SYSTEMIC THERAPIES FOR CRPC: Chemotherapy and Radium-223 ELENA CASTRO Spanish National Cancer Research Centre Prostate Preceptorship. Lugano 4-5 October 2018
Disclosures Participation in advisory boards: Astellas, Bayer, Janssen Research funding: Astra Zeneca, Bayer, Janssen Speaker fees: Astra Zeneca, Astellas, Bayer, Janssen, Pfizer Travel, accomodation, expenses: Astellas, Bayer, Bristol-Myers,Janssen, Roche
Mitoxantrone Abiraterone Acetate Enzalutamide Orchiectomy Antiandrogens Zoledronic Acid Abiraterone Acetate Enzalutamide
Mitoxantone Metastatic disease Symptomatic (pain) ECOG 3 n=161 Mitoxantrone12 mg/m 2 q3w + Prednisone 5 mg/12h Placebo q3w + Prednisone 5 mg/12h Palliative response(29% vs 12%, p=0.01) Longer in Mitox. Arm (43 vs 18 weeks, p<.0001) No difference in Overall Survival Study endpoints: Primary: Pain improvement Secondary: PSA response, OS
Docetaxel TAX-327 Docetaxel75mg/m 2 q3w + Prednisone 5 mg/12h N=335 Metastatic No Chemo ECOG 2 n=1006 Docetaxel30 mg/m 2 1w + Prednisone 5 mg/12h N=334 Mitoxantrone12mg/m 2 q3w + Prednisone 5 mg/12h N=337 Study end points: Primary: OS Secondary: Pain reduction, QoL, 50% PSA decline, tumor response Improved OS (18.9m vs 16.5 m, p<0.001) 50% PSA decline (45% vs 32 %, p<0.001) Reduction in pain: 35 % vs 22 % (p=0.01) QoL:22% vs 13% (p=0.009) Tannock, NEJM, 2004
Docetaxel SWOG 99-16 Metastatic disease ECOG 2 N=674 Estramustine 380 mg/8h D1-5 + Docetaxel60 mg/m 2 q21w + Prednisone 5 mg/12h N=338 Mitoxantrone12 mg/m 2 q3w + Prednisone 5 mg/12h N=336 Study end points: Primary: OS Secondary: PFS, 50% PSA decline, tumour response rate Petrylack, NEJM, 2004 Improved OS (17.5m vs 15.6 m, p=0.02) Improved PFS (6.3 m vs 3.2 m, p<0.001) 50% PSA decline: 50% vs 27%, p<0.001) Grade 3 or 4 Febrile Neutropenia (p=.01), nausea and vomiting (p=.001) and CV events (p=.001)
Cabazitaxel TROPIC Metastatic Symptomatic ECOG 2 Progression to docetaxel N=755 Cabazitaxel25 mg/m 2 q21w + Prednisone 5 mg/12h N=378 Mitoxantrone12 mg/m 2 q3w + Prednisone 5 mg/12h N=377 Study end points: Primary: OS Secondary: PFS, 50% PSA decline, PSA progression, objective tumour response rate, pain progression Improved OS (15.1m vs 12.7 m, p<.0001) Improved PFS (2.8 m vs 1.4 m, p<0.0002) 50% PSA decline: 39% vs 18%, p<0.001) No difference in pain response Febrile neutropenia: 8% vs 1% De Bono, 2010, Lancet
Efficacy NOV-22 (Mitoxantrone) TAX-327 (Docetaxel) SWOG 99-16 (Docetaxel- Estr) TROPIC (Cabazitaxel) N 161 OS Exp arm OS Control Δ OS HR (CI95%) RECIST Response PSA Response - - - - - - 1006 18.9 months 16.5 months 2.4 months 0.76 (0.62-0.94) 674 17.5 months 15.6 months 1.9 months 0.80 (0.67-0.97) 755 15.1 month 12.7 months 2.4 months 0.70 (0.59-0.83) 12% vs7 % (p=0.11) 17% vs11% (p=0.3) 14.4% vs4% (p<0.001) 45% vs32% (p<001) 50% vs27% (p<0.001) 39% vs18% (p<0.001) QoL Yes Yes No No
TOXICITY DOCETAXEL (TAX-327) CABAZITAXEL (TROPIC) Neutropenia(G3, G4): 32% vs 22% Febrile Neutropenia: 3% vs 2% Neutropenia(G3, G4): 82% vs 58% Febrile Neutropenia: 8% vs 1% Diarrhea(Any grade): 32% vs 10% Diarrhea(Any grade): 47% vs 11% (G3, G4): 6% vs <1% Peripheral neuropathy: 32% vs 10% Peripheral neuropathy: 14% vs 3% Others: Alopecia (65% vs 13%), Nail changes(30% vs 7%), stomatitis (20% vs8%), Edema (19% vs1%) Deaths due to causes other than disease progression 5% vs <1% Patients 65 years Neutropenia Diarrhea Monitoring GCSF
FIRSTANA Sartor, ASCO 2016
C20 and C25 not superior to D75 for OS Oudard et al, JCO, 2017
Oudard et al, JCO, 2017
