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2556 Biweekly cabazitaxel is a safe treatment option for metastatic castration resistant prostate cancer (mCRPC) patients postdocetaxel - Prosty II trial
S496
Abstracts
2556 POSTER Biweekly cabazitaxel is a safe treatment option for metastatic castration resistant prostate cancer (mCRPC) patients postdocetaxel − Prosty II trial P.L. Kellokumpu-Lehtinen1 , T. Martila2 , P. Hervonen1 , V. Kataja3 , T. Utriainen4 , M. Luukkaa5 , M. Leskinen2 , K. Pulkkanen6 , M. Taalikka7 , A.L. Kautio1 . 1 Tampere University Hospital, Department of Oncology, ¨ ¨ Tampere, Finland; 2 Seinajoki Central Hospital, Surgery, Seinajoki, Finland; 3 ¨ ¨ ¨ Finland; 4 Helsinki Jyvaskyl a¨ Central Hospital, Oncology, Jyvaskyl a, University Central Hospital, Oncology, Helsinki, Finland; 5 Turku University Central Hospital, Oncology, Turku, Finland; 6 Kuopio University Hospital, Oncology, Kuopio, Finland; 7 4Pharma, Research Unit, Turku, Finland Background: Biweekly docetaxel (D) was better tolerated than the standard triweekly D in mCRPC. In addition, the overall survival was longer with the biweekly dosing in our Prosty I trial (Kellokumpu-Lehtinen et al. Lancet Oncology 2013;14:117–124). Our aim in this Prosty II trial (NCT01558219) was to evaluate the safety of biweekly cabazitaxel (C) as post-docetaxel treatment for mCRPC. Methods: The first 47 patients (pts) who were allocated to receive C 16 mg/m2 i.v. on day 1 and day14 at the 4 weeks’ cycle, are reported here. At baseline, WHO performance status was 0 in 33% of pts, 1 in 65% of pts and 2 in one patient. The median serum PSA level was 306 mg/L (range 3.7–2425) and the mean age 67 (range 50−79). The primary endpoint was safety. Results: A total number of 194 cycles of C (one cycle is twice biweekly dosings) were administered. No prophylactic G-CSF was used. The most common Grade 3/4 adverse events (CTCAE) shown in table.
Neutropenia Pain Fatique Anemia Neutropenic infection Infection without neutropenia Leucopenia Mucositis Elevated ALP Limb edema
Grade 3 (%)
Grade 4 (%)
14.9 12.8 6.4 4.3 2.1 10.6 4.3 2.5 4.3 2.1
4.3 0 2.1 0 0 0 0 0 0 0
In addition one Grade 4 pulmonary embolism and one intracerebral hemorrhage occurred. In one patient, a cancer related bone fracture occurred during the second C cycle (Grade 4 AE). Altogether up to11 cycles no AE was reported in 1 patient (2.1%) and Grade 1 AEs were reported in 3 pts (6.4%), Grade 2 AEs in 19 pts (40.4%), Grade 3 AEs in 18 pts (38.3%) and Grade 4 AEs in 6 pts (12.8%). No Grade 3 or 4 peripheral motor or sensory neuropathy, nail loss, nausea or vomiting occurred. Conclusions: Our results show that biweekly cabazitaxel is a well-tolerated treatment for heavily pretreated advanced mCRPC patients. Conflict of interest: Ownership: No. Advisory Board: No. Board of Directors: No. Corporate-sponsored Research: Sanofi, Roche, Lilly, Merck, BMS. Other Substantive Relationships: No. 2557 POSTER Platinum-based therapy in heavily pretreated m CRPC patients E. Bournakis1 , E. Kostouros2 , N. Soupos3 , A.M. Dimopoulos2 , C. Papadimitriou1 . 1 Aretaieio University Hospital, 2Nd Surgical University Clinic, Oncology Department, Athens, Greece; 2 Alexandra Hospital, Oncology, Athens, Greece; 3 Agioi Anargyroi Hospital, Oncology, Athens, Greece Background: Platinum based therapy is a potentially valid choice for heavily pretreated mCRPC patients (pts) whose/when disease progresses with some anaplastic features. Methods: This is a retrospective analysis of heavily pretreated symptomatic mCRPC pts with progressive mCRPC, treated with weekly cisplatin 25mg/m2 or carboplatin 150mg iv and oral cyclophosphamide 50mg bid for 3/4weeks in 28day cycles. Pt performance status (PS ECOG) pretreatment and at best response were monitored as well as symptoms, adverse events, PSA, LDH, ALP and imaging. Weekly CBC, chemistry and physical examination were performed. Results: Since May 2010, 42 pts initiated the regimen and 38/42 were evaluable. Median PS ECOG was 3 (range 1−4). 