Using real-world outcomes to evaluate the predictive power of tissue-assessed genomic biomarkers for taxane versus novel hormonal therapy (NHT) outcomes in metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5054-5054
Author(s):  
Ryon Graf ◽  
Virginia Fisher ◽  
Ole Gjoerup ◽  
Alexa Betzig Schrock ◽  
Russell Madison ◽  
...  
Keyword(s):  
Hormonal Therapy ◽  
Propensity Scores ◽  
Treatment Decisions ◽  
Castration Resistant Prostate Cancer ◽  
Cox Models ◽  
Tissue Samples ◽  
Genomic Biomarkers ◽  
Psa Response ◽  
Line Of Therapy ◽  
Taxane Chemotherapy

5054 Background: No established genomic biomarkers exist for guiding treatment decisions between novel hormonal therapy (NHT) vs taxane chemotherapy in mCRPC. However, specific alterations in AR have been associated to decreased responsiveness to NHT in this setting. Leveraging routine comprehensive genomic profiling (CGP) testing of mCRPC tissue samples, we hypothesized that patients (pts) with AR amplification ( ARamp) would have better outcomes on taxanes over NHT. Methods: Pts were selected from Flatiron Health (FH)-Foundation Medicine (FMI) clinico-genomic database (CGDB), a nationwide deidentified electronic health record database linked to CGP. Data originated from approximately 280 US cancer clinics (̃800 sites). CGP results (including analysis of AR and 15 other genomic biomarkers) were obtained from mCRPC tumor tissue collected up to 180 days before or 30 days after initiation of new systemic therapy between 1/1/11 - 6/30/20, and linked to PSA response, time to next therapy (TTNT) and overall survival (OS). Multivariable treatment interaction models were adjusted for drug assignment imbalances (line of therapy, prior NHT or taxane use, PSA, alkaline phosphatase, hemoglobin, albumin, years to CRPC, biopsy site) using inverse probability of treatment weighting via propensity scores. Results: Among 5754 evaluable mCRPC lines of therapy, 180 receiving NHT and 179 receiving taxanes met inclusion criteria, 359 total from 308 unique patients. Pts with ARamp vs no ARamp on NHT had worse PSA response (median +57.3% vs. -31.4%, p = 0.002), TTNT (HR: 2.03, p < 0.001), and OS (HR: 2.28, p < 0.001), but had no difference in outcomes on taxanes. Multivariable interaction Cox models found ARamp independently associated to better TTNT on taxanes vs. NHT (HR: 0.48, p = 0.010), similar to pts with RB1 alterations (HR: 0.46, p = 0.027). Consistent treatment interactions were seen with OS for ARamp (HR: 0.53, p = 0.025) and RB1 (HR: 0.32, p = 0.024). While CDK12 was not predictive, it independently associated with worse OS overall (HR: 2.25, p = 0.0011). In the 55 pts who received NHT followed by taxane immediately after, ARamp pre-NHT was associated with better TTNT on the subsequent taxane than on the initial NHT (HR: 0.40, p = 0.028). Of these, 33 had PSA responses evaluable, and ARamp pre-NHT was significantly associated with better PSA decline on the subsequent taxane, despite disadvantage of first progressing on NHT (OR: 10.9, p = 0.021). Conclusions: Genomic biomarkers routinely identified with CGP such as ARamp may aid in identifying mCRPC pts who are to obtain greater benefit from taxane chemotherapy instead of NHT. Prospective efforts are needed to further validate the utility of CGP for assisting treatment decisions for mCRPC patients.

ERG rearrangements and association with clinical outcome in patients (pts) receiving abiraterone acetate (AA): Results from the COU-AA-302 study in chemotherapy (chemo)-naïve metastatic castration-resistant prostate cancer (mCRPC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5004-5004 ◽  
Author(s):  
Gerhardt Attard ◽  
Johann Sebastian De Bono ◽  
Weimin Li ◽  
Arturo Molina ◽  
Thomas W. Griffin ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Tissue Samples ◽  
Psa Response ◽  
Psa Progression

