Outcomes in patients (Pts) with advanced prostate cancer and inactivating germline mutations in BRCA2 or ATM.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 242-242 ◽  
Author(s):  
Steven Yip ◽  
Daniel Khalaf ◽  
Werner J. Struss ◽  
Katherine Sunderland ◽  
Gillian Vandekerkhove ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Median Time ◽  
Advanced Prostate Cancer ◽  
Germline Mutations ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Available N ◽  
Atm Gene

242 Background: Germline mutations in homologous recombination repair (HRR) genes, including BRCA2, are present in 6-12% of pts with metastatic castration-resistant prostate cancer (mCRPC). BRCA2 germline mutations are associated with high-grade and poor-prognosis localized disease, while outcomes in pts with advanced prostate cancer continue to be defined. Methods: Germline DNA from 536 consecutive mCRPC pts in our liquid biopsy program were screened for BRCA2 and ATM gene mutations using targeted sequencing. Kaplan-Meier curves were used to estimate the median time from androgen deprivation therapy (ADT) initiation to mCRPC, progression free survival (PFS) on first-line androgen receptor (AR) targeted therapy, and overall survival (OS). Outcomes in BRCA2 or ATM germline mutation carriers and a subset of the total sample of HRR wild-type (WT) pts, who had clinical data available (n = 113), were compared using the log-rank test. Results: 26/536 (4.9%) of pts had germline BRCA2 (n = 22) or ATM mutations (n = 4). After ADT initiation, HRR mutated pts progressed to mCRPC with a median time of 13.4 mo compared to 19.0 mo in WT pts (HR = 1.6, [95% CI 1.0-2.5], p = 0.03). HRR mutated pts had a median PFS on first-line AR-targeted therapy in the mCRPC setting of 3.3 mo versus 7.9 mo in WT pts (HR = 2.2, [95% CI 1.3-3.5], p = 0.002). OS for HRR mutated pts from the time of ADT was 57.7 mo in contrast to 104.9 mo in WT pts (HR = 1.8, [95% CI 1.0-3.4], p = 0.07). OS from time of CRPC was 29.7 mo in HRR mutated pts versus 50.3 mo in WT pts (1.6, [95% CI 0.8-2.9], p = 0.16). Conclusions: Germline HRR mutated pts perform poorly with shorter PFS on first-line AR-targeted therapy and time to mCRPC, in contrast to WT pts. These findings support the hypothesis that BRCA2 and ATM gene mutated pts have poor outcomes with current AR-targeted treatments and should be evaluated for alternate regimens.

Impact of germline DNA-repair gene BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-naïve prostate cancer: A single center analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5056-5056
Author(s):  
Vsevolod Borisovich Matveev ◽  
Liudmila Lyubchenko ◽  
Andrey Kirichek
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Median Time ◽  
Germline Mutations ◽  
Castration Resistance ◽  
First Line ◽  
Chek2 Mutation ◽  
Mutation Carriers ◽  
Significant Difference ◽  
The Impact

5056 Background: Germline mutations in DNA repair genes are common in patients with andvanced and metastatic prostate cancer (mPCa). Although BRCA mutation carriers have worse outcomes than noncarriers when conventionally treated for local or locally advanced PCa, recent studies reported conflicting results regarding their aggressiveness in patients with advanced disease. This study aimed to examine the impact of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with mPCa, receiving hormonal androgen deprivation therapy (ADT). Methods: A total of 76 patients with hormone-naive mPCa treated with first line ADT by luteinizing hormone-releasing hormone analogue (LHRHa) between 2014 and 2017 were recruited. Median follow-up was 34,8 mo. We focused on age, volume of metastatic spread, histologic grade, family history. All patients were genotyped for germline mutations in the BRCA1, BRCA2 and CHEK2 genes by polymerase chain reaction real-time and the Sanger sequencing. We used the standard definition of castration-resistance PCa (CRPC). Median time to CRPC were estimated using the Kaplan-Meier method, generated curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA1/2 and CHEK2 mutations. Results: Pathogenic and likely pathogenic germline mutations in the BRCA2 and CHEK2 gene were identified in 19 (25 %) patients. No cases of BRCA1 mutations were detected. Median time to CRPC was significantly shorter in BRCA2 and CHEK2 mutation carriers (7.9 mo, 95 % confidence interval (CI) 2.6 – 13.3), than in non-carriers (48.7 mo, 95 % CI 31.1 – 68.3, p < 0,001). There was no significant difference in median time to CRPC in BRCA2 (7.9 mo, 95 % CI 0.0 - 16.3) and CHEK2 mutation carriers (6.1 mo, 95 CI 5.0 - 7.2, p = 0,448) meanwhile both were shorter than in non-carriers (p = 0.002 and < 0,001). Multivariate analysis confirmed both BRCA2 (hazard ratio [HR]: 2.63; 95 CI 1.32-5.26, p = 0.006) and CHEK2 (HR 6.66, 95 CI 2.35-18.89, p < 0.001) mutations as an independent prognostic factor for time to CRPC, particularly in mPCa with low-volume metastatis spread (HR 3.09, 95 % CI 1.36–7.05, р = 0.007 and HR 14.1, 95 % CI 3.65-54.4, p < 0.001). Conclusions: BRCA2 and CHEK2 carriers had worse outcomes (shortened time to CRPC) than noncarriers when conventionally treated for metastatic PCa by standard first-line hormone treatment with LHRHa.