33/42 experienced “explosive” disease progression prior to treatment, 38/42 had >20 bone mets, 32/42 lymph node mets and 16/42 visceral mets (2 brain mets) while
23/42 had bone marrow infiltration >50% of which had CBC findings (anemia-thrombopenia). All pts but one had received at least one prior chemotherapy regimen, median 2 chemotherapy lines (range 1−5) and >50% had also received one of the novel androgen signaling inhibitors (abiraterone acetate, orteronel, enzalutamide), median 1 (range 1−3). 29/40 evaluable pts experienced ECOG PS benefit, >30% had imaging response and >25% had >50% PSA decline. Main Grade 3 adverse event (AE) was anemia. Most common grade 2 AE was thrombopenia. Median therapy duration was 5.5 months (range 1.5−7.5) with 14 discontinuing upon progression and 4 due to attending physician’s decision. Among non-responders, all had only bone metastatic disease. >70% of patients received the regimen in >3rd line, while >40% over 4+5th line. 5/40 received this regimen for more than 1 lines. Carboplatin based regimen seems to be more effective than cisplatin based regimen, since 5 patients receiving cisplatin turned to carboplatin while not responding and responded to that change. Most patients (>60%) received carboplatin due to this observation since 10/2012. Conclusions: Platinum based therapy plus oral cyclophosphamide is a tolerable and promising regimen for heavily pretreated poor PS mCRPC pts with some anaplastic disease features as opposed to best supportive care. Hematologic safety is the main concern. Further evaluation is warranted. No conflict of interest. 2558 POSTER Impact of PTEN protein loss on response to docetaxel and overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC) patients P. Rescigno1 , D. Lorente1 , D. Bianchini1 , M. Kolinsky1 , Z. Zafeiriou1 , R. Ferraldeschi1 , J. Mateo1 , F. Recine1 , A. Jayaram1 , D. Nava Rodrigues1 , R. Riisnaes1 , S. Miranda1 , I. Figueiredo1 , M. Crespo1 , N. Mehra1 , R. Perez-Lopez1 , N. Tunariu1 , A. Reid1 , G. Attard1 , J. De Bono1 . 1 The Institute of Cancer Research and The Royal Marsden Hospital NHS Trust, Prostate Targeted Therapy Group, Sutton, United Kingdom Background: Preclinical and clinical evidence suggests that activation of PI3K/AKT signaling through loss of the tumour suppressor phosphatase and tensin homolog (PTEN) can result in resistance to treatments mainly acting on the androgen receptor pathway. We explored the antitumour activity of docetaxel in CRPC patients with and without loss of PTEN protein expression. Materials and Methods: We identified patients treated with docetaxel for metastatic CRPC between 01.01.2006 and 31.12.2014 and with hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis (IHC). We defined PTEN lossas the complete absence of PTEN staining or weak intensity staining in no more than 10% of cancer cells (H-score 10) compared with internal control, using a binary classification system. The primary end point was overall survival from initiation of docetaxel treatment. PSA response was defined as 30% or 50% decline from baseline, confirmed at least 4 weeks later. Time to progression (TTP) was defined as the time from docetaxel start to time of biochemical, radiological and/or symptomatic progression. Patients that stopped the treatment prematurely due to allergic reaction or severe toxicity were not considered for the TTP analysis. Relationship with outcome was analyzed using multivariate (MVA) Cox regression and log-rank analyses. Demographics and clinical data were retrospectively collected from the hospital electronic patient record system (EPR). Results: A total of 177 patients who had received docetaxel and had available tumour tissue were included. Overall, loss of PTEN expression was observed in 72 patients (40,7%). The two groups were balanced for established mCRPC prognostic factors including ECOG Performance Status, albumin, PSA at baseline, alkaline phosphatase, lactate dehydrogenase (LDH), haemoglobin and neutrophil to lymphocyte ratio. Matched HSPC and CRPC tumour biopsies were available for 49 patients; HSPC and CRPC biopsy PTEN status was concordant in 89.8%. PTEN loss was associated with a shorter median overall survival (25.3vs 34.4mo; hazard ratio [HR]: 1.6; 95% confidence interval [CI], 1.2−2.2; p = 0.04) in MVA. High LDH and ECOG PS were also identified as independent prognostic factors in MVA. Median duration of docetaxel treatment (5.1vs 5.5 mo; HR: 1,2; 95% CI, 0.9−1.7; p=0,97) and TTP (8.2vs 9.1mo; HR: 1.1; 95%Cl, 0.8−1.6; p=0,38) were not significantly different in PTEN loss vs PTEN normal pts. No significant difference in 30% PSA response rate (41.5% vs 48.6%; HR: 1.3; 95% CI, 0.7−2.7; p = 0.43)or 50% PSA response rate (54.7% vs 41.7%; HR 1.7; 95% CI: 0.8−3.5; p = 0.15) was observed between the two groups. Conclusions: Our results suggest that PTEN loss is associated with poor survival but does not associate with duration of docetaxel treatment, TTP or biochemical response. No conflict of interest.
Abstracts
2556 POSTER Biweekly cabazitaxel is a safe treatment option for metastatic castration resistant prostate cancer (mCRPC) patients postdocetaxel − Prosty II trial P.L. Kellokumpu-Lehtinen1 , T. Martila2 , P. Hervonen1 , V. Kataja3 , T. Utriainen4 , M. Luukkaa5 , M. Leskinen2 , K. Pulkkanen6 , M. Taalikka7 , A.L. Kautio1 . 1 Tampere University Hospital, Department of Oncology, ¨ ¨ Tampere, Finland; 2 Seinajoki Central Hospital, Surgery, Seinajoki, Finland; 3 ¨ ¨ ¨ Finland; 4 Helsinki Jyvaskyl a¨ Central Hospital, Oncology, Jyvaskyl a, University Central Hospital, Oncology, Helsinki, Finland; 5 Turku University Central Hospital, Oncology, Turku, Finland; 6 Kuopio University Hospital, Oncology, Kuopio, Finland; 7 4Pharma, Research Unit, Turku, Finland Background: Biweekly docetaxel (D) was better tolerated than the standard triweekly D in mCRPC. In addition, the overall survival was longer with the biweekly dosing in our Prosty I trial (Kellokumpu-Lehtinen et al. Lancet Oncology 2013;14:117–124). Our aim in this Prosty II trial (NCT01558219) was to evaluate the safety of biweekly cabazitaxel (C) as post-docetaxel treatment for mCRPC. Methods: The first 47 patients (pts) who were allocated to receive C 16 mg/m2 i.v. on day 1 and day14 at the 4 weeks’ cycle, are reported here. At baseline, WHO performance status was 0 in 33% of pts, 1 in 65% of pts and 2 in one patient. The median serum PSA level was 306 mg/L (range 3.7–2425) and the mean age 67 (range 50−79). The primary endpoint was safety. Results: A total number of 194 cycles of C (one cycle is twice biweekly dosings) were administered. No prophylactic G-CSF was used. The most common Grade 3/4 adverse events (CTCAE) shown in table.