5004 Background: ERG rearrangements result in androgen receptor-modulated up-regulation of ERG and may predict for AA response in mCRPC. Concordance has been shown between ERG status in archival samples and fresh CRPC biopsies (Attard et al., Cancer Res. 2009;69:2912). In this prospectively defined biomarker sub-study, the association between ERG subtypes and clinical outcome in chemo-naïve mCRPC pts receiving AA was evaluated. Methods: COU-AA-302 is a randomized double blind study of AA (1 g) + prednisone (P) (5 mg BID) vs placebo + P in chemo-naïve mCRPC. Fluorescence in situ hybridization (FISH) assays to evaluate ERG subtypes (Attard et al., Oncogene. 2008;27:253) were conducted on 524 archival prostate tissue samples (365 biopsies, 107 RPEs, 44 TURPs, 3 bone marrows, 5 lymph nodes) from 497 pts. Clinical outcome measures included radiographic progression-free survival (rPFS) (central [CEN] and investigator [INV] reviewed), time to PSA progression (TTPP), and PSA ≥ 50% decline. Cox regression was used to evaluate association with time to event endpoints and Cochran-Mantel-Haenszel for PSA response. Results: 337 of 497 pts with tumor samples had evaluable FISH results. An ERG rearrangement was present in 117 of 337 (35%) pts. 112 pts were class Edel, 50 were 2+Edel (interstitial deletion with duplication of fusion sequences) and 18 were ESplit. A trend for an association with greater improved rPFS (CEN) and TTPP in 2+ Edel pts treated with AA + P vs ERG non-rearranged was observed (22 months [m] vs 16 m [HR: 0.59, 95% CI: 0.30-1.16], p = 0.12, and 14 m vs 8 m [HR: 0.68; 95% CI: 0.41-1.15], p = 0.15, respectively). No differences in 2+ Edel vs ERG non-rearranged were observed in the P-alone arm. No association between any ERG sub-class and either rPFS [INV] or PSA ≥ 50% decline in either treatment arm was observed. Conclusions: This represents the largest study to date to molecularly characterize CRPC pts participating in a therapeutic phase 3 trial. These data suggest that chemo-naïve mCRPC pts with a 2+ Edel rearrangement may derive a slightly greater benefit from AA and P than other pts. Clinical trial information: NCT00887198.

Validation of nuclear-localized AR-V7 on circulating tumor cells (CTC) as a treatment-selection biomarker for managing metastatic castration-resistant prostate cancer (mCRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 273-273 ◽  
Author(s):  
Howard I. Scher ◽  
Ryon P Graf ◽  
Nicole A. Schreiber ◽  
Eric Winquist ◽  
Brigit McLaughlin ◽  
...  
Keyword(s):  
Decision Making ◽  
High Risk ◽  
Risk Group ◽  
High Risk Group ◽  
Castration Resistant Prostate Cancer ◽  
Cross Sectional ◽  
Risk Of Death ◽  
Physician Decision Making ◽  
Line Of Therapy ◽  
Taxane Chemotherapy

273 Background: A previous analysis of 161 patients (pts) tested for nuclear-localized AR-V7(+) CTCs showed a therapy interaction between AR-V7 positivity and improved overall survival (OS) on taxane chemotherapy vs. androgen receptor signaling inhibitors (ARSI). To validate the use of the biomarker result for physician decision making, we prospectively analyzed an independent, multicenter, blinded, cross-sectional cohort (n = 225) to confirm a therapy interaction with AR-V7. We corrected for possible pt selection bias by the treating physician by analyzing the association of therapy to OS in low and high risk groups defined by the test cohort. Methods: Two analyses were performed: (1) the validation of a therapy interaction between AR-V7 positivity and superior OS benefit for pts treated with taxanes in the context of use for 2nd+ line pts; and (2) as the choice between ARSI or taxanes was at the discretion of the attending physician, pt risk was incorporated into the predictive biomarker assessment. A pt-specific risk score was developed from line of therapy and other covariates to stratify pts as low and high risk, and the association of AR-V7 status and OS was performed within each risk group to correct for physician decision making and address possible confounding with treatment assignment. Results: (1) A therapy interaction between AR-V7(+) pts and lower risk of death on taxanes vs. ARSI (HR: 0.23, p = 0.003, 95% CI: 0.09 – 0.61) was validated. (2) In the validation cohort, high risk AR-V7(+) pts had an OS benefit when treated with taxanes (p = 0.02) and the AR-V7(-) pts had an improved OS with ARSI therapy (p = 0.02). AR-V7 incidence was low in the low risk pts, precluding the analysis for this sub-cohort. Conclusions: The results validate that the nuclear-localized AR-V7(+) biomarker has an interaction with therapy and improved survival on taxanes. Further, when adjusting for pt risk, the biomarker is predictive of OS in the high risk group. Nuclear-localized AR-V7 protein in CTCs can aid in the decision between ARSI and taxane chemotherapy in the 2nd or greater line of therapy for mCRPC.

