Niven Mehra

Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer.

BACKGROUNDnThe availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS).nnnOBJECTIVEnTo evaluate the association between early PSA decline and OS following abiraterone acetate (AA) treatment.nnnDESIGN, SETTING, AND PARTICIPANTSnWe identified mCRPC patients treated with AA before or after docetaxel at the Royal Marsden NHS Foundation Trust between 2006 and 2014. Early PSA decline was defined as a 30% decrease in PSA at 4 wk relative to baseline, and early PSA rise as a 25% increase.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnAssociation with OS was analyzed using multivariate Cox regression and log-rank analyses. Spearmans rho correlation coefficient (r) was calculated to evaluate the association between PSA changes at 4 wk and 12 wk.nnnRESULTS AND LIMITATIONSnThere were 274 patients eligible for this analysis. A 30% PSA decline at 4 wk was associated with longer OS (25.8 vs 15.1 mo; hazard ratio [HR] 0.47, p<0.001), and a 25% PSA rise at 4 wk with shorter OS (15.1 vs 23.8 mo; HR 1.7, p=0.001) in both univariate and multivariable models. The percentage PSA decline at 4 wk was significantly correlated with the percentage PSA change at 12 wk (r=0.82; p<0.001). Patients achieving a 30% PSA decline at 4 wk were 11.7 times more likely to achieve a 50% PSA decrease at 12 wk (sensitivity 90.9%, specificity 79.4%). Limitations include the retrospective design of this analysis.nnnCONCLUSIONSnPatients not achieving 30% PSA decline after 4 wk of AA have a lower likelihood of achieving PSA response at 12 wk and significantly inferior OS. Prospective multicentre validation studies are needed to confirm these findings.nnnPATIENT SUMMARYnProstate-specific antigen (PSA) is commonly used to evaluate response to treatment in metastatic castration-resistant prostate cancer. Expert recommendations discourage reliance on PSA changes earlier than 12 wk after treatment initiation. Our data suggest that early PSA changes are associated with survival in patients receiving abiraterone acetate.

Castration-Resistant Prostate Cancer Tissue Acquisition From Bone Metastases for Molecular Analyses

Micro-Abstract We analyzed 115 iliac crest bone marrow biopsy specimens from 101 patients with metastatic castration-resistant prostate cancer, divided into a test (n = 57) and a validation (n = 58) set. We developed a score based on computed tomography Hounsfield units and lactate dehydrogenase levels, which were associated with a positive biopsy result. The score can be used to select patients for whom a bone marrow biopsy will provide tissue for molecular characterization.

CCR 20th Anniversary Commentary: Circulating Tumor Cells in Prostate Cancer

Circulating tumor cells (CTC) have substantial promise for multipurpose biomarker studies in prostate cancer. The IMMC-38 trial conducted by de Bono and colleagues, which was published in the October 1, 2008, issue of Clinical Cancer Research, demonstrated for the first time that CTCs are the most accurate and independent predictor of overall survival in metastatic prostate cancer. Since the publication of prospective trials demonstrating prognostic utility, CTCs have been utilized for nucleic acid analyses, for protein analyses, and in intermediate endpoint studies. CTC studies are also now facilitating the analysis of intrapatient heterogeneity. Clin Cancer Res; 21(22); 4992–5. ©2015 AACR. See related article by de Bono et al., Clin Cancer Res 2008;14(19) October 1, 2008;6302–9

Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone

Abstract Background Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536). Patients and methods The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as au2009≥u200950% decrease confirmed ≥3 weeks later with this combination (phase II). Results Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25u2009mg/m2 every 3 weeks and abiraterone 1000u2009mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5u2009mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1–28). Grade 3–4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6–66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1–10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors. Conclusions The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.BACKGROUNDnAbiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536).nnnPATIENTS AND METHODSnThe primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as au2009≥u200950% decrease confirmed ≥3 weeks later with this combination (phase II).nnnRESULTSnTen patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25u2009mg/m2 every 3 weeks and abiraterone 1000u2009mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5u2009mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors.nnnCONCLUSIONSnThe combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.