Neutropenia Pain Fatique Anemia Neutropenic infection Infection without neutropenia Leucopenia Mucositis Elevated ALP Limb edema
Grade 3 (%)
Grade 4 (%)
14.9 12.8 6.4 4.3 2.1 10.6 4.3 2.5 4.3 2.1
4.3 0 2.1 0 0 0 0 0 0 0
In addition one Grade 4 pulmonary embolism and one intracerebral hemorrhage occurred. In one patient, a cancer related bone fracture occurred during the second C cycle (Grade 4 AE). Altogether up to11 cycles no AE was reported in 1 patient (2.1%) and Grade 1 AEs were reported in 3 pts (6.4%), Grade 2 AEs in 19 pts (40.4%), Grade 3 AEs in 18 pts (38.3%) and Grade 4 AEs in 6 pts (12.8%). No Grade 3 or 4 peripheral motor or sensory neuropathy, nail loss, nausea or vomiting occurred. Conclusions: Our results show that biweekly cabazitaxel is a well-tolerated treatment for heavily pretreated advanced mCRPC patients. Conflict of interest: Ownership: No. Advisory Board: No. Board of Directors: No. Corporate-sponsored Research: Sanofi, Roche, Lilly, Merck, BMS. Other Substantive Relationships: No. 2557 POSTER Platinum-based therapy in heavily pretreated m CRPC patients E. Bournakis1 , E. Kostouros2 , N. Soupos3 , A.M. Dimopoulos2 , C. Papadimitriou1 . 1 Aretaieio University Hospital, 2Nd Surgical University Clinic, Oncology Department, Athens, Greece; 2 Alexandra Hospital, Oncology, Athens, Greece; 3 Agioi Anargyroi Hospital, Oncology, Athens, Greece Background: Platinum based therapy is a potentially valid choice for heavily pretreated mCRPC patients (pts) whose/when disease progresses with some anaplastic features. Methods: This is a retrospective analysis of heavily pretreated symptomatic mCRPC pts with progressive mCRPC, treated with weekly cisplatin 25mg/m2 or carboplatin 150mg iv and oral cyclophosphamide 50mg bid for 3/4weeks in 28day cycles. Pt performance status (PS ECOG) pretreatment and at best response were monitored as well as symptoms, adverse events, PSA, LDH, ALP and imaging. Weekly CBC, chemistry and physical examination were performed. Results: Since May 2010, 42 pts initiated the regimen and 38/42 were evaluable. Median PS ECOG was 3 (range 1−4). 33/42 experienced “explosive” disease progression prior to treatment, 38/42 had >20 bone mets, 32/42 lymph node mets and 16/42 visceral mets (2 brain mets) while
23/42 had bone marrow infiltration >50% of which had CBC findings (anemia-thrombopenia). All pts but one had received at least one prior chemotherapy regimen, median 2 chemotherapy lines (range 1−5) and >50% had also received one of the novel androgen signaling inhibitors (abiraterone acetate, orteronel, enzalutamide), median 1 (range 1−3). 29/40 evaluable pts experienced ECOG PS benefit, >30% had imaging response and >25% had >50% PSA decline. Main Grade 3 adverse event (AE) was anemia. Most common grade 2 AE was thrombopenia. Median therapy duration was 5.5 months (range 1.5−7.5) with 14 discontinuing upon progression and 4 due to attending physician’s decision. Among non-responders, all had only bone metastatic disease. >70% of patients received the regimen in >3rd line, while >40% over 4+5th line. 5/40 received this regimen for more than 1 lines. Carboplatin based regimen seems to be more effective than cisplatin based regimen, since 5 patients receiving cisplatin turned to carboplatin while not responding and responded to that change. Most patients (>60%) received carboplatin due to this observation since 10/2012. Conclusions: Platinum based therapy plus oral cyclophosphamide is a tolerable and promising regimen for heavily pretreated poor PS mCRPC pts with some anaplastic disease features as opposed to best supportive care. Hematologic safety is the main concern. Further evaluation is warranted. No conflict of interest. 