systemic therapies for crpc: chemotherapy …...systemic therapies for crpc: elena castro spanish...

SYSTEMIC THERAPIES FOR CRPC:

ELENA CASTRO

Spanish National Cancer Research Centre

Prostate Preceptorship. Lugano 4-5 October 2018

Chemotherapy and Radium-223

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

Orchiectomy

Antiandrogens

Mitoxantrone

Zoledronic

Acid

Abiraterone

Acetate

Abiraterone

Acetate Enzalutamide

Enzalutamide

Palliative response(29% vs 12%, p=0.01)

Longer in Mitox. Arm (43 vs 18 weeks, p<.0001)

No difference in Overall Survival

Palliative response(29% vs 12%, p=0.01)

Longer in Mitox. Arm (43 vs 18 weeks, p<.0001)

No difference in Overall SurvivalMetastatic

disease

Symptomatic

(pain)

ECOG ≤3

n=161

Mitoxantrone 12 mg/m2 q3w +

Prednisone 5 mg /12h

Placebo q3w +


Placebo q3w +


Study endpoints:

• Primary: Pain improvement

• Secondary: PSA response, OS

Mitoxantone

Metastatic

No Chemo

ECOG ≤2

n=1006

Docetaxel 75mg/m2 q3w +


Docetaxel 75mg/m2 q3w +


Mitoxantrone 12mg/m2 q3w +


Mitoxantrone 12mg/m2 q3w +


Docetaxel 30 mg/m2 1w +


Docetaxel 30 mg/m2 1w +


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)

Docetaxel

TAX-327

Tannock, NEJM, 2004

N=335

N=334

N=337

Metastatic

disease

ECOG ≤2

N=674





Estramustine 380 mg/8h D1-5 +

Docetaxel 60 mg/m2 q21w +


Estramustine 380 mg/8h D1-5 +

Docetaxel 60 mg/m2 q21w +


≥50% PSA decline: 50% vs 27%, p<0.001)

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)

N=338

N=336

Study end points:

• Primary: OS

• Secondary: PFS, ≥50% PSA decline, tumour response rate

Docetaxel

SWOG 99-16

Petrylack, NEJM, 2004

Cabazitaxel

TROPIC

Metastatic

Symptomatic

ECOG ≤2

Progression

to docetaxel

N=755





Cabazitaxel 25 mg/m2 q21w +


Cabazitaxel 25 mg/m2 q21w +


N=378

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

N OS

Exp arm

OS

Control

Δ OS HR (CI95%) RECIST

Response

PSA

Response

QoL

NOV-22

(Mitoxantrone)

161- - - - - -

Yes

TAX-327

(Docetaxel)

1006 18.9 months 16.5 months 2.4 months 0.76

(0.62-0.94)

12% vs 7 %

(p=0.11)

45% vs 32%

(p<001)

Yes

SWOG 99-16

(Docetaxel-

Estr)

674 17.5 months 15.6 months 1.9 months 0.80

(0.67-0.97)

17% vs 11%

(p=0.3)

50% vs 27%

(p<0.001)

No

TROPIC

(Cabazitaxel)

755 15.1 month 12.7 months 2.4 months 0.70

(0.59-0.83)

14.4% vs 4%

(p<0.001)

39% vs 18%

(p<0.001)

No

TOXICITY

DOCETAXEL

(TAX-327)

DOCETAXEL

(TAX-327)

CABAZITAXEL

(TROPIC)

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: 14% vs 3%Peripheral neuropathy: 32% vs 10%

Others: Alopecia (65% vs 13%), Nail

changes (30% vs 7%), stomatitis

(20% vs 8%), Edema (19% vs 1%)

Deaths due to causes other than

disease progression 5% vs <1%

Patients ≥65 years

Neutropenia

Diarrhea

Monitoring

GCSF

…

Sartor, ASCO 2016

FIRSTANAFIRSTANAFIRSTANAFIRSTANA

Oudard et al, JCO, 2017

C20 and C25 not superior to D75 for OS

Oudard et al, JCO, 2017

PROSELICA

De Bono, ASCO 2016

Post-marketing requirement trial

Hypothesis: C20 mantains at least 50% of the OS benefit of C25

relative to mitroxantrone observed on the TROPIC study

Eisenberg, JCO, 2017

C20 maintained ≥50% of the OS benefit of C25

Secondary efficacy end-points favoured C25


Less adverse events were observed with C20


Combinations with docetaxel

Antonarakis, JCO, 2013

D

Henriksen et al. Cancer Re 2002

Parker et al, Prostate Cancer Prost Dis, 2018

Apha particles induce double-

strand DNA breaks in adjacent

tumour cells.

