specific antigen responses (both P<0.001) but not to clinical responses. Absolute changes in BSI and BSI response classification correlated significantly with standardized clinical response criteria for the assessment of treatment responses of skeletal metastases in prostate cancer.

Abstract PO-077: Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH) - Trial in progress

Abstract Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177Lu-PNT2002 (also known as [Lu-177]-PSMA-I&amp;T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526. Citation Format: Kim N. Chi, Ur Metser, Johannes Czernin, Jeremie Calais, Vikas Prasad, Matthias Eiber, Neal Shore, Jessica Jensen, Neil Fleshner, Scott Tagawa, Oliver Sartor. Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH) - Trial in progress [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-077.

Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): The phase III KEYNOTE-991 study.

TPS184 Background: The combination of pembro, an anti–PD-1 antibody, added to enza, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC) in the KEYNOTE-365 trial (NCT02861573) and in pts with mCRPC for whom enza was ineffective in the KEYNOTE-199 trial (NCT02787005). The efficacy of enza may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembro. These data indicate that pembro + enza with ADT warrants phase 3 evaluation. Methods: KEYNOTE-991 (NCT04191096) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial evaluating the efficacy and safety of enza + ADT (luteinizing hormone-releasing hormone agonist/antagonist during study treatment or bilateral orchiectomy) + pembro or placebo in pts with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Pts must provide tissue for biomarker analysis. Approximately 1232 pts will be randomized in a 1:1 ratio to receive enza 160 mg orally once daily + ADT + pembro 200 mg intravenously (IV) every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembro up to 35 cycles and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Computed tomography or magnetic resonance imaging and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) every 12 weeks (Q12W) from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The dual-primary endpoints are BICR-assessed radiographic progression-free survival (rPFS; according to PCWG3-modified RECIST v1.1) and overall survival (OS). Key secondary endpoints are time to first subsequent anticancer therapy (TFST) and time to symptomatic skeletal-related event (TTSSRE). Safety and tolerability will be evaluated using a tiered approach. The dual-primary (rPFS and OS) and key secondary (TFST and TTSSRE) endpoints will be evaluated using a stratified log-rank test. Event rates will be summarized using the Kaplan-Meier method, and hazard ratios will be estimated using a stratified Cox regression model. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Germany, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States. Clinical trial information: NCT04191096.

Has the COVID-19 outbreak changed the way we are treating prostate cancer? An EAU - YAU Prostate Cancer Working Group multi-institutional study.

IntroductionThe COVID-19 outbreak has become the dominant issue throughout the world whilst the governments, nations and health services are trying to deal with its impact. The aim of our study is to assess the impact of COVID-19 on patients treated with radical prostatectomy (RP) for prostate cancer (PCa) at European referral centers in terms of surgical volume (SV), waiting list meant as time from biopsy to surgery (WL) and risk of adverse pathologic findings at RP due to the selection of men with more adverse disease characteristics at final pathology.Material and methodsConsecutive patients with a diagnosis of histologically proven PCa treated with RP between March 2020 (WHO declaration of pandemic) and December 2020 were identified. Patients with metastatic disease not eligible to local treatment and recurrent prostate cancer after RP or RT were excluded. Patients treated at the same institutions between March 2019 and December 2019 were considered as the control group. Multivariable logistic regression analysis tested the impact of the COVID-19 outbreak on the risk of adverse pathologic findings at RP after adjusting for confounders. The percentage change of SV and WL was assessed comparing the months of pandemic with the equivalent timespan of the previous year.ResultsA total of 2,574 patients treated with RP (927 cases and 1647 controls) were identified in 8 European tertiary referral centers. At multivariable analysis patients who were treated during the pandemic had higher risk of extra prostatic disease (OR:1.35, p = 0.038) and lymph node invasion (LNI) (OR:1.72, p = 0.048). An average 23% reduction of the SV with the equivalent timespan of the previous year allowed an illusory reduction of the WL after the peak gained during the first wave of COVID-19.ConclusionsOur results showed that the COVID-19 outbreak resulted in a delay in the administration of curative-intent therapies in patients with localized PCa. This, in turn, resulted in a stage migration phenomenon with a potential impact on oncologic control.

