41 research outputs found
Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma
No full textCirculating tumor DNA (ctDNA) and correlations with clinical prognostic factors in patients with metastatic castration-resistant prostate cancer (mCRPC).
No full text 186 Background: Sequencing of ctDNA is a minimally invasive method to study somatic DNA alterations. Quantitation and characterization of ctDNA may correlate with tumor burden and poor risk clinical features, but this is unproven in mCRPC. Methods: We performed deep targeted sequencing of 73 mCRPC-related genes in plasma ctDNA from 136 treatment naïve mCRPC patients. Fraction of ctDNA was determined by quantifying somatic mutant allele frequency and the deviation from heterozygosity for germline single nucleotide polymorphisms at regions of somatic copy number alterations. Baseline clinical factors were correlated with ctDNA fraction and genomic aberrations. Results: ctDNA could be quantified in 86/136 (63%) patients. Increasing fraction correlated with elevated ALP (chi2, p < 0.001), LDH (p < 0.001) and presence of liver metastasis (p = 0.01). Patients with any one of these factors were more likely to have a ctDNA fraction ≥ 40% (67% vs 36% of patients with neither factor, p = 0.001) and less likely to have unquantifiable ctDNA (26% vs 49%, p = 0.006). A decreased ctDNA fraction was associated with metastases only to lymph nodes (p = 0.012). Among the most frequently aberrant genes were Androgen Receptor (AR), p53, RB1, and PTEN, present in 38%, 30%, 23% and 22% of patients, respectively. Aberrations were associated with poor prognosis factors, including: AR and p53 alterations, which both correlated with presence of liver metastasis (p = 0.020 and p = 0.004 respectively), elevated LDH (p = 0.001, p < 0.001), and presence of ≥ 10 bone metastasis (p = 0.018, p = 0.017); PTEN deletion which correlated with elevated ALP (p < 0.001), elevated LDH (p = 0.001), ≥ 10 bone metastasis (p = 0.009) and time to CPRC of < 12 months (p = 0.021); and RB1 correlated with ≥ 10 bone metastasis (p = 0.009). Conclusions: We found an association between poor prognostic factors and increasing ctDNA fraction in patients with mCRPC. Genomic aberrations, particularly alteration in AR, p53 and PTEN, correlated with poor prognostic factors. These data show that clinical factors may help predict ctDNA yield in patients with mCRPC, and also provide insight into the role of deleterious genetic alterations. </jats:p
Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T‐cell lymphoma
No full textClinical effectiveness of docetaxel for castration‐sensitive prostate cancer in a real‐world population‐based analysis
No full textReal-world experience with docetaxel for castration-sensitive prostate cancer from a population-based analysis.
No full text 297 Background: Phase III clinical trials have demonstrated efficacy with an overall survival (OS) benefit for the addition of docetaxel (DOC) to androgen deprivation therapy (ADT) for the treatment of metastatic castration-sensitive prostate cancer (mCSPC). The clinical effectiveness of DOC with ADT in the general patient population remains undefined. Methods: A population-based retrospective review was conducted of patients (pts) with mCSPC who received DOC at the BC Cancer Agency from 04/2015 to 02/2017. Patient and disease characteristics were extracted. Safety and clinical-effectiveness were evaluated. Results: 183 records were identified; 156 pts received DOC in the mCSPC setting. Baseline characteristics included a median age of 67 years (range 44-86) and visceral metastases (mets) present in 18%; 80% had high volume disease with 74% having > 3, and 54% > 10 bone mets; 76% had de-novo metastatic disease. All 6 planned DOC cycles were delivered in 126 cases (81%); it was stopped early for: toxicity in 15 (10%), unrelated death in 1 (0.6%), pt preference in 5 (3%) or disease progression in 9 (6%) cases. Dose reductions and delays were required in 61 (39%) and 25 (16%) cases, respectively. Grade 3-5 adverse events were noted in 62 (40%) cases, with 28 (18%) cases of febrile neutropenia (FN); there were no treatment-related deaths. Pts with FN had more bone mets (p = 0.046), but there was no difference in time from start of ADT to initiation of docetaxel, age, baseline performance status, PSA, or visceral involvement. PSA ≤ 0.2 ng/L was achieved in 41 (28%) cases after 6 months of ADT and maintained in 13 (8%) cases after 12 months. 41% of pts had developed CRPC within 1-yr, with a median time to CRPC of 14.3 months. Treatment for CRPC was given in 54 cases, with most pts receiving either abiraterone or enzalutamide (87%) with a PSA decline ≥50% occurring in 47%. Conclusions: Effectiveness of DOC with ADT in a general population of pts with mCSPC was associated with poorer outcomes and high rates of toxicity compared to the phase III studies. Response rates to first-line treatment for mCRPC with abiraterone or enzalutamide appear similar to those previously reported. </jats:p