Genomic characteristics associated with clinical activity of rucaparib in patients (pts) with BRCA1 or BRCA2 (BRCA)-mutated metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 178-178 ◽  
Author(s):  
Wassim Abida ◽  
David Campbell ◽  
Akash Patnaik ◽  
Brieuc Sautois ◽  
Jeremy David Shapiro ◽  
...  
Keyword(s):  
Parp Inhibitor ◽  
Objective Response ◽  
Response Rates ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Tissue Samples ◽  
Damage Repair ◽  
Measurable Disease ◽  
Psa Response ◽  
Somatic Alterations

178 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in pts with mCRPC and a deleterious germline or somatic alteration in BRCA ( BRCA pts) or 1 of 13 other DNA damage repair (DDR) genes. Methods: Eligible pts had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy. Deleterious DDR gene alterations were identified from central testing of plasma and/or tissue samples by Foundation Medicine or from local testing. Results: As of Jul 2, 2019 (visit cutoff), 98 BRCA pts had received rucaparib; median (range) duration of follow-up was 13.0 (4.1–25.8) mo. Confirmed objective response rate (ORR) in BRCA pts (with investigator-assessed measurable disease) and PSA response rates (in pts with and without measurable disease) are shown in the Table. A biallelic alteration was observed in 81.4% (35/43) of BRCA pts for whom zygosity could be determined, and pts with homozygous BRCA loss (20.4%; 20/98) demonstrated high ORR (66.7% [95% CI, 38.4-88.2]; 10/15) and PSA response rates (75.0% [95% CI, 50.9-91.3]; 15/20). The safety profile in BRCA pts was consistent with the overall TRITON2 pt population. Conclusions: Results from TRITON2 showed antitumor activity with rucaparib in pts with mCRPC and a deleterious BRCA alteration. Responses were observed in patients with germline or somatic alterations in BRCA1 or BRCA2. The activity of rucaparib in these and additional genomic subgroups (e.g., based on zygosity, plasma genomic testing, or co-occurring alterations) will be reported. Clinical trial information: NCT02952534. [Table: see text]

Efficacy of sequencing of cytotoxic and endocrine therapies in veterans with metastatic castration-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16501-e16501
Author(s):  
Nina Mosallaei Lamble ◽  
Julie Nicole Graff ◽  
Tomasz M. Beer
Keyword(s):  
Endocrine Therapy ◽  
Response Rate ◽  
Progression Free Survival ◽  
Cross Resistance ◽  
Rank Test ◽  
P Value ◽  
Castration Resistant Prostate Cancer ◽  
Male Veterans ◽  
Psa Response ◽  
Line Of Therapy

e16501 Background: The optimal sequencing of therapies in the treatment of mCRPC has not been established. We examined the efficacy of one to two lines of endocrine therapy with chemotherapy sequencied before or in between endocrine therapies versus without chemotherapy. Methods: We prospectively enrolled 103 male veterans from 2013 to 2016 receiving abiraterone or enzalutamide for mCRPC therapy. Participants received usual care. Through chart review, for each line of therapy, we analyzed progression-free survival (PFS), defined as PSA increase 25% and 2ng/mL above nadir and confirmed by a second value, and PSA response rate, defined as a 50% PSA reduction from baseline at treatment initiation, for participants receiving various sequences of endocrine therapies with or without docetaxel chemotherapy. Results: We observed no statistically significant differences between the above measures except for an improvement in PFS when comparing those that received two lines of endocrine therapy without chemotherapy between treatments to those with who received chemotherapy between treatments ( p-value = 0.027, Log-rank test). Conclusions: There were no compelling clinically significant differences noted in PFS or PSA response rate amongst the various sequences of endocrine and cytotoxic therapies. Our results suggest that various sequences of therapy may yield similar results. Larger randomized studies analyzing sequencing of therapies will help determine if cross-resistance arises with use of multiple therapies. [Table: see text]

