Publications by authors named "Emmanuel S Antonarakis"

279 Publications

Olaparib and rucaparib for the treatment of DNA repair-deficient metastatic castration-resistant prostate cancer.

Expert Opin Pharmacother 2021 Apr 7:1-8. Epub 2021 Apr 7.

Department of Oncology and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: Metastatic prostate cancer is a heterogeneous disease characterized by clinical and genomic heterogeneity. Many prostate cancers harbor mutations causing DNA repair deficiency, specifically homologous recombination deficiency, sensitizing to drugs that inhibit poly ADP-ribose polymerase (PARP). PARP is an enzyme that is involved in single-stranded DNA repair and is the target of newly approved treatments for metastatic prostate cancer.

Areas Covered: Here, the authors' review the clinical trials leading to the recent approvals of two PARP inhibitors (PARPi), olaparib and rucaparib, specifically TOPARP-A, TOPARP-B, PROfound and TRITON-2. They also compare the different FDA approvals for both of these medications and outline the safety of this class of drugs in prostate cancer.

Expert Opinion: Because PARPi are particularly effective in men with somatic or germline alterations in BRCA1 and BRCA2, we recommend that all men be tested for DNA alterations with next-generation sequencing in tumor cells obtained from either tissue or blood. We also recommend that olaparib or rucaparib be considered relatively early in the treatment sequence in metastatic castration-resistant prostate cancer patients with BRCA1 or BRCA2 mutations. Other DNA alterations might also sensitize to PARPi though the response rates are lower, so other standard therapies should be prioritized first.
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http://dx.doi.org/10.1080/14656566.2021.1912015DOI Listing
April 2021

Circulating tumor cell chromosomal instability and neuroendocrine phenotype by immunomorphology and poor outcomes in men with mCRPC treated with abiraterone or enzalutamide.

Clin Cancer Res 2021 Apr 5. Epub 2021 Apr 5.

Divisions of Medical Oncology and Urology, Departments of Medicine and Surgery, Duke Cancer Institute

Background: While the detection of the AR-V7 in CTCs is associated with resistance to abiraterone or enzalutamide (abi/enza) in men with metastatic castration resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance.

Methods: PROPHECY was a multicenter prospective study of men with poor risk mCRPC starting abi/enza. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abi/enza and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression free survival (PFS) and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at MSKCC.

Results: We enrolled 118 men with mCRPC starting on abi/enza; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS (HR 2.2, 95% CI 1.2-4.0 and HR 3.8, 95% CI 1.2-12.3, respectively) when treated with abi/enza. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n=173, HR 5.7, 95% CI 2.6-12.7).

Conclusions: A high chromosomal instability and neuroendocrine CTC phenotype is independently associated with worse survival in men with mCRPC treated with abi/enza, warranting further prospective controlled predictive studies to inform treatment decisions.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3471DOI Listing
April 2021

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

Prostate 2021 May 1;81(7):433-439. Epub 2021 Apr 1.

Department of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana, USA.

Background: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations.

Methods: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed.

Results: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men.

Conclusions: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.
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http://dx.doi.org/10.1002/pros.24123DOI Listing
May 2021

A Randomized Phase II Study of Androgen Deprivation Therapy with or without Palbociclib in RB-positive Metastatic Hormone-Sensitive Prostate Cancer.

Clin Cancer Res 2021 Mar 16. Epub 2021 Mar 16.

Northwestern University/Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.

Purpose: Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, blocks proliferation in a RB and cyclin D-dependent manner in preclinical prostate cancer models. We hypothesized that cotargeting androgen receptor and cell cycle with palbociclib would improve outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Experimental Design: A total of 60 patients with RB-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD + palbociclib. Primary endpoint was PSA response rate (RR) after 28 weeks of therapy. Secondary endpoints included safety, PSA, and clinical progression-free survival (PFS), as well as PSA and radiographic RR. Tumors underwent exome sequencing when available. Circulating tumor cells (CTC) were enumerated at various timepoints.

