Donatello Gasparro

Clinical Outcomes of Castration-resistant Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study

BACKGROUND The availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit. OBJECTIVE To provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA. DESIGN, SETTING, AND PARTICIPANTS We retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis. RESULTS AND LIMITATIONS We assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences. CONCLUSIONS We were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy. PATIENT SUMMARY It is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent.

Real-world cabazitaxel safety: the Italian early-access program in metastatic castration-resistant prostate cancer.

AIM Cabazitaxel is a novel taxane that is approved for use in metastatic castration-resistant prostate cancer based on the Phase III TROPIC study, which showed improved overall survival with cabazitaxel/prednisone versus mitoxantrone/prednisone. A global early-access program was initiated in order to provide early access to cabazitaxel in docetaxel-pretreated patients and to obtain real-world data. PATIENTS & METHODS We report interim safety results from an Italian prospective, single-arm, multicenter, open-label trial of 218 patients receiving cabazitaxel 25 mg/m2 every 3 weeks plus prednisolone 10 mg/day, until disease progression, unacceptable toxicity, investigators decision or death. RESULTS Patients completing treatment received a median of six cabazitaxel cycles. The most common grade 3/4 adverse events were neutropenia (33.9%), leukopenia (15.6%), anemia (6%) and asthenia (6%). No peripheral neuropathy or nail disorders were observed. CONCLUSION These results confirm that cabazitaxel has a manageable safety profile in daily clinical practice and support its use in patients with prostate cancer who progress during or after a docetaxel-based therapy.

Could Interferon Still Play a Role in Metastatic Renal Cell Carcinoma? A Randomized Study of Two Schedules of Sorafenib Plus Interferon-Alpha 2a (RAPSODY)

BACKGROUND Sorafenib has proven efficacy in metastatic renal cell carcinoma (mRCC). Interferon (IFN) has antiangiogenic activity that is thought to be both dose- and administration-schedule dependent. OBJECTIVE To compare two different schedules of IFN combined with sorafenib. DESIGN, SETTING, AND PARTICIPANTS Single-stage, prospective, noncomparative, randomized, open-label, multicenter, phase 2 study on previously untreated patients with mRCC and Eastern Cooperative Oncology Group performance status 0-2. INTERVENTION Sorafenib 400mg twice daily plus subcutaneous IFN, 9 million units (MU) three times a week (Arm A) or 3 MU five times a week (Arm B). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary end points were progression-free survival (PFS) for each arm and safety. Data were evaluated according to an intent-to-treat analysis. RESULTS AND LIMITATIONS A total of 101 patients were evaluated. Median PFS was 7.9 mo in Arm A and 8.6 mo in Arm B (p=0.049) and the median duration of response was 8.5 and 19.2 mo, respectively (p=0.0013). Nine partial responses were observed in Arm A, and three complete and 14 partial responses were observed in Arm B (17.6% vs 34.0%; p=0.058); 24 and 21 patients (47% and 42%), respectively, achieved stable disease. The most common grade 3-4 toxicities were fatigue plus asthenia (28% vs 16%; p=0.32) and hand-foot skin reactions (20% vs 18%). CONCLUSIONS Sorafenib plus frequent low-dose IFN showed good efficacy and tolerability. Further investigations should be warranted to identify a possible positioning of this intriguing regimen (6% complete response rate) in the treatment scenario of mRCC.