Interrogating Metastatic Prostate Cancer Treatment Switch Decisions: A Multi-institutional Survey

BACKGROUNDnEvaluation of responses to treatment for metastatic castration-resistant prostate cancer (mCRPC) remains challenging. Consensus criteria based on prostate-specific antigen (PSA) and clinical and radiologic biomarkers are inconsistently utilized. Circulating tumor cell (CTC) counts can inform prognosis and response, but are not routinely used.nnnOBJECTIVEnTo evaluate the use of biomarkers and trends in clinical decision-making in current mCRPC treatment.nnnDESIGN, SETTING, AND PARTICIPANTSnA 23-part online questionnaire was completed by physicians treating mCRPC.nnnOUTCOME MEASURES AND STATISTICAL ANALYSISnResults are presented as the proportion (%) of physicians responding to each of the options. We used χ2 and Fishers tests to compare differences.nnnRESULTS AND LIMITATIONSnA total of 118 physicians (22.1%) responded. Of these, 69.4% treated ≥50 mCRPC patients/year. More physicians administered four or fewer courses of cabazitaxel (27.9%) than for docetaxel (10.4%), with no significant difference in the number of courses between bone-only disease and Response Evaluation Criteria in Solid Tumours (RECIST)-evaluable disease. Some 74.5% of respondents considered current biomarkers useful for monitoring disease, but only 39.6% used the Prostate Cancer Working Group (PCWG2) criteria in clinical practice. PSA was considered an important biomarker by 55.7%, but only 41.4% discarded changes in PSA before 12 wk, and only 39.4% were able to identify bone-scan progression according to PCWG2. The vast majority of physicians (90.5%) considered clinical progression to be important for switching treatment. The proportion considering biomarkers important was 71.6% for RECIST, 47.4% for bone scans, 23.2% for CTCs, and 21.1% for PSA. Although 53.1% acknowledged that baseline CTC counts are prognostic, only 33.7% would use CTC changes alone to switch treatment in patients with bone-only disease. The main challenges in using CTC counts were access to CTC technology (84.7%), cost (74.5%), and uncertainty over utility as a response indicator (58.2%).nnnCONCLUSIONSnA significant proportion of physicians discontinue treatment for mCRPC before 12 wk, raising concerns about inadequate response assessment. Many physicians find current biomarkers useful, but most rely on symptoms to drive treatment switch decisions, suggesting there is a need for more precise biomarkers.nnnPATIENT SUMMARYnIn this report we analyse the results of a questionnaire evaluating tools for clinical decision-making completed by 118 prostate cancer specialists. We found that most physicians favour clinical progression over prostate-specific antigen or imaging, and that criteria established by the Prostate Cancer Working Group are not widely used.

Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)

Background Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. Objective To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. Design, setting, and participants Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25 mg/m2) as second-line chemotherapy (PROSELICA). Outcome measurements and statistical analysis Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. Results and limitations In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR] = 1.54; 95% confidence interval [CI]: 1.15–2.08; p = 0.004), and shorter OS on taxane therapy (HR = 1.53; 95% CI: 1.18–1.97; p = 0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle −0.03; 95% CI: −0.044 to −0.009; p = 0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. Conclusions We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. Patient summary In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3–9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA.

791PSEQUENCING OF DOCETAXEL (D) AND ABIRATERONE ACETATE (AA) FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)