Results: A total of 72 patients with mHSPC underwent metastatic disease biopsy and 64 had adequate tissue for RB assessment. A total of 62 of 64 (97%) retained RB expression. A total of 60 patients initiated therapy (Arm 1: 20; Arm 2: 40). Neutropenia was the most common grade 3/4 adverse event in Arm 2. Eighty percent of patients (Arm 1: 16/20, Arm 2: 32/40; = 0.87) met primary PSA endpoint ≤4 ng/mL at 28 weeks. PSA undetectable rate at 28 weeks was 50% and 43% in Arms 1 and 2, respectively ( = 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively ( = 0.72). TP53 and PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS.

Conclusions: Palbociclib did not impact outcome in RB-intact mHSPC. Pretreatment CTC, TP53 and PIK3 pathway mutations, and 8q gain were associated with poor outcome.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0024DOI Listing
March 2021

mutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types.

J Immunother Cancer 2021 Mar;9(3)

Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, North Carolina, USA

Background: Low-density lipoprotein receptor-related protein 1b (encoded by ) is a putative tumor suppressor, and preliminary evidence suggests mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).

Methods: We conducted a multicenter, retrospective pan-cancer analysis of patients with alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) alterations compared with variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by status.

Results: We identified 101 patients (44 Duke, 35 JHU, 22 UM) with alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).

Conclusions: This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.
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http://dx.doi.org/10.1136/jitc-2020-001792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929846PMC
March 2021

Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial.

Prostate 2021 May 26;81(6):326-338. Epub 2021 Feb 26.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival.

Methods: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7-expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS).

Results: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1-NR) in cohort 1 and 2.7 (95% CI: 2.1-5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8-7.5) in cohort 1 and 2.9 (95% CI: 1.3-5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%-45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%-52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5-10.4) in cohort 1 and 14.2 (95% CI: 8.5-NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11-0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06-0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03-0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47-13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels.

Conclusion: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, -7, and -17) may be prognostic for outcomes to immunotherapy.
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http://dx.doi.org/10.1002/pros.24110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018565PMC
May 2021

Association between BRCA2 alterations and intraductal and cribriform histologies in prostate cancer.

Eur J Cancer 2021 Apr 21;147:74-83. Epub 2021 Feb 21.

Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain; Genitourinary Cancer Translational Research Group, Instituto de Investigación Biomédica de Málaga, Spain; Medical Oncology, UGCI, Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, Málaga, Spain. Electronic address:

Background: Intraductal (IDC) and cribriform (CRIB) histologies in prostate cancer have been associated with germline BRCA2 (gBRCA2) mutations in small retrospective series, leading to the recommendation of genetic testing for patients with IDC in the primary tumour.

Patients And Methods: To examine the association of gBRCA2 mutations and other tumour molecular features with IDC and/or cribriform (CRIB) histologies, we conducted a case-control study in which primary prostate tumours from 58 gBRCA2 carriers were matched (1:2) by Gleason Grade Group and specimen type to 116 non-carriers. Presence/absence of IDC and CRIB morphologies was established by two expert uropathologists blinded to gBRCA2 status. Fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS) were used to detect BRCA2 alterations, PTEN deletions and TMPRSS2-ERG fusions. Chi-squared tests were used to compare the frequency of IDC and CRIB in gBRCA2 carriers and controls and to assess associations with other variables. Logistic regression models were constructed to identify independent factors associated with both histology patterns.

Results: No significant differences between gBRCA2 carriers and non-carriers were observed in the prevalence of IDC (36% gBRCA2 versus 50% non-carriers, p = 0.085) or CRIB (53% gBRCA2 versus 43% non-carriers p = 0.197) patterns. However, IDC histology was independently associated with bi-allelic BRCA2 alterations (OR 4.3, 95%CI 1.1-16.2) and PTEN homozygous loss (OR 5.2, 95%CI 2.1-13.1). CRIB morphology was also independently associated with bi-allelic BRCA2 alterations (OR 5.6, 95%CI 1.7-19.3).

Conclusions: While we found no association between gBRCA2 mutations and IDC or CRIB histologies, bi-allelic BRCA2 loss in primary prostate tumours was significantly associated with both variant morphologies, independently of other clinical-pathologic factors.
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http://dx.doi.org/10.1016/j.ejca.2021.01.027DOI Listing
April 2021

TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer.

J Clin Oncol 2021 Feb 22:JCO2002759. Epub 2021 Feb 22.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC).