Prediction of favorable outcome in a docetaxel rechallenge setting in metastatic castration-resistant prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 68-68
Author(s):  
Matthias Michael Heck ◽  
Mark K. Thalgott ◽  
Margitta Retz ◽  
Petra Wolf ◽  
Tobias Maurer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Oncological Outcome ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Treatment Variable ◽  
Castration Resistant ◽  
Line Chemotherapy

68 Background: To identify predictors of favourable oncological outcome in metastatic castration-resistant prostate cancer (mCRPC) patients who are treated with docetaxel rechallenge following first-line chemotherapy with docetaxel. Methods: We retrospectively evaluated the oncological outcome of mCRPC patients who were treated with 3-weekly docetaxel (75mg/m2) at first-line chemotherapy and rechallenge plus prednisone/ prednisolone. The endpoints of oncological outcome were PSA-progression-free survival (PSA-PFS) and overall survival (OS) after initiation of docetaxel rechallenge. The effect of clinical variables on PSA-PFS and OS was statistically analysed by a log-rank test or Cox regression with hazard ratios. All analyses were performed using a 0.05 level of significance. Results: 47 patients were included on analysis. At a median follow-up of 25.8 months (range 9.8-89.8 months) after the first administration of docetaxel, 27 (57.4%) patients had died. Median PSA-PFS was 5.9 months (95% CI 3.5-6.8 months) and median OS was 21.4 months (95% CI 18.9-23.9 months) after initiation of docetaxel rechallenge. PSA-reduction ≥ 30% was the only pre-treatment variable that correlated significantly with prolonged PSA-PFS (p=0.03) and OS (p=0.002). Patients with PSA-reduction ≥ 30% at first-line chemotherapy showed a median OS of 21.8 months since initiation of docetaxel rechallenge in comparison to 4.5 months in patients with < 30% PSA-reduction. Conclusions: Docetaxel rechallenge represents an active treatment option in selected docetaxel-pretreated patients with mCRPC. In this retrospective study, PSA-reduction ≥ 30% at first-line chemotherapy with docetaxel predicted superior PSA-PFS and OS in the rechallenge setting and might, therefore, present a rational indication for docetaxel rechallenge.

Effect of germline DNA repair gene mutations on outcomes in men with metastatic castration-resistant prostate cancer receiving first-line abiraterone and enzalutamide.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 221-221
Author(s):  
Emmanuel S. Antonarakis ◽  
Changxue Lu ◽  
Brandon Luber ◽  
Hao Wang ◽  
Yan Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Germline Mutations ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Repair Gene ◽  
Castration Resistant ◽  
Dna Repair Gene

221 Background: Inherited DNA repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Here we investigated the clinical significance of germline DNA repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line novel hormonal therapy (NHT), with a particular emphasis on BRCA1/2 and ATM mutations. Methods: We interrogated 50 DNA repair genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT: abiraterone or enzalutamide. We assessed the impact of germline DNA repair gene mutation status on ≥50% and ≥90% PSA response rates, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results: Among 172 mCRPC patients, germline mutations (in any DNA repair gene) were found in 12.8% (22/172) of men, and germline BRCA/ATM mutations were found in 5.2% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs. no mutations) with respect to ≥90% PSA responses (78% vs. 28%, P = 0.004), PSA-PFS (HR 0.47, P = 0.061), PFS (HR 0.50, P = 0.090) and OS (HR 0.28, P = 0.059). In propensity score-weighted multivariable analyses, outcomes remained superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95%CI 0.25–0.92, P = 0.027), PFS (HR 0.52, 95%CI 0.28–0.98, P = 0.044) and OS (HR 0.34, 95%CI 0.12–0.99, P = 0.048), but this was not true for men with non- BRCA/ATM germline mutations (all endpoints, P > 0.10). Conclusions: Outcomes to first line NHT appeared better in mCRPC patients harboring germline BRCA/ATM mutations (vs. no mutations), but not for patients with other non- BRCA/ATM germline mutations. These results support the hypothesis that AR may promote DNA repair, and that inhibiting AR in the context of homologous recombination deficiency may lead to synthetic lethality.