ABSTRACT Aim: D and AA are approved as front-line treatments for mCRPC. Their optimal sequencing is as yet undefined. We retrospectively evaluated whether sequencing of AA and D has an effect on survival in mCRPC. Methods: We retrospectively identified mCRPC patients (pts) who received both D and AA at the Royal Marsden Hospital. Pts were divided into two groups, the first having received D followed by AA (D- > AA) and the second AA followed by D(AA- > D). Pts who received D in the non-castrate setting or enzalutamide prior to D or AA were excluded. Hormonal treatments or phase I/II investigational agents were allowed between D and AA. Cabazitaxel(C) was allowed either before or after the second part of treatment. Overall survival (OS) was defined as time from initiation of first treatment, D or AA, to death or last follow-up (LFU). Log-Rank testing was used to compare OS between the two groups and two-sided Pearsons Chi-Square and Students t-test to compare categorical and continuous variables respectively. Results: Time between treatment stages in months. Mean; Median (Min;Max) Diagnosis to CRes CRes to D End of D to AA End of AA to C End of AA to LFU D- > AA 50.0;33.8 (2.4;190.1) 15.0;10.3 (0.0;122.1) 11.5;9.2 (0.0;47.8) -1.5;1.0 (-17.0;9.1) 9.7;6.8 (0.0;57.0) Diagnosis to CRes Cres to AA End of AA to D End of D to C End of D to LFU AA- > D 54.4;35.8 (4.8;210.7) 14.9;13.7 (0.2;71.5) 7.5; 4.0 (0.9; 28.5) 14.7;9.2 (1.6;38.8) 12.5;8.2 (0.4;51.0) CRes: Castration Resistance. Between 10/2004 and 06/2012 161 and 37 mCRPC pts were identified who received D- > AA and AA- > D respectively. Baseline mean values of prognostic parameters were comparable in the two groups: Hg was 11.9g/dl and 12.7g/dl (p = 0.04), LDH 195.2u/l and 203.6u/l(p = 0.5), ALP 252.1u/l and 156u/l(p = 0.1), albumin 35.2g/l and 36.9g/l(p = 0.06), PSA 786.3ng/ml and 118.7ng/ml (p = 0.7) –median(m)PSA 131ng/ml and 72ng/ml- in D- > AA and AA- > D group respectively. Similar proportion of pts received C in the two groups: 36 pts (22.4%) in D- > AA and 4 (10.8%) in AA- > D (p = 0.1). After a mFU of 2.7 years 18 pts (11.2%) in the D- > AA group were alive and 2 (5.4%) in the AA- > D group; mOS was 31.4 months (95%CI: 28.3-34.4) in D- > AA and 38.6months (95% CI:30.3-46.9) in AA- > D (p = 0.6). The difference was not statistically significant. Conclusions: This retrospective analysis did not identify a statistically significant difference in mOS between pts treated with D- > AA or AA- > D. Prospective studies to evaluate optimal treatment sequencing for mCRPC are warranted. Disclosure: Z. Zafeiriou: Employee at the time of manuscript preparation of the Institute of Cancer Research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Z.Z has received grants from Hellenic Society of Medical Oncology; R. Ferraldeschi, A. Altavilla, S. Sideris, P. Rescigno, D. Bianchini, A. Smith, R. Perez Lopez, N. Mehra, P. Ravi, E. Grist and N. Tunariu: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone; A. Omlin: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Advisory role: Janssen as COI; C. Pezaro and D. Mukherji: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Has has received honoraria from Sanofi-Aventis and Janssen-Cilag; D. Lorente: Employed at the Institute of Cancer Research, which has a commercial interest in the development of abiraterone; J. Mateo: Employed at the Institute of Cancer Research when the abstract was created, which has a commercial interest in the development of this agent; G. Attard: GA is listed in the ICR co-inventors reward scheme for abiraterone acetate; J.S. de Bono: JSB has a consultant role with Johnson & Johnson, and received honoraria from Johnson & Johnson. Consultant and Chief Investigator of the Abiraterone Trial.

Single-Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis

Purpose: Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by their low frequency. Experimental Design: We evaluated liquid biopsies by apheresis to increase CTC yield from patients suffering from metastatic prostate cancer, allow precise gene copy-number calls, and study disease heterogeneity. Results: Apheresis was well tolerated and allowed the separation of large numbers of CTCs; the average CTC yield from 7.5 mL of peripheral blood was 167 CTCs, whereas the average CTC yield per apheresis (mean volume: 59.5 mL) was 12,546 CTCs. Purified single CTCs could be isolated from apheresis product by FACS sorting; copy-number aberration (CNA) profiles of 185 single CTCs from 14 patients revealed the genomic landscape of lethal prostate cancer and identified complex intrapatient, intercell, genomic heterogeneity missed on bulk biopsy analyses. Conclusions: Apheresis facilitated the capture of large numbers of CTCs noninvasively with minimal morbidity and allowed the deconvolution of intrapatient heterogeneity and clonal evolution. Clin Cancer Res; 24(22); 5635–44. ©2018 AACR.