Methods: The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL).

Results: The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT.

Conclusion: This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.
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http://dx.doi.org/10.1200/JCO.20.02759DOI Listing
February 2021

Prospective, Single-Arm Trial Evaluating Changes in Uptake Patterns on Prostate-Specific Membrane Antigen (PSMA)-Targeted F-DCFPyL PET/CT in Patients with Castration-Resistant Prostate Cancer Starting Abiraterone or Enzalutamide.

J Nucl Med 2021 Feb 19. Epub 2021 Feb 19.

Johns Hopkins University School of Medicine, United States.

Positron emission tomography (PET) with small molecules targeting prostate-specific membrane antigen (PSMA) is being adopted as a clinical standard for prostate cancer (PCa) imaging. In this study, we evaluated changes in uptake on PSMA-targeted PET in men starting abiraterone or enzalutamide. This prospective, single-arm, two-center, exploratory clinical trial enrolled men with metastatic castration-resistant prostate cancer (CRPC) initiating abiraterone or enzalutamide. Each patient was imaged with F-DCFPyL at baseline and within 2-4 months after starting therapy. Patients were followed for up to 48 months from enrollment. A central review evaluated baseline and follow-up PET scans recording change in maximum standardized uptake value (SUV) at all disease sites and classifying the pattern of change. Two parameters: the delta percent SUV (DPSM) of all lesions and the delta absolute SUV (DASM) of all lesions were derived. Kaplan-Meier curves were used to estimate time to therapy change (TTTC) and overall survival (OS). Sixteen evaluable patients were accrued to the study. Median TTTC was 9.6 months (95% confidence interval (CI), 6.9-14.2) and median OS was 28.6 months (95% CI 18.3-not available (N/A)). Patients with a mixed-but-predominantly-increased pattern of radiotracer uptake had shorter TTTC and OS. Men with low DPSM had median TTTC 12.2 months (95% CI 11.3-N/A) and median OS 37.2 months (95% CI 28.9-N/A), while those with high DPSM had median TTTC 6.5 months (95% CI 4.6-N/A, = 0.0001) and median OS 17.8 months (95% CI 13.9-N/A, = 0.02). Men with low DASM had median TTTC 12.2 months (95% CI 11.3-N/A) and median OS N/A (95% CI 37.2 months-N/A), while those with high DASM had median TTTC 6.9 months (95% CI 6.1-N/A, = 0.003) and median OS 17.8 months (95% CI 13.9-N/A, = 0.002). Findings on PSMA-targeted PET 2-4 months after initiation of abiraterone or enzalutamide are associated with TTTC and OS. Development of new lesions and/or increasing intensity of radiotracer uptake at sites of baseline disease are poor prognostic findings suggesting shorter TTTC and OS.
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http://dx.doi.org/10.2967/jnumed.120.259069DOI Listing
February 2021

NCCN Guidelines Insights: Prostate Cancer, Version 1.2021.

J Natl Compr Canc Netw 2021 02 2;19(2):134-143. Epub 2021 Feb 2.

National Comprehensive Cancer Network.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.
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http://dx.doi.org/10.6004/jnccn.2021.0008DOI Listing
February 2021

Streamlining Germline Genetic Testing in Prostate Cancer.

Eur Urol Oncol 2021 Feb 20;4(1):10-11. Epub 2021 Jan 20.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Electronic address:

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http://dx.doi.org/10.1016/j.euo.2020.12.013DOI Listing
February 2021

Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer.

Mod Pathol 2021 Jan 18. Epub 2021 Jan 18.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median = 27) than those with germline ATM or CHEK2 mutations (median = 16.5 [p = 0.029] and 9 [p < 0.001], respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median = 28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs. 11; p = 0.015); this finding was confirmed in the PROGENE cohort (24 vs. 16; p = 0.001). Finally, among eight BRCA2-altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs. 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2-altered cases have significantly higher HRD scores than germline ATM-altered or CHEK2-altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.
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http://dx.doi.org/10.1038/s41379-020-00731-4DOI Listing
January 2021

Detection of Early Progression with F-DCFPyL PET/CT in Men with Metastatic Castration-Resistant Prostate Cancer Receiving Bipolar Androgen Therapy.