Safety and Efficacy of Sunitinib in Patients from Italy with Metastatic Renal Cell Carcinoma: Final Results from an Expanded-Access Trial

Objectives: Patients with metastatic renal cell carcinoma (mRCC) received sunitinib in a global expanded-access program (EAP). Here, we report the efficacy and safety results for the EAP subpopulation in Italy. Methods: Patients ≥18 years old with previously treated or treatment-naïve mRCC received oral sunitinib 50 mg/day on a 4-weeks-on/2-weeks-off schedule. Tumor measurements were scheduled per local practice (using Response Evaluation Criteria in Solid Tumors). Safety was regularly assessed. Results: A total of 521 patients participated, including 40% aged ≥65 years, 11% with an Eastern Cooperative Oncology Group performance status ≥2, 14% with non-clear cell RCC, and 11% with brain metastases. The median treatment duration and posttreatment follow-up were 7.4 and 12.3 months, respectively. The objective response rate was 12%, and the median progression-free and overall survival was 9.1 and 27.2 months, respectively. 514 patients (99%) discontinued treatment; reasons included death (17%), nonresponse (46%), or adverse events (AEs; 13%). The most common any-grade treatment-related AEs were asthenia (44%, plus 15% reporting fatigue), thrombocytopenia and stomatitis (both 37%), diarrhea (36%), mucosal inflammation (29%), hypertension (26%), and dysgeusia (25%). The most common grade 3/4 treatment-related AEs were thrombocytopenia (10%), asthenia (9%, plus 3% reporting fatigue), neutropenia, stomatitis (both 6%), and hypertension (5%). Conclusion: In a large population of Italian mRCC patients, sunitinib had a manageable safety profile and encouraging efficacy.

ALK and ROS1 rearrangements tested by fluorescence in situ hybridization in cytological smears from advanced non-small cell lung cancer patients.

The identification of ALK and ROS1 rearrangements and the availability of an effective target therapy, such as crizotinib, represent a new option in the treatment of advanced non‐small cell lung cancer (NSCLC) patients. In light of recent advances in non‐invasive diagnostic procedures, we aimed to demonstrate that direct cytological smears are suitable for assessing ALK and ROS1 rearrangements in patients with NSCLC.

Sorafenib as first- or second-line therapy in patients with metastatic renal cell carcinoma in a community setting

AIM The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. PATIENTS & METHODS Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). RESULTS Median OS was 17.2 months (95% CI: 15.5-19.6): 19.9 months (95% CI: 15.9-25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1-18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9-6.7): 6.6 (95% CI: 4.9-9.3) and 5.3 months (95% CI: 4.3-6.0) in first- and second-line patients, respectively. CONCLUSION The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.

Lack of Cumulative Toxicity Associated With Cabazitaxel Use in Prostate Cancer

AbstractCabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3–4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed “per cycle” incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel.The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis.“Per cycle” incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86–0.93; P < 0.01), febrile neutropenia (OR = 0.52; 95% CI: 0.34–0.81; P < 0.01) and G3 to 4 anemia (OR = 0.93; 95% CI: 0.86–1; P = 0.07). Patients with a body surface area >2 m2 presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86–1; P = 0.07), but decreased odds of having G3 to 4 anemia.Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.

Safety and Clinical Outcomes of Abiraterone Acetate after Docetaxel in Octogenarians with Metastatic Castration-Resistant Prostate Cancer: Results of the Italian Compassionate Use Named Patient Programme

UNLABELLED Metastatic castration-resistant prostate cancer mainly affects older men, opening issues about the efficacy and safety of therapies in this population. We have demonstrated that abiraterone, a selective androgen biosynthesis inhibitor, is a safe and active therapeutic option in a subgroup of 47 very elderly adults (aged > 80 years) enrolled in the Italian named patient program, with a tolerability profile and clinical outcomes comparable to those of younger population. BACKGROUND Prostate cancer mainly affects elderly men, who are often frail and whose reduced physiological reserves and multiple comorbidities increase the risk of side effects. The availability of new drugs has improved the overall survival (OS) of patients with castration-resistant prostate cancer (CRPC) but has increased the number of very elderly CRPC patients receiving anticancer drugs, raising questions about their efficacy and safety in this population. PATIENTS AND METHODS We assessed the tolerability of abiraterone (AA) in a cohort of very elderly adults with metastatic CRPC (mCRPC) enrolled in the Italian AA named patient program and analyzed their clinical outcomes. We retrospectively reviewed the clinical records of 47 mCRPC patients aged > 80 years who had received AA after docetaxel. The Kaplan-Meier method was used to calculate OS and progression-free survival (PFS). Safety and clinical outcomes were also analyzed by age group (< 80 and > 80 years). Cox regression analysis was used to calculate the differences in PFS and OS between the groups according to the stratification variables. RESULTS In very elderly men, the prostate-specific antigen response rate was 48.9%, and the median PFS and OS were 8 and 18 months, respectively. The differences in toxicities between the older and younger age groups were not major. The limitation of the present study was mainly its retrospective nature. CONCLUSION Our data show that AA is active and safe in very elderly patients and leads to outcomes similar to those observed in younger patients, thus confirming that AA is a manageable therapeutic option for this patient population.