Comparison of Timed Automata with Discrete Event Simulation for Modeling of Biomarker-Based Treatment Decisions: An Illustration for Metastatic Castration-Resistant Prostate Cancer

BACKGROUNDnWith the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required.nnnOBJECTIVESnTo illustrate the usability of two such techniques, timed automata (TA) and discrete event simulation (DES), for modeling personalized treatment decisions.nnnMETHODSnAn early health technology assessment on the use of circulating tumor cells, compared with prostate-specific antigen and bone scintigraphy, to inform treatment decisions in metastatic castration-resistant prostate cancer was performed. Both modeling techniques were assessed quantitatively, in terms of intermediate outcomes (e.g., overtreatment) and health economic outcomes (e.g., net monetary benefit). Qualitatively, among others, model structure, agent interactions, data management (i.e., importing and exporting data), and model transparency were assessed.nnnRESULTSnBoth models yielded realistic and similar intermediate and health economic outcomes. Overtreatment was reduced by 6.99 and 7.02 weeks by applying circulating tumor cell as a response marker at a net monetary benefit of -€1033 and -€1104 for the TA model and the DES model, respectively. Software-specific differences were observed regarding data management features and the support for statistical distributions, which were considered better for the DES software. Regarding method-specific differences, interactions were modeled more straightforward using TA, benefiting from its compositional model structure.nnnCONCLUSIONSnBoth techniques prove suitable for modeling personalized treatment decisions, although DES would be preferred given the current software-specific limitations of TA. When these limitations are resolved, TA would be an interesting modeling alternative if interactions are key or its compositional structure is useful to manage multi-agent complex problems.

Neutrophil to Lymphocyte Ratio in Castration-Resistant Prostate Cancer Patients Treated With Daily Oral Corticosteroids

Micro‐Abstract Concerns exist that low‐dose corticosteroids may adversely affect outcome in patients with castration‐resistant prostate cancer (CRPC), due to its tumor‐promoting and immunosuppressive characteristics. In treatment‐naïve CRPC patients treated with low‐dose corticosteroids, the patients harboring an increased neutrophil to lymphocyte, an indirect measure of tumor‐inflammation, had a lower prostate‐specific antigen (PSA) > 50% response rate, shorter PSA progression‐free interval and a shorter overall survival. Background: The neutrophil to lymphocyte ratio (NLR) has been shown to be highly prognostic across many tumor types, and predictive of treatment outcome in advanced prostate cancer, and has been postulated to be an indirect measure of tumor inflammation. We evaluated the effect of low‐dose steroids on NLR in men suffering from castration‐resistant prostate cancer (CRPC). Patients and Methods: The NLR was evaluated in a prospective randomized phase II trial that compared prednisolone 5 mg twice daily and dexamethasone 0.5 mg daily administered to 75 chemotherapy and abiraterone/enzalutamide‐naive CRPC patients. NLR was examined at baseline (BL), after 6 and 12 weeks of corticosteroid treatment; associations with >50% prostate‐specific antigen (PSA) response, duration of response (PSA progression‐free interval), and overall survival (OS) were tested using logistic regression and Cox regression analysis. Results: The median NLR for all evaluable patients was 2.6 at BL; 2.9 at 6 weeks; and 4.0 at 12 weeks. After low‐dose corticosteroid initiation, 46 patients had a decline in PSA with 24 confirmed responders. BL NLR (log10) associated with a PSA response (odds ratio, .029, 95% confidence interval [CI], .002‐.493; P = .014), and with the extent of the PSA decline (P = .009). A favorable BL NLR (less than median) associated with a 5.5‐fold higher odds of a PSA >50% response (95% CI, 1.3‐23.9; P = .02). Higher BL NLR (log10) associated with a shorter time to PSA progression (hazard ratio [HR], 9.5; 95% CI, 2.3‐39.9; P = .002). In multivariate analysis BL NLR as a discrete variable was independently associated with PSA progression (HR, 3.5; 95% CI, 1.5‐8.1; P = .003). NLR at 6 weeks was also associated with duration of benefit; in the favorable NLR category time to PSA progression was 10.8 months, for those who converted to an unfavorable (greater than median) category 4.5 months, and for those remaining in a unfavorable category only 1.5 months (95% CI, 0.5‐2.5; P = .003). OS was 33.1 months (95% CI, 24.2‐42.0) and 21.9 months (95% CI, 19.3‐24.4) for those with an favorable and unfavorable BL NLR, respectively. Conclusion: Treatment‐naive CRPC patients with a high BL or during‐treatment NLR appear not to benefit from low‐dose corticosteroids. The immunological implications of an unfavorable NLR, and whether corticosteroids might drive prostate cancer progression in patients harboring a high NLR, warrant further study.