J Nucl Med 2021 Jan 15. Epub 2021 Jan 15.

Johns Hopkins University, United States.

Bipolar androgen therapy (BAT) is an emerging treatment for metastatic castration resistant prostate cancer (mCRPC). F-DCFPyL is a small-molecule positron emission tomography (PET) radiotracer targeting prostate-specific membrane antigen (PSMA). We analyzed the utility of F-DCFPyL PET/CT in determining clinical response to BAT. Six men with mCRPC receiving BAT were imaged with F-DCFPyL PET/CT at baseline and after 3 months of treatment. Progression by PSMA-targeted PET/CT was defined as the appearance of any new F-DCFPyL-avid lesion. Three of 6 (50%) patients had progression on F-DCFPyL PET/CT. All three had stable disease or better on contemporaneous conventional imaging. Radiographic progression on CT and/or bone scan was observed within 3 months of progression on F-DCFPyL PET/CT. For the 3 patients that did not have progression on F-DCFPyL PET/CT, radiographic progression was not observed for > 6 months. New radiotracer-avid lesions on F-DCFPyL PET/CT in men with mCRPC undergoing BAT can indicate early progression.
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http://dx.doi.org/10.2967/jnumed.120.259226DOI Listing
January 2021

Randomized Phase II Trial of Sipuleucel-T with or without Radium-223 in Men with Bone-metastatic Castration-resistant Prostate Cancer.

Clin Cancer Res 2021 Mar 15;27(6):1623-1630. Epub 2021 Jan 15.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.

Purpose: To investigate whether radium-223 increases peripheral immune responses to sipuleucel-T in men with bone-predominant, minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

Patients And Methods: A total of 32 patients were randomized 1:1 in this open-label, phase II multicenter trial. Patients in the control arm received three sipuleucel-T treatments, 2 weeks apart. Those in the combination arm received six doses of radium-223 monthly, with sipuleucel-T intercalated between the second and fourth doses of radium-223. The primary endpoint was a comparison of peripheral antigen PA2024-specific T-cell responses (measured by proliferation index). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and PSA responses.

Results: We enrolled 32 patients, followed for a median of 1.6 years. Six weeks after the first sipuleucel-T dose, participants in the control arm had a 3.2-fold greater change in PA2024-specific T-cell responses compared with those who received combination treatment ( = 0.036). Patients in the combination arm were more likely to have a >50% PSA decline [5 (31%) vs. 0 patients; = 0.04], and also demonstrated longer PFS [39 vs. 12 weeks; HR, 0.32; 95% confidence interval (CI), 0.14-0.76] and OS (not reached vs. 2.6 years; HR, 0.32; 95% CI, 0.08-1.23).

Conclusions: Our data raise the possibility of greater clinical activity with the combination of sipuleucel-T and radium-223 in men with asymptomatic bone mCRPC, despite the paradoxically lower immune responses observed. Additional study to confirm these findings in a larger trial is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4476DOI Listing
March 2021

The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited.

Eur Urol 2021 Jan 5. Epub 2021 Jan 5.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical.

Objective: To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.

Design, Setting, And Participants: This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.

Outcome Measurements And Statistical Analysis: We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).

Results And Limitations: The frequency of driver mutations in TP53 (p =  0.01), WNT (p =  0.08), and cell cycle (p =  0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p =  0.002), and time to CRPC (95.6 vs 155.8 mo; p =  0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p =  0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p =  0.004) and DNA double-strand break repair (IRR 1.61; p <  0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p =  0.03) and the development of CRPC (HR 1.71; p =  0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.

Conclusions: Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.

Patient Summary: Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.
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http://dx.doi.org/10.1016/j.eururo.2020.12.040DOI Listing
January 2021

Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy.

Eur J Cancer 2021 Feb 29;144:302-309. Epub 2020 Dec 29.

The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Cyclical, high-dose testosterone administration, termed bipolar androgen therapy (BAT), can induce clinical responses and restore sensitivity to androgen signalling inhibition in patients with previously treated castration-resistant prostate cancer (PCa) (CRPC). This trial evaluated whether BAT is a safe and effective first-line hormonal therapy for patients with CRPC.