Prostate-specific Antigen Progression in Enzalutamide-treated Men with Nonmetastatic Castration-resistant Prostate Cancer: Any Rise in Prostate-specific Antigen May Require Closer Monitoring

BackgroundThere is no universally accepted definition for prostate-specific antigen (PSA) progression. However, changes in PSA in patients with castration-resistant prostate cancer (CRPC) are used to inform treatment decisions. ObjectiveTo determine whether the Prostate Cancer Working Group 2 (PCWG2) definition of PSA progression is adequate to predict radiographic or clinical progression in enzalutamide-treated men with nonmetastatic CRPC (nmCRPC). Design, setting, and participantsA post hoc, retrospective analysis of men with nmCRPC from PROSPER (NCT02003924) was performed. InterventionContinued androgen deprivation therapy; patients randomized 2:1 to enzalutamide 160 mg/d or placebo. Outcome measurements and statistical analysisMetastasis-free survival (MFS) in men with and without PSA progression, defined by PCWG2, and PSA at the time of radiographic progression were assessed. Results and limitationsAs of June 28, 2017, in enzalutamide-treated patients, the risk of metastasis or death was increased significantly in those with PSA progression versus those without (hazard ratio [HR] 3.99; 95% confidence interval [CI], 2.95–5.41; p < 0.0001). Median MFS was not reached (NR; 95% CI, NR–NR) in patients without PSA progression and was 22.6 mo (95% CI, 21.9–29.0) in those with PSA progression. In placebo-treated patients, PSA progression was not significantly associated with MFS (HR 1.72; 95% CI, 0.86–3.45; p = 0.1). Median MFS was NR (95% CI, 25.6–NR) in patients without PSA progression and 18.3 mo (95% CI, 14.9–19.4) in those with PSA progression. The median PSA increase from nadir at the time of radiographic progression was 1.4 ng/mL in enzalutamide-treated men and 25.6 ng/mL for the placebo arm. ConclusionsIn men with nmCRPC and rapidly rising PSA, radiographic progression often occurred without PCWG2-defined PSA progression, suggesting that any increase in PSA may warrant closer monitoring. While PCWG2-defined PSA progression was associated with radiographic progression in enzalutamide-treated men, our findings argue for prospective re-evaluation of this threshold. Patient summaryIn this report, we looked at changes in prostate-specific antigen (PSA) in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer who no longer respond to testosterone-lowering treatment. We found that even very small changes in PSA while on treatment could be an early indication of disease progression and should trigger closer monitoring.

Abstract CT269: A phase 2 study of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) and/or homologous recombination repair deficiency (HRD): KEYLYNK-007