Real world patterns of treatment sequencing in Canada for metastatic castrate-resistant prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 320-320
Author(s):  
Sebastien J. Hotte ◽  
Antonio Finelli ◽  
Shawn Malone ◽  
Bobby Shayegan ◽  
Alan I. So ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Best Practices ◽  
Real World ◽  
Advanced Prostate Cancer ◽  
First Line ◽  
Online Questionnaire ◽  
Physician Practices ◽  
Research Education ◽  
Treatment Sequencing

320 Background: The Canadian GU Research Consortium (GURC) was recently established to bring advanced prostate cancer centres together to collaborate on research, education, and adoption of best practices. As an initial step to inform the work of the GURC, an electronic questionnaire was designed to assess management of advanced prostate cancer care in Canada and how prostate cancer treatments are sequenced in a real-world setting. Methods: A 59-item online questionnaire was developed by a multidisciplinary scientific committee to measure physician practices, patterns of care, treatment sequencing, and management of mCRPC. After pre-testing, the online questionnaire was sent to 93 urologists, uro-oncologists, medical oncologists, radiation oncologists, and general practitioner oncologists who are actively involved in the treatment of prostate cancer. Results: A total of 49 (53%) respondents completed the questionnaire between April 17, 2017 to May 17, 2017. Based on physician reports, the most frequently used treatment for first-line mCRPC was AR-targeted therapy (94%, n = 46 physicians) such as abiraterone acetate plus prednisone and enzalutamide. Among those 46 physicians, AR-targeted therapy was usually followed by docetaxel second-line therapy (57%, 31 physicians). The most common line 1 to line 3 treatment sequence for mCRPC was: AR-targeted therapy--Docetaxel--AR-targeted therapy (35%, 17 physicians), followed by AR-targeted therapy--Docetaxel--Radium 223 (14%, n = 7), Provincial differences were observed in the line 1 to line 3 treatment sequences, which aligned to variation in provincial policies for access to the treatments. In patients previously treated with docetaxel in the hormone sensitive setting, the most frequently used treatment for first-line mCRPC was AR-targeted therapy (76%, 37 physicians). Conclusions: AR targeted therapy followed by docetaxel is the predominant pattern of practice for management of mCRPC, with variability beyond these lines of therapy. Prospective ongoing work through the GURC in research, education and best practices will aim to understand these practice patterns.

Retrospective cohort analysis of real-world clinical outcomes in nonmetastatic (M0) castration-resistant prostate cancer (CRPC) treated with novel androgen receptor pathway inhibitors (ARPI).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 51-51
Author(s):  
Richard Gagnon ◽  
Nimira S. Alimohamed ◽  
Alexander Watson ◽  
Eugene Batuyong ◽  
Alyssa Chow ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcomes ◽  
Real World ◽  
Retrospective Cohort ◽  
Cohort Analysis ◽  
Progression Free Survival ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Survival Times ◽  
Free Survival