Patients And Methods: In cohort C of this single-centre, open-label, phase II, multi-cohort trial (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance study), 29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist. The primary end-point of the study was the PSA response rate to BAT treatment.

Results: After treatment with BAT, four of 29 patients (14%; 95% confidence interval [CI]: 4-32%) experienced a PSA response. The median radiographic progression-free survival to BAT was 8.5 months (95% CI: 6.9-15.1) for patients with metastatic CRPC. After progression on BAT, 17 of 18 patients (94%; 95% CI: 73-100%) achieved a PSA response and 15 of 18 patients (83%; 95% CI: 59-96) achieved a PSA response on abiraterone or enzalutamide. Twelve of 15 patients (80%; 95% CI: 52-96) with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months.

Conclusion: As first-line hormonal treatment for CRPC, BAT was well tolerated and resulted in prolonged disease stabilisation. After progression on BAT, patients had favourable responses to second-generation androgen receptor-targeted therapy.

Trial Registration: ClinicalTrials.gov NCT02090114.
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http://dx.doi.org/10.1016/j.ejca.2020.11.043DOI Listing
February 2021

Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair-Deficient Prostate Cancer.

Oncologist 2021 Feb 3;26(2):e270-e278. Epub 2020 Dec 3.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Genomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer.

Methods: To enrich for response to anti-PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort.

Results: Nineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy. The PSA response rate was 65%, and the median progression-free survival (PFS) was 24 (95% confidence interval 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment and with density of CD8+ tumor-infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort.

Conclusion: Tumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity.

Implications For Practice: Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti-PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.
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http://dx.doi.org/10.1002/onco.13601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873327PMC
February 2021

Deficiency and the Immune Microenvironment in Prostate Cancer.

Clin Cancer Res 2021 Jan 16;27(2):380-382. Epub 2020 Nov 16.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

CDK12 inactivation in prostate cancer is associated with tandem genomic duplications that may generate fusion-associated neoantigens and elicit immune responses amenable to checkpoint blockade. In the first study to comprehensively characterize the T-cell immune microenvironment of CDK12-deficient prostate cancers, subsets of immunosuppressive CD4FOXP3 T cells were increased compared with CDK12-proficient controls..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855343PMC
January 2021

Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis.

Cancer Cell 2021 Jan 12;39(1):68-82.e9. Epub 2020 Nov 12.

Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Università della Svizzera Italiana, Lugano 6900, Switzerland; Department of Medicine, University of Padua, Padua 35128, Italy; Department of Health Sciences and Technology (D-HEST) ETH Zurich, Zurich 8093, Switzerland. Electronic address:

Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by PTEN deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.
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http://dx.doi.org/10.1016/j.ccell.2020.10.012DOI Listing
January 2021

Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer.

JCO Precis Oncol 2020 28;4. Epub 2020 Oct 28.

Department of Biostatistics and Bioinforamtics, Duke University, Durham, NC.

Purpose: Androgen receptor splice variant 7 (AR-V7) detection in circulating tumor cells (CTCs) is associated with a low probability of response and short progression-free (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide or abiraterone. However, it is unclear whether such men benefit from taxane chemotherapy.

Patients And Methods: PROPHECY is a multicenter prospective blinded study of patients with poor-risk mCRPC starting abiraterone or enzalutamide and observed through subsequent progression and taxane chemotherapy. We assessed AR-V7 status using the Johns Hopkins modified AdnaTest CTC AR-V7 messenger RNA assay and the Epic Sciences CTC nuclear-localized AR-V7 protein assay before treatment. The primary objective was to validate the independent prognostic value of CTC AR-V7 status based on radiographic/clinical PFS. OS, confirmed prostate-specific antigen (PSA), and objective radiologic responses were secondary end points.

Results: We enrolled 118 men with mCRPC treated with abiraterone or enzalutamide, 51 of whom received subsequent docetaxel or cabazitaxel. Pretreatment CTC AR-V7 status by the Johns Hopkins and Epic Sciences assays was independently associated with worse PFS (hazard ratio [HR], 1.7; 95% CI, 1.0 to 2.9 and HR, 2.1; 95% CI, 1.0 to 4.4, respectively) and OS (HR, 3.3; 95% CI, 1.7 to 6.3 and HR, 3.0; 95% CI, 1.4 to 6.3, respectively) and a low probability of confirmed PSA responses, ranging from 0% to 11%, during treatment with abiraterone or enzalutamide. At progression, subsequent CTC AR-V7 detection was not associated with an inferior PSA or radiographic response or worse PFS or OS with subsequent taxane chemotherapy after adjusting for CellSearch CTC enumeration and clinical prognostic factors.