Abstract Background: Treatment with the anti-PD-1 antibody pembrolizumab has improved clinical outcomes in multiple previously treated advanced solid tumors. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity as monotherapy in patients with previously treated advanced ovarian, breast, pancreatic, and prostate cancers with BRCA1/BRCA2 mutations (BRCAm). Activity was also seen in patients with previously treated advanced solid tumors with other HRRm and in those with ovarian cancer with HRD phenotype. PARP inhibitors have been found to increase interferon signaling and tumor infiltrating lymphocytes, enhancing tumor susceptibility to immune checkpoint blockade. Antitumor activity of PD-(L)1 plus PARP inhibition was found to be higher than expected with either agent alone in patients with recurrent ovarian cancer regardless of BRCAm or HRD status and in patients with BRCAm breast cancer. KEYLYNK-007 (NCT04123366) evaluates the antitumor activity and safety of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with HRRm and/or HRD. Methods: This phase 2, nonrandomized, multicenter, open-label study plans to enroll approximately 300 patients aged ≥18 years with histologically/cytologically confirmed, previously treated, advanced solid tumors with HRRm and/or HRD per Lynparza HRR-HRD assay (Foundation Medicine, Inc., Cambridge, MA, USA), with an ECOG PS of 0-1. Patients will be grouped by biomarker status: subgroup 1: BRCAm; subgroup 2: HRRm without BRCAm; and subgroup 3: HRD positive without HRRm (loss of heterozygosity score ≥16 per Lynparza HRR-HRD assay). Patients will receive olaparib 300 mg twice daily + pembrolizumab 200 mg intravenously Q3W (35 cycles) until PD, unacceptable AEs, intercurrent illness, investigator decision, withdrawal of consent, or pregnancy. Tumor imaging assessment by blinded independent central review (BICR) per RECIST version 1.1 or Prostate Cancer Working Group (PCWG)-modified RECIST version 1.1 for prostate cancer will occur Q9W for 12 months, then Q12W until PD, start of new anticancer treatment, withdrawal of consent, pregnancy, or death. AEs will be monitored throughout the study and for 30 days after final dose (90 days for serious AEs) and are graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5. The primary endpoint is ORR (RECIST version 1.1 or PCWG-modified RECIST version 1.1 by BICR). Secondary endpoints include duration of response (DOR) and PFS (RECIST version 1.1 or PCWG-modified RECIST version 1.1 by BICR), OS, and safety. Point estimate and exact Clopper-Pearson CI for ORR, and Kaplan-Meier estimates for DOR, PFS, and OS will be calculated. Citation Format: Timothy A. Yap, Mallika Dhawan, Andrew E. Hendifar, Michele Maio, Taofeek K. Owonikoko, Miguel Quintela-Fandino, Ronnie Shapira-Frommer, Sanatan Saraf, Ping Qiu, Fan Jin, Alexander Gozman, Douglas A. Levine. A phase 2 study of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) and/or homologous recombination repair deficiency (HRD): KEYLYNK-007 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT269.

Evaluating biomarkers in metastatic castration-resistant prostate cancer patients treated with enzalutamide: PSA, circulating tumor cell counts, AR-V7 status and radiographic progression.

e17569 Background: Enzalutamideis ahighly effective treatment in metastatic castration resistant prostate cancer (mCRPC). Although Prostate Cancer Working Group (PCWG) guidelines recommend continuing treatment until radiographic/clinical progression (rPD/cPD), many patients discontinue therapy for rising PSA alone. Methods: We conducted an open label, randomized phase 2 trial in mCRPC patients untreated with docetaxel, abiraterone, or enzalutamide, comparing enzalutamide alone or in combination with PROSTVAC, a therapeutic cancer vaccine designed to induce an anti-tumor immune response. The study discontinued accrual after planned interim analysis indicated no difference in progression between the two arms. Patients were followed beyond 1st of 3 confirmed PSA rises until rPD. 49 patients were analyzed for Circulating Tumor Cell (CTC) count and AR-V7 status at 1st PSA rise and at rPD/cPD or last follow up. Results: 57 patients were enrolled with median follow up time of 55.4 mo. 49/57 (86%) patients had rising PSA; median time to 1st PSA rise for all patients was 6.4 mo (95% CI: 3.7-11.0 mo) after starting enzalutamide. 38/57 (67%) patients had progressive disease (majority with rPD; 1/38 (3%) with cPD); median time to progression for all patients was 23.3 mo (95% CI: 16.1-27.8 mo). 5 patients tested positive for AR-V7 within 30 days of rPD. In patients who experienced rPD/cPD, CTCs were detected in 11/24 (46%) samples taken at rPD vs. in only 3/24 (13%) samples taken at rising PSA. CTC counts were higher at rPD compared to samples taken at rising PSA (P = 0.004, Wilcoxon unpaired test). Of the 7 patients still being treated (median time on drug = 4.2 yrs), 2 experienced rising PSA; however none of the patients had detectable CTCs at a median of 30 days from last follow up. Conclusions: These data suggest that a rising PSA may not be a warning of near-term clinically significant disease progression in mCRPC patients treated with enzalutamide, given the 17-month difference between the first rise in PSA and ultimate rPD/cPD seen in this analysis. Further, CTCs and AR-V7 status associate strongly with rPD but not with rising PSA, adding biological rationale to the hypothesis that CTC counts and AR-V7 status are associated with disease progression. Collectively, these data highlight the need to continue to educate patients and providers on PCWG criteria for progression and appropriately-timed utilization of both therapies and diagnostic tests to maximize drug efficacy in mCRPC. Clinical trial information: NCT01867333 .