51 Background: The landscape of M0 CRPC has changed with the recent demonstration of metastasis-free survival (MFS) and overall survival (OS) improvements with the use of ARPIs in clinical trial settings. However, the extrapolation of this data to clinical practice is limited by strict exclusion criteria in these trials, including prior or concurrent malignancy, cardiovascular disease, or hypertension. The purpose of this study was to assess real-world outcomes in patients with M0 CRPC treated with ARPIs compared to historical controls. Methods: We designed a retrospective cohort study with the inclusion of patients in Alberta, Canada diagnosed with M0 CRPC between 2001-2020. Via chart review, we identified baseline characteristics, potential confounders, treatment details, and clinical outcomes. The primary outcome of interest was MFS. Secondary outcomes included: second progression-free survival (PFS2) and OS. Median survival times were measured using the Kaplan-Meier method and the log-rank test was used for comparison of outcomes based on ARPI exposure. Cox proportional hazard regression models were used to calculate hazard ratios (HR) accounting for impact of PSA doubling time (PSADT), use of osteoclast inhibiting agents, and presence of pelvic lymphadenopathy. Results: We identified 211 patients across multiple centres in Alberta with M0 CRPC, with 54 having received apalutamide (40/54), enzalutamide (7/54), or darolutamide (7/54). Median age at M0 CRPC diagnosis was 74 years; median PSADT was 4.4 months; and 19% of patients (40/211) had pelvic lymphadenopathy at diagnosis. Median MFS in patients treated with ARPIs was 47.5 months compared to 20.6 months in those not treated with ARPIs (HR, 0.23; 95% confidence interval [CI], 0.11-0.49; p < 0.001). Median PFS2 in ARPI treated patients was 66.3 months compared with 35.6 months (HR, 0.40; 95% CI, 0.18-0.87; p = 0.022). Median OS for patients treated with ARPI was not reached. Conclusions: Given the older age of men with advanced prostate cancer, real-world outcomes that include patients with comorbidities are important adjuncts to the interpretation of clinical trials exploring the benefit of novel therapeutics. Here, we demonstrate that in a real-world, unselected population of men with M0 CRPC, apalutamide, enzalutamide, and darolutamide seem to confer similar MFS and PFS2 benefits to those demonstrated in the SPARTAN, PROSPER, and ARAMIS studies. Real-world OS data remain immature and will be an important addition to these findings.

Mental health care utilization among veterans with castration-resistant prostate cancer receiving abiraterone or enzalutamide.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18680-e18680
Author(s):  
Phoebe A. Tsao ◽  
Jennifer A. Burns ◽  
Shami Entenman ◽  
Kyle Kumbier ◽  
Jordan Sparks ◽  
...  
Keyword(s):  
Mental Health ◽  
Prostate Cancer ◽  
Health Care ◽  
Mental Health Care ◽  
Health Administration ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Castration Resistant ◽  
Diagnostic Characteristics ◽  
Comorbidity Burden

e18680 Background: Abiraterone and enzalutamide are oral therapies widely used to treat men with castration-resistant prostate cancer (CRPC). Recent data have suggested potentially worsened quality of life and depression with use of enzalutamide compared to abiraterone. Because Veterans are at a higher risk for mental health conditions, we sought to compare mental health service utilization in Veterans with CRPC receiving enzalutamide to those receiving abiraterone. Methods: The Veterans Health Administration Corporate Data Warehouse was used to identify men with CRPC who received abiraterone or enzalutamide for ≥ 30 days as first-line treatment between 2010-2017. We compared the rate of mental health visits per 100 patient-months for men on abiraterone versus enzalutamide using an exact rate ratio test, assuming Poisson counts. Results: Among 2902 male Veterans, 68.6% (n=1992) received abiraterone and 31.4% (n=910) enzalutamide as first-line therapy. Men who received enzalutamide were older (76 vs 74, p<0.01) and had a higher comorbidity burden (Charlson Comorbidity Index [CCI] ≥ 2 in 28.7% vs 21.6%, p<0.01); no differences were noted in race or prevalence of preexisting documented mental health diagnoses. Median time on drug was 8 months for both medications. There was no difference in the rate of mental health visits per 100 patients-months on enzalutamide versus abiraterone (6.6 v. 6.7, p=0.66). However, within patient sub-groups, men who were age 75 or older, not married, or without notable comorbidities had lower rates of mental health visits with enzalutamide compared to abiraterone; whereas those who were younger than 75, married, had higher comorbidities, or a preexisting mental health diagnosis had higher rates of mental health visits with enzalutamide (Table). Conclusions: Among Veterans with CRPC who received a novel antiandrogen therapy first-line, there was no difference in engagement in mental health care between those who received abiraterone versus enzalutamide. Sub-group analysis revealed significant differences between patients on the two medications in demographic and diagnostic characteristics associated with number of visits, suggesting that vulnerability for mental health symptoms may vary by medication type. Further work in understanding the long-term impact of novel antiandrogens on mental health is needed.[Table: see text]

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 25-25
Author(s):  
Hanna Tukachinsky ◽  
Russell Madison ◽  
Jon Chung ◽  
Lucas Dennis ◽  
Bernard Fendler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Acquired Resistance ◽  
Genomic Analysis ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Cancer Tissue ◽  
Castration Resistant Prostate Cancer ◽  
High Level ◽  
Tumor Dna

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.

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