A prognostic model for stratifying clinical outcomes in chemotherapy-naive metastatic castration-resistant prostate cancer patients treated with abiraterone acetate
No full textIntroduction: Recently, a prognostic index including six risk factors (RFs) (unfavourable Eastern Cooperative Oncology Group performance status [ECOG PS], presence of liver metastases, short response to luteinizing hormone-releasing hormone [LHRH] agonists/ antagonists, low albumin, increased alkaline phosphatase [ALP] and lactate dehydrogenase [LDH]) was developed from the COUAA- 301 trial in post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate. Our primary objective was to evaluate this model in a cohort of chemotherapy-naive mCRPC patients receiving abiraterone.Methods: We identified 197 chemotherapy-naive patients who received abiraterone at six BC Cancer Agency centres and who had complete information on all six RFs. Study endpoints were prostate-specific antigen (PSA) response rate (RR), time to PSA progression, time on treatment, and overall survival (OS). PSA RR and survival outcomes were compared using Χ2 test and log-rank test. Multivariable Cox proportional hazard analysis was performed to identify RFs independently associated with OS.Results: Patients were classified into good (0‒1 RFs), intermediate (2‒3 RFs), and poor (4‒6 RFs) prognostic groups (33%, 52%, and 15%, respectively). For good-, intermediate-, and poor-risk patients, PSA RR (≥50% decline) was 60% vs. 42% vs. 40% (p=0.05); median time to PSA progression was 7.3 vs. 5.3 vs. 5.0 months (p=0.02); and median OS was 29.4 vs. 13.8 vs. 8.7 months (p<0.0001).Conclusions: The six-factor prognostic index model stratifies clinical outcomes in chemotherapy-naive mCRPC patients treated with abiraterone. Identifying patients at risk of poor outcome is important for informing clinical practice and clinical trial design.</jats:p
Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer
No full textPrimary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. SIGNIFICANCE: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.</p
Figures S1-S18 from Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer
No full textSupplementary Figures S1 - S18</p
IND 205B: A phase II study of the PI3K inhibitor PX-866 and continued abiraterone/prednisone in patients with recurrent or metastatic castration resistant prostate cancer (CRPC) with PSA progression on abiraterone/prednisone.
No full text 279 Background: PX-866 is an irreversible, pan-isoform inhibitor of Class I PI-3K. In part A of this study, PX-866 as a single agent was well tolerated and showed modest activity in CRPC but did not meet a priori benchmarks as a single agent in unselected patients (pts). As androgen receptor inhibition promotes PI3K activity in PTEN-loss PC models, the addition of PX-866 in patients whose PSA is rising on abiraterone acetate plus prednisone (AA+P) may reverse resistance and phase B of the study tested this hypothesis clinically. Methods: In this multicentre, phase II study, CRPC pts with PSA progression on AA+P received PX-866, 8mg daily on a 6-week cycle while continuing AA+P. Primary endpoint was lack of progression at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA and objective response rates. PX-866 would be deemed worthy of further study if at least four of 25 pts were progression free at 12 weeks. Results: 25 pts were accrued and all are evaluable for toxicity and PSA response. Eleven pts had measurable disease of which 11 are evaluable for objective response. Median age was 72, ECOG PS was 0/1 in 10/15 pts. Eighteen pts received prior chemotherapy. Median number of cycles was 2 (range 1–3). 52% of pts received at least 90% of planned dose of PX-866. Most common adverse events (AEs) were fatigue (21 patients), diarrhea, (18), nausea (13), vomiting (11) and anorexia (12); one patient discontinued because of protocol therapy toxicity (grade 3 anemia). Other grade 3 AEs (one patient for each) were diarrhea, vomiting, fatigue, AST and ALT elevation and lymphocyte and platelet changes. Six pts were progression free at 12 weeks. No objective or PSA responses were seen. Of the pts with measurable disease, best objective response was stable disease in six (2.3-3.6m) and best PSA response was non-response in eight pts. Conclusions: The addition of PX-866 to AA+P in unselected pts progressing on AA+P shows no evidence of antitumour effects. Strategies to combine PI3K inhibition with AR targeted therapies should consider initiation earlier in the disease course and/or recruiting a selected population. Clinical trial information: NCT01331083. </jats:p