Multicenter prospective study of switching from GnRH agonists to GnRH antagonist for patients with early stage of castration resistant prostate cancer as a second-line hormonal therapy.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 183-183
Author(s):  
Yumiko Yokomizo ◽  
Narihiko Hayashi ◽  
Akitoshi Takizawa ◽  
Kazuki Kobayashi ◽  
Jun-ichi Ohta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gnrh Agonist ◽  
Hormonal Therapy ◽  
Gnrh Antagonist ◽  
Early Stage ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Psa Response

183 Background: It was reported that GnRH antagonist could extend progression free survival for prostate cancer patients significantly longer than GnRH agonist in a first line hormonal therapy. However, the usefulness of switching from GnRH agonist to GnRH antagonist as a second hormonal therapy remains obscure. We performed a multicentral prospective study to investigate whether the switching from GnRH agonist to GnRH antagonist (degalerix) for patients with castration resistant prostate cancer (CRPC) as the 2nd line hormonal therapy was effective. Methods: 37 patients who were pathologically diagnosed as prostatic adenocarcinoma and developed CRPC after 1st line hormonal therapy with GnRH agonist plus anti-androgens were enrolled. After confirming anti-androgen withdrawal syndrome, they were treated with switching from GnRH agonists to degalerix. The primary endpoint was PSA response (PSA decline or up to 10% over baseline PSA). Secondary endpoints were the time to 25% PSA increase from the baseline (PSA response time), PSA progression free survival (PPFS), the time to treatment failure, cancer specific survival, radiographic PFS (rPFS), and safety. Results: Mean age was 76 years old, super high risk; 20 cases (54.1%), high risk; 11 cases (29.7%), intermediate risk; 5 cases (13.5%), low risk; one case (2.7%). PSA responder rate was 24.3% (9 cases). In responders, the median PSA response time was 5.75 months, the median PPFS was 1.77 months, and rPFS rate at 3 months was 96%. Regarding safety, only 2 cases (5.4%) showed G3 of AE. The PSA response had no relationship with the change of serum testosterone, LH nor FSH. Conclusions: The effectiveness of switching from GnRH agonist to GnRH antagonist showed to be limited. Although no predictive factor of the switching was recognized, some long-term responders were seen. We expect the possibility of switching to GnRH antagonist for patients in the early stage of CRPC, especially non-metastatic status. Clinical trial information: UNKNOWN.

scholarly journals The Prognostic Value of Androgen Receptor Splice Variant 7 in Castration-Resistant Prostate Cancer Treated With Novel Hormonal Therapy or Chemotherapy: A Systematic Review and Meta-analysis

2020 ◽  
Vol 10 ◽  
Author(s):  
Zhize Wang ◽  
Haixiang Shen ◽  
Nieying Ma ◽  
Qinchen Li ◽  
Yeqing Mao ◽  
...  
Keyword(s):  
Hormonal Therapy ◽  
Meta Analysis ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Positive Proportion ◽  
Castration Resistant ◽  
Hazard Ratios ◽  
Psa Response ◽  
Androgen Receptor Splice Variant

PurposeThis study aimed to evaluate the prognostic role of AR-V7 in terms of prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) in CRPC patients treated with novel hormonal therapy (NHT) (Abiraterone and Enzalutamide) or taxane-based chemotherapy (Docetaxel and Cabazitaxel).MethodsA comprehensive literature search was conducted on PubMed, Embase, and the Web of Science from inception to February 2020. Studies focusing on the prognostic values of AR-V7 in CRPC patients treated with NHT or chemotherapy were included in our meta-analysis. The OS and PFS were analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for the AR-V7 conversion after treatment and the PSA response.ResultsThe AR-V7 positive proportion increased significantly after NHT treatment (OR 2.56, 95% CI 1.51–4.32, P&lt;0.001), however, it declined after chemotherapy (OR 0.51, 95% CI 0.28–0.93, P=0.003). AR-V7-positive patients showed a significantly decreased PSA response rate after NHT (OR 0.13, 95% CI 0.09–0.19, P&lt;0.001) but not statistically significant for chemotherapy (OR 0.63, 95% CI 0.40-1.01, P=0.06). Notably, PFS (HR 3.56, 95% CI 2.53–5.01, P&lt;0.001) and OS (HR 4.47, 95% CI 3.03–6.59, P&lt;0.001) were worse in AR-V7-positive ttreated with NHT. Similarly, AR-V7 positivity correlated with poor prognosis after chemotherapy as evidenced by shorter OS (HR 1.98, 95% CI 1.48-2.66, P&lt;0.001) and a significantly shorter PFS (HR 1.35, 95% CI 0.97-1.87, P=0.07).ConclusionNHT treatment increased AR-V7 positive proportion whereas chemotherapy decreased it. Moreover, AR-V7 positivity correlated with lower PSA response, poorer PFS, and OS in CRPC treated with NHT, and shorter OS in patients receiving chemotherapy.