2558 POSTER Impact of PTEN protein loss on response to docetaxel and overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC) patients P. Rescigno1 , D. Lorente1 , D. Bianchini1 , M. Kolinsky1 , Z. Zafeiriou1 , R. Ferraldeschi1 , J. Mateo1 , F. Recine1 , A. Jayaram1 , D. Nava Rodrigues1 , R. Riisnaes1 , S. Miranda1 , I. Figueiredo1 , M. Crespo1 , N. Mehra1 , R. Perez-Lopez1 , N. Tunariu1 , A. Reid1 , G. Attard1 , J. De Bono1 . 1 The Institute of Cancer Research and The Royal Marsden Hospital NHS Trust, Prostate Targeted Therapy Group, Sutton, United Kingdom Background: Preclinical and clinical evidence suggests that activation of PI3K/AKT signaling through loss of the tumour suppressor phosphatase and tensin homolog (PTEN) can result in resistance to treatments mainly acting on the androgen receptor pathway. We explored the antitumour activity of docetaxel in CRPC patients with and without loss of PTEN protein expression. Materials and Methods: We identified patients treated with docetaxel for metastatic CRPC between 01.01.2006 and 31.12.2014 and with hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis (IHC). We defined PTEN lossas the complete absence of PTEN staining or weak intensity staining in no more than 10% of cancer cells (H-score 10) compared with internal control, using a binary classification system. The primary end point was overall survival from initiation of docetaxel treatment. PSA response was defined as 30% or 50% decline from baseline, confirmed at least 4 weeks later. Time to progression (TTP) was defined as the time from docetaxel start to time of biochemical, radiological and/or symptomatic progression. Patients that stopped the treatment prematurely due to allergic reaction or severe toxicity were not considered for the TTP analysis. Relationship with outcome was analyzed using multivariate (MVA) Cox regression and log-rank analyses. Demographics and clinical data were retrospectively collected from the hospital electronic patient record system (EPR). Results: A total of 177 patients who had received docetaxel and had available tumour tissue were included. Overall, loss of PTEN expression was observed in 72 patients (40,7%). The two groups were balanced for established mCRPC prognostic factors including ECOG Performance Status, albumin, PSA at baseline, alkaline phosphatase, lactate dehydrogenase (LDH), haemoglobin and neutrophil to lymphocyte ratio. Matched HSPC and CRPC tumour biopsies were available for 49 patients; HSPC and CRPC biopsy PTEN status was concordant in 89.8%. PTEN loss was associated with a shorter median overall survival (25.3vs 34.4mo; hazard ratio [HR]: 1.6; 95% confidence interval [CI], 1.2−2.2; p = 0.04) in MVA. High LDH and ECOG PS were also identified as independent prognostic factors in MVA. Median duration of docetaxel treatment (5.1vs 5.5 mo; HR: 1,2; 95% CI, 0.9−1.7; p=0,97) and TTP (8.2vs 9.1mo; HR: 1.1; 95%Cl, 0.8−1.6; p=0,38) were not significantly different in PTEN loss vs PTEN normal pts. No significant difference in 30% PSA response rate (41.5% vs 48.6%; HR: 1.3; 95% CI, 0.7−2.7; p = 0.43)or 50% PSA response rate (54.7% vs 41.7%; HR 1.7; 95% CI: 0.8−3.5; p = 0.15) was observed between the two groups. Conclusions: Our results suggest that PTEN loss is associated with poor survival but does not associate with duration of docetaxel treatment, TTP or biochemical response. No conflict of interest.