Nieuwe ontwikkelingen bij de behandeling van mcrpc. F. van den Berkmortel Internist-Oncoloog Atrium mc Parkstad, Heerlen

Nieuwe ontwikkelingen bij de behandeling van mCRPC F. van den Berkmortel Internist-Oncoloog Atrium mc Parkstad, Heerlen 18 november 2014

Prostaatcarcinoom: Het ‘nieuwe sexy tumortype’

Prostaat kanker • •

Meest voorkomende vorm van kanker bij mannen in Europa. (Ref 1) Ongeveer 1 op 6 mannen krijgt deze diagnose tijdens“Prostate zijn leven. Cancer (Ref is currently one of the most 2)

• • •

important problems facing the male De incidentie en mortaliteit verschillen tussen depopulation” verschillende landen. (Ref 3) (European Association of Urology, 2010). PK is de tweede oorzaak van overlijden door kanker bij de man, na longkanker. (Ref 4) In 2008, zeker 70.000 overlijdens door PK in Europa. (Ref 5)

Proportion of Older Patients with Metastatic Disease and Who Die from Prostate Cancer

Presented By Supriya Mohile at 2014 ASCO Annual Meeting

Relatieve overleving: leeftijd 100% 90% 80%

% overleving

70% 15-54 jaar 60%

55-64 jaar

50%

65-74 jaar

40%

75-84 jaar >85 jaar

30% 20% 10% 0% 1

2

3

4

5

6

7

8

9

10

11

jaren na diagnose

• landelijke cijfers 1998-2007; n=80.378 • slechtere prognose voor 75+ • grootste stijging 5 jaarsoverleving in lftcategorie 45-54: 1.8%/jaar*

* Cremers et al Eur J Canc 2010

Relatieve overleving naar stadium 100% 90% 80%

% overleving

70% stadium I

60%

stadium II

50%

stadium III

40%

stadium IV

30% 20% 10% 0% 1

2

3

4

5

6

7

jaren na diagnose

8

9

10

11

Risicofactoren LEEFTIJD

ETNICITEIT

Prostaat Kanker

EXOGENE FACTOREN

FAMILIALE GESCHIEDENIS

Prostaat kanker: diagnose  Rectaal toucher (DRE)  PSA

 Prostaatbiopsie  Transrectale Ultrasonografie (TRUS)  CT-scan en/of MRI-scan

Behandeling Gelokaliseerde ziekte (afhankelijk van stadium, Gleason, comorbiditeit etc) • • • •

Observatie Prostatectomie (robot?) Radiotherapie/Brachytherapie Androgeen suppressie

Castraat resistent prostaat carcinoom (CRPC) • • • • •

Immunotherapie Chemotherapie ‘Endocriene’ therapie Radiotherapie ‘Botspecifieke’ therapie

Gelokaliseerde ziekte

Doelen • Behandeling CRPC: – – – –

Immunotherapie Chemotherapie Nieuwe hormoon therapie Bot specifieke middelen

• Discussie: Rol van de verpleegkundige bij behandeling

Prostaatcarcinoom: Het ‘nieuwe sexy tumortype’

Oudard S. Cancer Treat Rev (2012)

Castratie resistente prostaatkanker • Definitie:

• “Progressie van de ziekte, ondanks androgen deprevatie therapie (ADT)” • Continue stijging van PSA niveaus (3 xPSA in min. 3 wk, 2 ↑ 50% boven nadir), ondanks lage testosteronspiegel (<50 ng/dl/<1,7 nmol/l), na min.4 wk staken anti-androgenen

• Progressie van de ziekte of nieuwe nieuwe uitzaaiingen

Saad F et al. Eur Urol 2006, 49:429–440. Hotte & Saad .Curr Oncol. 2010; 17(Supplement 2): S72–S79

Landschap: NU

Progressie prostaatkanker

Sipuleucel-T Abirateron/Enzalutamide: bij geen of milde klachten na falen ADT1*

Androgeen Deprivatie Therapie

Abirateron/ Enzalutamide/cabazitaxel: progressie tijdens of na docetaxel1,2

overlijden Docetaxel behandeling na LHRH agonisten / anti-androgenen

lokale behandeling

Docetaxel: gemet. en hoge ziekte last bij diagnose

Radium 223: symptomatische botmeta’s en geen viscerale meta’s

Tijd Botondersteunende therapie

* En chemotherapie klinisch niet geïndiceerd is. Opm: dit schema toon t het beeld van ziekteprogressie zoals deze frequent optreedt. Er zijn echter ook mannen die bij diagnose gemetastaseerde prostaatkanker hebben: hun behandel schema is afwijkend van bovenstaand schema.