Short penetration of alpha–

emitters (2-10 ∅ cells) = highly

localized tumour cell killing and

minimal damage to surrounding

normal tissue

- Calcium mimetic

- Accumulates in hydroxyapatite

areas surrounding tumor lesions

where it binds to áreas of

increased turnover

Radium-223

20

ALSYMPCA: Study Design

Radium-223 (50 kBq/kg IV) 6 injections at 4-week intervals

+ best standard of care

Radium-223 (50 kBq/kg IV) 6 injections at 4-week intervals


Placebo (saline)6 injections at 4-week intervals


Placebo (saline)6 injections at 4-week intervals


PATIENTS (N=921)

• Confirmed symptomatic CRPC

(EBRT or analgesia)

• ≥2 bone metastases

• No known visceral metastases

• Post-docetaxel, unfitfor docetaxel, or refused docetaxel

STRATIFICATION

• Total ALP: <220 U/L vs ≥220 U/L

• Bisphosphonate use: Yes vs No

• Prior docetaxel: Yes vs No

RR 2:1

ALSYMPCA was halted early after the positive efficacy results reported from a planned interim

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.

ALSYMPCA was halted early after the positive efficacy results reported from a planned interim

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.

21

Study Endpoints

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.

• Overall survival

PRIMARY ENDPOINT

• Overall survival

PRIMARY ENDPOINT

• Time to total ALP progression

• Total ALP response

• Total ALP normalization

• Time to occurrence of first SSE

• Time to PSA progression

• Other secondary efficacy endpoints

• Safety

• Quality of life

SECONDARY ENDPOINTS

• Time to total ALP progression

• Total ALP response

• Total ALP normalization

• Time to occurrence of first SSE

• Time to PSA progression

• Other secondary efficacy endpoints

• Safety

• Quality of life

SECONDARY ENDPOINTS

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.

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.

MonthRadium 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

Radium 223 Placebo

Median OS (months) 14.9 11.3

HR 0.70

95% CI 0.58-0.83

P <0.001

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Radium 223 + BSoC

Placebo + BSoC

Median OS Δ: 3.6 months

Radium-223 Significantly Improved Overall Survival

30% reduction in risk of death (HR=0.70) for patients in the Radium-223 group

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

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

Wit

ho

ut

SS

E (

%)

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

Median Δ: 5.8 months

Radium-223 Significantly Improved Time to SSE

The significant improvement in all main secondary efficacy endpoints provided

support for the benefit of radium-223 (+ BSoC) over placebo (+ BSoC).

24

Secondary Efficacy Endpoints

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.

SECONDARY EFFICACY ENDPOINTSRADIUM-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

• 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

Radium-223 Reduced the Risk of each individual SSE

component

25

CI, confidence interval. CRPC, castration-resistant prostate cancer. NE, not estimable.

a. Number of patients.b. Median time to first event.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.

RADIUM-223 (N=614) PLACEBO (N=307)

INDIVIDUAL SSE COMPONENTS na (%)

MEDIAN,b

MONTHS na (%)MEDIAN,b

MONTHS HR

(95% CI) P VALUEc

External beam radiation therapy

186 (30) 17.1 105 (34) 17.5E0.67

(0.53-0.85)0.00117

Symptomatic pathologic bone fracture

32 (5) NE 20 (7) NE0.62

(0.35-1.09)0.10

Spinal cordcompression

25 (4) NE 21 (7) NE0.52

(0.29-0.93)0.03

Tumor-related orthopedic surgical intervention

12 (2) NE 7 (2) NE0.72

(0.28-1.82)0.48

FavorsRadium-223

FavorsPlacebo

0 21

ALSYMPCA Efficacy: Biomarkers

•ALP Response

• PSA Responsea

Radium 223 Placebo P Value

≥30% Reduction in PSA blood levels at week 12 16% 6% <0.001

≥30% Reduction in PSA blood levels sustained through

end of treatment (4 weeks after last injection)14% 4% <0.001

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).

Radium-223 patients with a confirmed tALP or 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

PREVIOUS DOCETAXEL USE NO PREVIOUS DOCETAXEL USE

PATIENTS WITH GRADE 3 or 4 AEs*, n (%)

RADIUM-223(n=347)

PLACEBO(n=171)

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)

Prior docetaxel use did not affect the incidence of grade 3 or 4 non-hematologic AEs

Data review suggests that patients in the combination arm had an increased risk

of fractures (28% vs 11%) and shorter survival (median 31 vs 33 months)

- EMA recommendation:

- Symptomatic patients

- not to use XOFIGO in combination

- After 2 previous treatments for mCRPC

- patients who cannot tolerate other treatments

systemic therapies for crpc: chemotherapy …...systemic therapies for crpc: elena castro spanish...

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