Post-marketing requirement trial PROSELICA Hypothesis: C20 mantainsat least50% of theos benefitof C25 relative to mitroxantrone observed on the TROPIC study De Bono, ASCO 2016
C20 maintained 50% of the OS benefit of C25 Eisenberg, JCO, 2017
Secondary efficacy end-points favoured C25 Eisenberg, JCO, 2017
Less adverse events were observed with C20 Eisenberg, JCO, 2017
Combinations with docetaxel D Antonarakis, JCO, 2013
Radium-223 - Calcium mimetic - Accumulates in hydroxyapatite areas surrounding tumor lesions whereitbindsto áreas of increased turnover Apha particles induce doublestrand DNA breaks in adjacent tumour cells. Short penetration of alpha emitters(2-10 cells) = highly localizedtumourcellkillingand minimal damage to surrounding normal tissue Henriksen et al. Cancer Re 2002 Parker et al, Prostate Cancer Prost Dis, 2018
ALSYMPCA: Study Design PATIENTS (N=921) Confirmed symptomatic CRPC (EBRT or analgesia) 2 bone metastases Noknown visceral metastases Post-docetaxel, unfit for docetaxel, or refused docetaxel STRATIFICATION Total ALP: <220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R 2:1 Radium-223 (50 kbq/kg IV) 6 injections at 4-week intervals + best standard of care Placebo (saline) 6 injections at 4-week intervals + best standard of care ALSYMPCA was halted early after the positive efficacy results reported froma plannedinterim analysis of 809 patients with 314 deaths occurred. An updated analysis of efficacy and safety was performed from all 921 enrolled patients when 528 deaths had occurred. 20
Study Endpoints PRIMARY ENDPOINT Overall survival SECONDARY ENDPOINTS Time to total ALP progression Total ALP response Total ALP normalization Time to occurrence of first SSE ALSYMPCA had no radiographic review and so only symptomatic pathologic bone fractures were captured. Thus symptomatic skeletal event (SSE) was deemed a more clinically relevant term for this measurement. Time to PSA progression Other secondary efficacy endpoints Safety Quality of life ALP, alkaline phosphatase; PSA, prostate-specific antigen; SSE, symptomatic skeletal event. a.see slides ( Other Secondary Efficacy Endpoints ) for more details. b.defined as return of total ALP to within normal range at 12 weeks [confirmed by two consecutive measurements 2 weeks apart] in patients with total ALP values above upper limit of normal (ULN) at baseline. c. Defined as 25% increase from baseline and an absolute value increase 2 ng/ml at 12 weeks [in patients with no PSA decline from baseline] or 25% increase and an absolute value increase 2 ng/ml above nadir confirmed 3 weeks later, in patients with an initial decrease from baseline. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 223. 21
Radium-223 Significantly Improved Overall Survival 100 80 60 Radium 223 Placebo Median OS (months) 14.9 11.3 HR 0.70 95% CI 0.58-0.83 P <0.001 40 20 Median OS Δ: 3.6 months Radium 223 + BSoC Placebo + BSoC 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Month Radium 223 614 578 504 369 274 178 105 60 41 18 7 1 0 0 Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0 30% reduction in risk of death (HR=0.70) for patients in the Radium-223 group
Radium-223 Significantly Improved Time to SSE Patients Without SSE (%) 100 90 80 70 60 50 40 30 20 10 Median Δ: 5.8 months Radium 223 + BSoC Placebo + BSoC Radium 223 Placebo Median Time to SSE (months) 15.6 9.8 HR 0.66 95% CI 0.52-0.83 P <0.001 0 Month 0 3 6 9 12 15 18 21 24 27 30 Radium 223 614 496 342 199 129 63 31 8 8 1 0 Placebo 307 211 117 56 36 20 9 7 4 1 0