Conclusion: Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7-positive disease still experience clinical benefits from taxane chemotherapy.
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http://dx.doi.org/10.1200/PO.20.00200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608579PMC
October 2020

Role of androgen receptor splice variant-7 (AR-V7) in prostate cancer resistance to 2nd-generation androgen receptor signaling inhibitors.

Oncogene 2020 11 28;39(45):6935-6949. Epub 2020 Sep 28.

Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

The role of truncated androgen receptor splice variant-7 (AR-V7) in prostate cancer biology is an unresolved question. Is it simply a marker of resistance to 2nd-generation androgen receptor signaling inhibitors (ARSi) like abiraterone acetate (Abi) and enzalutamide (Enza) or a functional driver of lethal resistance via its ligand-independent transcriptional activity? To resolve this question, the correlation between resistance to ARSi and genetic chances and expression of full length AR (AR-FL) vs. AR-V7 were evaluated in a series of independent patient-derived xenografts (PDXs). While all PDXs lack PTEN expression, there is no consistent requirement for mutation in TP53, RB1, BRCA2, PIK3CA, or MSH2, or expression of SOX2 or ERG and ARSi resistance. Elevated expression of AR-FL alone is sufficient for Abi but not Enza resistance, even if AR-FL is gain-of-function (GOF) mutated. Enza resistance is consistently correlated with enhanced AR-V7 expression. In vitro and in vivo growth responses of Abi-/Enza-resistant LNCaP-95 cells in which CRISPR-Cas9 was used to knockout AR-FL or AR-V7 alone or in combination were evaluated. Combining these growth responses with RNAseq analysis demonstrates that both AR-FL- and AR-V7-dependent transcriptional complementation are needed for Abi/Enza resistance.
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http://dx.doi.org/10.1038/s41388-020-01479-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655549PMC
November 2020

Practical Considerations and Challenges for Germline Genetic Testing in Patients With Prostate Cancer: Recommendations From the Germline Genetics Working Group of the PCCTC.

JCO Oncol Pract 2020 12 28;16(12):811-819. Epub 2020 Sep 28.

Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, CA.

Germline genetic testing is now routinely recommended for patients with prostate cancer (PCa) because of expanded guidelines and options for targeted treatments. However, integrating genetic testing into oncology and urology clinical workflows remains a challenge because of the increased number of patients with PCa requiring testing and the limited access to genetics providers. This suggests a critical unmet need for genetic services outside of historical models. This review addresses current guidelines, considerations, and challenges for PCa genetic testing and offers a practical guide for genetic counseling and testing delivery, with solutions to help address potential barriers and challenges for both providers and patients. As genetic and genomic testing become integral to PCa care, developing standardized systems for implementation in the clinic is essential for delivering precision oncology to patients with PCa and realizing the full scope and impact of genetic testing.
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http://dx.doi.org/10.1200/OP.20.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735040PMC
December 2020

PARP Inhibitors in Metastatic Prostate Cancer: Evidence to Date.

Cancer Manag Res 2020 7;12:8105-8114. Epub 2020 Sep 7.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are a unique class of antineoplastic agents that function by inducing synthetic lethality. Synthetic lethality occurs when PARPi and either another agent or an underlying genetic alteration together lead to overwhelming DNA damage and ultimately cell death. PARPi first showed promise as a cancer therapy in patients with mutations and have become part of standard treatment for breast and ovarian cancer. In prostate cancer, two PARPi, rucaparib and olaparib, have been FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). While both agents are approved for tumors with alterations, for olaparib the indication is also expanded to patients with 12 other homologous recombination deficiency (HRD) gene alterations including and . PARPi differ in their pharmacokinetics and pharmacodynamics, and additional studies are being conducted with niraparib, veliparib, and talazoparib in prostate cancer. While PARPi are fairly well tolerated, common toxicities include hematologic (anemia/thrombocytopenia) and gastrointestinal effects (nausea/vomiting). Ongoing studies are being conducted combining PARPi with other agents in patients with and without HRD alterations. Early data are promising for the combination of PARPi with second-generation antiandrogens and with immunotherapy. As additional trials are developed and reported, the hope is that the patient population who may benefit from PARPi will continue to expand.
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http://dx.doi.org/10.2147/CMAR.S227033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489946PMC
September 2020

Preclinical studies show using enzalutamide is less effective in docetaxel-pretreated than in docetaxel-naïve prostate cancer cells.