scholarly journals Pain Progression at Initiation of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Post Hoc Analysis of the PROSELICA Study

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1284
Author(s):  
Nicolas Delanoy ◽  
Debbie Robbrecht ◽  
Mario Eisenberger ◽  
Oliver Sartor ◽  
Ronald de Wit ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Radiological Progression ◽  
Post Hoc Analysis ◽  
Psa Response ◽  
Phase Iii Study ◽  
Psa Progression ◽  
Previously Treated ◽  
Post Hoc

Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m2 (CABA20) was non-inferior to cabazitaxel 25 mg/m2 (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes. Methods: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (RADIO-p), no pain), RADIO-p (±PSA-p, no pain), or pain progression (PAIN-p, ±PSA-p, ±RADIO-p). Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed. Results: All randomized patients (n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients (PSA-p = 24.4%, RADIO-p = 20.8%, PAIN-p = 54.8%). Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups (12.0 versus 16.8 and 18.4 months, respectively, p < 0.001). In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS (HR = 1.44, p < 0.001). PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p. Conclusions: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise.

scholarly journals PSMA Expression Predicts Early Biochemical Response in Patients with Metastatic Castration-Resistant Prostate Cancer under 177Lu-PSMA-617 Radioligand Therapy

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2938
Author(s):  
Liam Widjaja ◽  
Rudolf A. Werner ◽  
Tobias L. Ross ◽  
Frank M. Bengel ◽  
Thorsten Derlin
Keyword(s):  
Prostate Cancer ◽  
Whole Body ◽  
Biochemical Response ◽  
Clinical Parameters ◽  
Castration Resistant Prostate Cancer ◽  
Radioligand Therapy ◽  
Castration Resistant ◽  
Psa Response ◽  
High Age ◽  
Psma Expression

177Lu-Prostate-specific membrane antigen (PSMA)-radioligand therapy (RLT) is a promising treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to determine the predictive value of pretherapeutic PSMA-ligand positron emission tomography (PET) and established clinical parameters for early biochemical response after two cycles of RLT. In total, 71 mCRPC patients who had undergone PET/computed tomography (CT) with 68Ga-PSMA-11 prior to two cycles of 177Lu-PSMA-617 RLT were included. Malignant lesions on pretherapeutic PET/CTs were manually segmented and average maximum PSMA expression (maximum standardized uptake values, SUVmax), whole-body PSMA-tumor volume (TV), and whole-body total lesion (TL)-PSMA were calculated. We then tested the predictive performance of these parameters for early biochemical response (defined as prostate-sepcific antigen (PSA) decrease of ≥50% according to PCWG2) after two cycles of RLT, relative to established clinical parameters. Early PSA response was observed in 34/71 patients. PSA change after two cycles of RLT correlated with pretherapeutic SUVmax (r = −0.49; p < 0.001), but not with PSMA-TV (r = 0.02; p = 0.89) or TL-PSMA (r = −0.15; p = 0.22). A cut-off of 19.8 for SUVmax and 75.5 years for age was defined by receiver operating characteristics and revealed a significant outcome difference for early biochemical response between patients with adversely low vs. high PSMA expression and low vs. high age (p < 0.001). Multivariate analysis identified SUVmax (HR, 7.94, p = 0.001) and age (HR, 8.05, p = 0.002) as independent predictors for PSA response early in the treatment course. Thus, high age and high PSMA expression in patients scheduled for RLT identify patients with early biochemical response. This study provides a rationale for further prospective studies exploring PET-guided treatment intensification in selected patients.

Sign in / Sign up

Export Citation Format

Share Document