Secondary Efficacy Endpoints The significant improvement in all main secondary efficacy endpoints provided support for the benefit of radium-223 (+ BSoC) over placebo (+ BSoC). SECONDARY EFFICACY ENDPOINTS RADIUM-223 (n=614) PLACEBO (n=307) HAZARD RATIO (95% CI) P VALUE Median time to first SSE(months) 15.6 9.8 0.66 (0.52-0.83) <0.001 Median time to total ALP progression(months) 7.4 3.8 0.17 (0.13-0.22) <0.001 Median time to PSA progression(months) 3.6 3.4 0.64 (0.54-0.77) <0.001 Total ALP response ( 30% reduction), n (%) a 233/497 (47) 7/211 (3) <0.001 Total ALP normalization, n (%) a,b 109/321 (34) 2/140 (1) <0.001 ALP, alkaline phosphatase; BSoC, best standard of care; CI, confidence interval; ITT, intention-to-treat; PSA prostate-specific antigen; SSE, symptomatic skeletal event. a. Number of patients without missing values. b.in patients who had elevated total ALP at baseline. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 223. 24
Radium-223 Reduced the Risk of each individual SSE component Radium-223 is the only agent in advanced CRPC shown to decrease the risk of spinal cord compression in a phase 3 trial: 48% risk reduction 33%reduction in need of EBRT for bone pain INDIVIDUAL SSE COMPONENTS n a (%) RADIUM-223 (N=614) MEDIAN, b MONTHS n a (%) PLACEBO (N=307) MEDIAN, b MONTHS HR (95% CI) P VALUE c External beamradiation therapy 186 (30) 17.1 105 (34) 17.5E 0.67 (0.53-0.85) 0.00117 Symptomatic pathologic bone fracture 32 (5) NE 20 (7) NE 0.62 (0.35-1.09) 0.10 Spinal cord compression 25 (4) NE 21 (7) NE 0.52 (0.29-0.93) 0.03 Tumor-relatedorthopedic surgical intervention 12 (2) NE 7(2) NE 0.72 (0.28-1.82) 0.48 CI, confidence interval. CRPC, castration-resistant prostate cancer. NE, not estimable. a. Number of patients. b. Median time to first event. 0 Favors 1 Favors 2 Radium-223 Placebo c. P values are for descriptive purpose only and not adjusted for multiplicity; the hazard ratio is the best interpretation of radium-223 effect. SOURCE:Sartor O, et al. Lancet Oncol. 2014;15(7):738 746. 25
ALP Response ALSYMPCA Efficacy: Biomarkers A significantly higher proportion of patients in the radium 223 group compared with the placebo group achieved total ALP response ( 30% reduction in total ALP; P <0.001) and normalization(p <0.001). PSA Response a Radium 223 Placebo P Value 30% Reduction in PSA blood levels at week 12 16% 6% <0.001 30% Reductionin PSA blood levels sustained through end of treatment (4 weeks after last injection) 14% 4% <0.001
Radium-223 patients with a confirmed talpor LDH decline at week 12 had a significantly longer median OS versus radium-223 patients without talp or LDH decline Sartor et al, Ann Oncol 2017
Sartor, Abstract 2530 ASCO 2015
Parker et al, NEJM, 2013
Prior docetaxel use did not affect the incidence of grade 3 or 4 non-hematologic AEs PATIENTS WITH GRADE 3 or 4 AEs*, n (%) PREVIOUS DOCETAXEL USE RADIUM-223 (n=347) PLACEBO (n=171) NO PREVIOUS DOCETAXEL USE RADIUM-223 (n=253) PLACEBO (n=130) Diarrhea 2 (1) 4 (2) 7 (3) 1 (1) Nausea 8(2) 3 (2) 2 (1) 2 (2) Vomiting 9(3) 5 (3) 1 (<1) 2 (2) Constipation 3(1) 1 (1) 3 (1) 3 (2) Fatigue 16 (5) 10 (6) 8 (3) 8 (6) Peripheral edema 6 (2) 2 (2) 4 (2) 2 (2) Urinary tract infection 3 (1) 4 (3) 4 (2) 1 (1) Weight decreased 4 (1) 5 (0) 0 0 Anorexia 4 (1) 2 (1) 5 (2) 0 Bone pain 74 (21) 53 (31) 51 (21) 24 (19) Malignant neoplasm progression 5 (1) 4 (3) 8 (3) 1 (1)
Data review suggests that patients in the combination arm had an increased risk of fractures (28% vs 11%) and shortersurvival(median 31 vs 33 months) - EMA recommendation: - Symptomatic patients - notto use XOFIGO in combination - After 2 previous treatments for mcrpc - patients who cannot tolerate other treatments