Aging (Albany NY) 2020 Sep 10;12(17):17694-17712. Epub 2020 Sep 10.

George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester, Rochester, NY 14642, USA.

Anti-androgen therapy with Enzalutamide (Enz) has been used as a therapy for castration resistant prostate cancer (CRPC) patients after development of resistance to chemotherapy with Docetaxel (Doc). The potential impacts of Doc-chemotherapy on the subsequent Enz treatment, however, remain unclear. Here we found the overall survival rate of patients that received Enz was significantly less in patients that received prior Doc-chemotherapy than those who had not. studies from 3 established Doc resistant CRPC (DocRPC) cell lines are consistent with the clinical findings showing DocRPC patients had decreased Enz-sensitivity as well as accelerated development of Enz-resistance enhanced androgen receptor (AR) splicing variant 7 (ARv7) expression. Mechanism dissection found that Doc treatment might increase the generation of ARv7 altering the MALAT1-SF2 RNA splicing complex. Preclinical studies using mouse models and cell lines proved that targeting the MALAT1/SF2/ARv7 axis with small molecules, including siMALAT1, shSF2, and shARv7 or ARv7 degradation enhancers: Cisplatin or ASC-J9, can restore/increase the Enz sensitivity to further suppress DocRPC cell growth. Therefore, combined therapy of Doc-chemotherapy with anti-ARv7 therapy, including Cisplatin or ASC-J9®, may be developed to increase the efficacy of Enz to further suppress DocRPC in patients.
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http://dx.doi.org/10.18632/aging.103917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521536PMC
September 2020

Versus and PARP Inhibitor Sensitivity in Prostate Cancer: More Different Than Alike?

J Clin Oncol 2020 11 1;38(32):3735-3739. Epub 2020 Sep 1.

Department of Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD.

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http://dx.doi.org/10.1200/JCO.20.02246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655018PMC
November 2020

When and How to Use PARP Inhibitors in Prostate Cancer: A Systematic Review of the Literature with an Update on On-Going Trials.

Eur Urol Oncol 2020 10 17;3(5):594-611. Epub 2020 Aug 17.

Smilow Cancer Center, Yale University, New Haven, CT, USA.

Context: The goal of precision oncology is to use the underlying genomic characteristics of the patient and the cancer to select the optimal treatment at a given time. The recent Food and Drug Administration (FDA) approval of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib for the treatment of advanced prostate cancer heralds the onset of precision medicine for this disease.

Objective: To discuss the emerging role that PARP inhibitors may play as a personalised future treatment option in patients with prostate cancer, with a focus on patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumour cells harbour mutations resulting from deficient homologous recombination repair (HRR).

Evidence Acquisition: To identify publications relevant to this review, a systematic literature search of PubMed was conducted for articles and proceedings of relevant major congresses, published between January 2010 and March 2020, reporting the use of PARP inhibitors in the treatment of cancers.

Evidence Synthesis: A total of 168 publications were identified, and 18 of these met the criteria for subsequent review. In addition, 15 phase 2 or on-going phase 3 (mCRPC) studies evaluating PARP inhibitors as monotherapy or in combination, which had not yet reported data, were identified through ClinicalTrials.gov. Emerging data suggest that the greatest efficacy with single-agent PARP inhibitors is seen in mCRPC patients with germline or somatic BRCA1/2 alterations (especially BRCA2 or biallelic mutations), with potential efficacy also observed in men with PALB2 and FANCA mutations.