Impact of visceral metastases on outcome to abiraterone after docetaxel in castration-resistant prostate cancer patients

BACKGROUND The objective of this study was to analyze the impact of visceral metastases in castration-resistant prostate cancer (CRPC) treated with abiraterone. MATERIALS & METHODS All CRPC patients received abiraterone 1000 mg daily plus prednisone 10 mg orally daily. Liver and lung metastases were considered as visceral metastases. RESULTS Of 265 CRPC patients, 49 had visceral metastases. Results on progression-free survival were not significantly different in patients with or without visceral metastases. Conversely, the median overall survival between the two groups was 12.4 and 18.5 months (p = 0.01), respectively, and median overall survival of patients with liver-only disease versus other sites was 10.5 versus 18.5 months (p = 0.006), respectively. CONCLUSION Visceral disease appears to be an important predictor of clinical outcome in CRPC patients treated with abiraterone.

Preliminary safety results of an Italian early-access program (EAP) with cabazitaxel plus prednisone (CbzP) in patients with docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).

253 Background: A significant number of docetaxel (D) refractory mCRPC patients (pts) have a life expectancy of > 15 months and ask for additional efficacious treatments. In the phase 3 TROPIC trial treatment of mCRPC patients with CbzP who progressed during or after docetaxel resulted in a statistically significant overall survival benefit compared with mitoxantrone / prednisone (Lancet 2010). This survival benefit supported establishment of a global early access program (EAP), allowing pts with mCRPC to have access to the drug prior to its commercial availability. Here we describe preliminary safety results from the EAP in Italy. METHODS We report here the data of the first 16 mCRPC patients (out of the 123 enrolled by 19 Italian centers until Sept 2011 in EAP) treated with Cbz (25mg/m2 Q3W) plus P(10mg bid). RESULTS Pts were median age 73.5 years (>75 years 38%), ECOG PS-0 81.3% and had received a median of 7 prior cycles of D (median cumulative D dose 562.5mg). Median time from last D dose to inclusion was 7.1 months. Overall, 62.5% (10 Pts) had 2 or more metastatic sites (bone 94%, regional/distant lymph nodes 25% and 44%, lung 12.5%, other sites 19%). A limited number of relevant adverse events (AE) were observed. All grade AEs were seen in 14/16 pts (81.3%), with 4/16 pts experiencing grade 3/4 leukopenia, 8/16 pts grade 3 - 4 neutropenia, one patient with febrile neutropenia and one with hypertransaminasaemia. Grade 1-2 asthenia and fatigue were experienced respectively by 2 pts. No grade 3 / 4 diarrhea, vomiting or constipation were observed and no AEs results in death. All pts received at least 2 cycles of CbzP (2÷5) and only one patient permanently discontinued treatment (disease progression). CONCLUSIONS This preliminary analysis of Italian pts enrolled in the EAP provides real world safety data and suggests a good safety profile of cabazitaxel even in heavily pretreated pts, which is in agreement with Italian experience in TROPIC. Results of the entire Italian cohort with a longer follow-up will be presented.