scholarly journals Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 334
Author(s):  
Dhruv Bansal ◽  
Melissa A. Reimers ◽  
Eric M. Knoche ◽  
Russell K. Pachynski
Keyword(s):  
Prostate Cancer ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Immunosuppressive Tumor Microenvironment ◽  
Prostate Cancers ◽  
Past Experiences

Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.

scholarly journals A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone

2020 ◽  
Vol 8 (2) ◽  
pp. e000642 ◽  
Author(s):  
Julie N Graff ◽  
Tomasz M Beer ◽  
Joshi J Alumkal ◽  
Rachel E Slottke ◽  
William L Redmond ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Specific Antigen ◽  
Subsequent Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Entire Cohort ◽  
Castration Resistant

BackgroundCheckpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response.MethodsWe evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens.ResultsFive (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression.ConclusionsPembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects.Trial registration numberclinicaltrials.gov (NCT02312557).

scholarly journals Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer

2021 ◽  
pp. 1200-1220
Author(s):  
Fadi Taza ◽  
Albert E. Holler ◽  
Wei Fu ◽  
Hao Wang ◽  
Nabil Adra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Missense Mutations ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

PURPOSE Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration–approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/ 2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/ 2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. RESULTS A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively ( P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.

The association of ATM alterations with clinical and molecular features in metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17019-e17019
Author(s):  
Guo Xi ◽  
Qing WANG ◽  
Qin Zhang ◽  
Qianqian Duan ◽  
Yaqin Liu
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Specific Antigen ◽  
Standard Of Care ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoints ◽  
Castration Resistant Prostate Cancer ◽  
Molecular Features ◽  
Castration Resistant ◽  
Homozygous Deletions

e17019 Background: Ataxia telangiectasia-mutated（ATM）is a serine/threonine kinase involved in DNA-damage repair (DDR) system and regulating cell cycle checkpoints, senescence, and apoptosis. Several clinical studies provide evidence about the DDR-mutated metastatic castration-resistant prostate cancer (mCRPC) benefit from PARP inhibitors (PARPi). However. the efficacy of PARPi was limited for mCRPC patients harboring ATM aberrations. We aimed to determine the association of ATM mutations with clinical and molecular features in patients with mCRPC. Methods: A total of three independent prostate cancer cohorts (MCTP, N = 61; SU2C-PCF, N = 429; MSKCC, N = 451) were used for analysis. We selected patients with characteristics “mCRPC” and “histology type: prostate adenocarcinoma”. Both the somatic and germline pathogenic alterations were analyzed, including single nucleotide variations (SNVs), in-frame insertions or deletions (Indels), frameshifts, homozygous deletions and fusions. The statistical analysis was conducted by R software (v.3.6.2). Results: We merged the three mCRPC cohorts, generating a new cohort consisting of 507 mCRPC patients. The median age was 62 (range, 38.6-89). The number of biopsies was 1-3 per patient. Of the 527 sequenced specimens, 39% were lymph node, 27% were bone, and 14% were liver. Forty percent of the patients had exposed to or on-treatment with next-generation androgen receptor signaling inhibitor (ARSI). A total of 44 patients (8.7%) harbored deleterious variations in ATM, including 10 homozygous deletions. The coexistence mutations were most commonly located in androgen receptor ( AR), followed by TTN/KMT2C/MUC16/TP53. Furthermore, we explored the association of pathogenic ATM alterations with clinical features. Compared with noncarriers of ATM mutations , carriers were diagnosed at a younger age (median: 59 vs 62.4, P = 0.022). In the subgroup from SU2C-PCF cohort, prostate specific antigen (PSA) at diagnosis and the proportion of Gleason score between 8-10 were analyzed, both showed no significant differences between the two groups. Notably, we observed a statistically significant higher TMB in ATM-altered group than ATM wildtype group (median, 2.04 vs 1.61, P = 0.013). Overall survival (OS) was not compared because of the limited clinical outcomes in ATM-mutated population. Conclusions: This study involving 3 cohorts identified the prevalence of pathogenic somatic or germline ATM mutations and explored the association of ATM alterations with both clinical and molecular features. Patients with ATM mutations tended to diagnose prostate cancer at an earlier age. Meanwhile, significantly higher TMB might imply potential immunotherapy opportunities in ATM-altered mCRPC without standard-of-care approaches.

scholarly journals Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors

2021 ◽  
Author(s):  
Fred Saad ◽  
Martin Bögemann ◽  
Kazuhiro Suzuki ◽  
Neal Shore
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Second Generation ◽  
Imaging Techniques ◽  
Specific Antigen ◽  
Conventional Imaging ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Therapeutic Decisions ◽  
Consensus Statements

Abstract Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit–risk profile of potential treatments is required. Methods In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function. Results and conclusions While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit–risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

Bone modifying agents in veterans with castration-resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6582-6582
Author(s):  
Jordan Bauman ◽  
Kyle Kumbier ◽  
Jennifer A. Burns ◽  
Jordan Sparks ◽  
Phoebe A. Tsao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Specific Antigen ◽  
Veterans Health ◽  
Health Administration ◽  
Castration Resistant Prostate Cancer ◽  
National Guidelines ◽  
Castration Resistant ◽  
Unit Increase

6582 Background: Skeletal related events (SREs) are a known complication for the 80% of men with metastatic prostate cancer who have bone metastases. Previous studies have demonstrated that bone modifying agents (BMAs) such as zoledronic acid and denosumab reduce SREs in men with metastatic castration-resistant prostate cancer who have bone metastases and are now recommended by national guidelines. We sought to investigate factors associated with use of BMAs in Veterans with CRPC across the Veterans Health Administration (VA). Methods: Using the VA Corporate Data Warehouse, consisting of aggregated medical record data from 130 facilities, we used an algorithm previously published to identify men with a diagnosis of castration-resistant prostate cancer (CRPC) based on rising prostate specific antigen (PSA) levels while on androgen deprivation therapy and who received systemic treatment for CRPC with one of the commonly used therapies: abiraterone, enzalutamide, docetaxel, ketoconazole between 2010 and 2017. To account for clustering among facilities, we used a multilevel multivariable logistic regression to determine the association of patient and disease-specific variables on the odds of a patient receiving a BMA after they started treatment for CRPC. Results: Of 4,998 patients with CRPC in our cohort, 2223 (44%) received either zoledronic acid or denosumab at some point after they were initiated on treatment for CRPC. After adjusting for other variables and accounting for a facility, the odds of receiving a BMA decreased by 3% for every additional year of age (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.96-0.98), and decreased significantly with increasing comorbid conditions (OR 0.94, 95% CI 0.72-0.98 for Charlson Comorbidity Index [CCI] of 1; OR 0.69, 95% CI 0.59-0.81 for CCI 2+). Patients who were Black had 25% lower odds of receiving a BMA than patients who were White (OR 0.75, 95% CI 0.65-0.87). PSA at time of CRPC treatment start had a small but not significant effect on receipt of a BMA (OR 1.04, 95% CI 1.00-1.08) for every unit increase of PSA on the log scale. PSA doubling time was not associated with receipt of a BMA. The presence of a diagnosis code for bone metastases was far lower than expected in this cohort of patients with CRPC (40.7%), and thus was not included in the model. We did not expect the presence of bone metastases to vary significantly among the other independent variables. Conclusions: Despite most patients with CRPC historically having bone metastases, less than half of patients with CRPC received a BMA. Patients who are older, had more comorbidities, or were Black were less likely to receive a BMA after starting treatment for CRPC. Understanding factors that lead to different patterns of treatment can guide initiatives toward more guideline-concordant care.

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