Conclusions: PARP inhibitors have demonstrated efficacy in mCRPC, and similar to ovarian and breast cancers, the greatest effect is observed in patients with HRR deficiency. The PARP inhibitors olaparib and rucaparib are now FDA approved for mCRPC patients with HRR mutations and BRCA1/2 mutations, respectively. Furthermore, when PARP inhibition is combined with novel hormonal therapies, a treatment benefit may be observed regardless of the HRR deficiency status. Gaps in the knowledge and understanding around PARP inhibitor use in prostate cancer, including the most appropriate diagnostic testing method for identifying an HRR mutation, remain to be resolved.

Patient Summary: The poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib are now approved by the Food and Drug Administration for the treatment of advanced prostate cancer. Here, we reviewed the literature and proceedings from meeting presentations and published papers relevant to the use of PARP inhibitors in the treatment of prostate cancer. Testing methods for detecting homologous recombination repair gene mutations, as diagnostic tools to help identify patients most likely to benefit from PARP inhibitor treatment, are also discussed.
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http://dx.doi.org/10.1016/j.euo.2020.07.005DOI Listing
October 2020

Patterns of Recurrence and Modes of Progression After Metastasis-Directed Therapy in Oligometastatic Castration-Sensitive Prostate Cancer.

Int J Radiat Oncol Biol Phys 2021 Feb 14;109(2):387-395. Epub 2020 Aug 14.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland. Electronic address:

Purpose: Metastasis-directed therapy (MDT) is increasingly used in castration-sensitive oligometastatic prostate cancer because it prolongs progression-free survival (PFS) and androgen deprivation free survival. Here we describe patterns of recurrence and identify modes of progression after MDT using SABR.

Methods And Materials: Two hundred fifty-eight patients with castration-sensitive oligometastatic prostate cancer (≤5 lesions at staging) were retrospectively identified from a multi-institutional database. Descriptive patterns of recurrence and modes of progression were reported. Other outcomes including median time to prostate-specific antigen (PSA) recurrence, time to next intervention, distant metastasis-free survival, overall survival, and biochemical PFS (bPFS) were reported. Survival analysis was performed using the Kaplan-Meier method, and multivariable analysis was performed.

Results: Median follow-up was 25.2 months, and 50.4% of patients received concurrent androgen deprivation. Median time to PSA recurrence was 15.7 months, time to next intervention was 28.6 months, distant metastasis-free survival was 19.1 months, and bPFS was 16.1 months. Two-year overall survival was 96.8%. On multivariable analysis, factors associated with bPFS included age (hazard ratio [HR], 1.03; P = .04), N1 disease at diagnosis (HR, 2.00; P = .02), M1 disease at diagnosis (HR, 0.44; P = .01), initial PSA at diagnosis (HR, 1.002; P = <.001), use of androgen deprivation therapy (HR, 0.41; P < .001), pre-SABR PSA (HR, 1.02; P = .01), and use of enhanced imaging for staging (HR, 2.81; P = .001). Patterns of progression favored an osseous component at recurrence; in patients initially treated to a bone lesion alone, the vast majority (86.5%) experienced a recurrence that included an osseous site. Patients treated initially to a nodal site alone tended to recur in a node only (64.5%); however, there was also a significant minority with an osseous component of recurrence at progression (32.3%). Modes of progressors were class I (patients with long term control [no recurrence ≥18 months after therapy]) occurring in 40.9%, class II (oligoprogressors [≤3 lesions at recurrence]) occurring in 36% (including 7.9% of patients with PSA recurrence but no metastatic disease), and class III (polyprogressors [>3 lesions]) occurring in 23.1% of patients.

Conclusions: After MDT, the majority of patients have long-term control or oligoprogression (class I or II). Recurrence tended to occur in osseous sites. These findings, if validated, have implications for future integration of MDT and clinical trial design.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856169PMC
February 2021

Reimagining Vaccines for Prostate Cancer: Back to the Future.

Clin Cancer Res 2020 Oct 31;26(19):5056-5058. Epub 2020 Jul 31.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Given the modest clinical benefits observed with immune checkpoint blockade in advanced prostate cancer, there is a renewed interest in exploring other forms of immunotherapy. Here, the authors report the use of a novel plasmid DNA vaccine encoding the androgen receptor, called pTVG-AR, in men with metastatic hormone-sensitive prostate cancer..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2257DOI Listing
October 2020