1. SmPC abirateron, 2. SmPC enzalutamide

Landschap: NU






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Sipuleucel-T Hypothesized mechanism of action of sipuleucel-T 2

• Mechanism of action1 – Induces an immune response targeted against prostatic acid phosphatase (PAP)

• Indication1 – For the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer

Antigen-presenting cells are cultured with PAP-GM-CSF

PAP-GM-CSF is expressed on the surface of antigenpresenting cells

T lymphocytes recognize PAP-GM-CSF and are activated to target PAP and PAP-GM-CSF

T lymphocytes incite PAPand PAP-GM-CSF-specific antibodies and both target tumor cells

PAP = prostatic acid phosphatase; PAP-GM-CSF = prostatic acid phosphatase–granulocyte–macrophage colony-stimulating factor. 1. Provenge Prescribing Information. Dendreon Corporation, 2011. 2. Sonpavde et al. Eur Urol 2012;4:639.

Sipuleucel-T Phase III Trial (IMPACT): Overall Survival 100

Sipuleucel-T Placebo

Sipuleucel-T (n = 341)

21.7

25.8

Median OS (months)

75

Survival, %

Placebo (n = 171)

Hazard ratio

0.775

95% CI

0.614–0.979

P

0.02

50

25

0

Median OS Δ: 4.1 months

0

6

12

18

24

30

36

Time, months Kantoff et al. N Engl J Med 2010;363:411.

42

48

54

60

66

Landschap: NU






lokale behandeling






Docetaxel: Phase III data •

Patients (n = 1006): • Progressive, metastatic CRPC

Docetaxel e3w + P Overall survival

Mitoxantrone + P

Difference (p-value)

18.9 months

16.5 months

2.4 months (p< 0.009)

Time to SRE

NA

NA

NA

Quality of Life response rate

22%

13%

9% (p = 0.009)

•

Adverse events (% grade 3/4): • Neutropenia (32%), anemia (5%), alopecia (63%)

•

Other considerations: • In combination with prednisone • No data on skelelal related events Tannock et al. n engl j med 351:15 (2004)

Docetaxel: Phase III data • 1x 3 weken intraveneus in ziekenhuis toegediend in combinatie met prednison .

+2,5 mo

• Haarverlies • moeheid • Neutropenie; neutropene koorts • Gastro-intestinale klachten • Infecties • Neuropathie Tannock et al. n engl j med 351:15 (2004)

Landschap: NU




UROLOOG

ONCOLOOG



lokale behandeling






Cabazitaxel Phase III TROPIC Study Design

TROPIC Study: Overall Survival

+2,4 mo

TROPIC Study: toxicities Cabazitaxel (n = 371) Grade Neutropenia

Mitoxantrone (n = 371)

All

Grades 3/4

All

Grades 3/4

347 (94%)

303 (82%)

325 (88%)

215 (58%)

Febrile neutropenia

28 (8%)

5 (1%)

Leukopenia

355 (96%)

253 (68%)

343 (92%)

157 (42%)

Anemia

361 (97%)

39 (11%)

302 (81%)

18 (5%)

Thrombocytopenia

176 (47%)

15 (4%)

160 (43%)

6 (2%)

Diarrhea

173 (47%)

23 (6%)

39 (11%)

1 (< 1%)

Fatigue

136 (37%)

18 (5%)

102 (27%)

11 (3%)

Asthenia

76 (20%)

17 (5%)

46 (12%)

9 (2%)

Back pain

60 (16%)

14 (4%)

45 (12%)

11 (3%)

Deaths ≤ 30 days after last dose of study drug

18 (5%)

9 (2%)

de Bono et al. Lancet 2010;376:1147.

Abiraterone • Selective, small-molecule inhibitor of CYP17, a critical enzyme in testosterone synthesis • Potently blocks androgen biosynthesis at all locations

Testes

↓ Testosterone ↓ Dihydrotestosterone

Prostate tumor cells

Adrenal gland

↓ Dehydroepiandrostenedione ↓ Androstenedione

↓ Dehydroepiandrostenedione ↓ Androstenedione

De Bono et al. Ann Oncol 2010;21(Suppl 8): Abstract LBA5.

Abiraterone - Phase III COU-AA-301 Study Design

Phase III COU-AA-301: Overall survival 100 Abiraterone Placebo

Survival (%)

80 60 40 20

Median survival (months)

Hazard Ratio

P

Abiraterone

14.8

0.66

< 0.0001

Placebo

10.9

0 0

100

200

300 500 400 Days from randomization

600

700

Data update (2011) 15.8 months vs. 11.2 months (4.6 months difference) HR = 0.74, P  0.0001 de Bono et al. NEJM 2011;364:1995.

Phase III COU-AA-301: Adverse events Abiraterone (n = 791)

Placebo (n = 394)

All Grades

Grades 3/4

All Grades

Grades 3/4

Fluid retention

30.5%

2.3%

22.3%

1.0%

Hypokalemia

17.1%

3.8%

8.4%

0.8%

LFT abnormalities

10.4%

3.5%

8.1%

3.0%

Hypertension

9.7%

1.3%

7.9%

0.3%

Cardiac disorders

13.3%

4.1%

10.4%

2.3%

LFT, Liver function test. de Bono et al. N Engl J Med 2011;364:1995.

Summary: abiraterone after chemotherapy •

Patients (n= 1195): • Progressive, metastatic CRPC • 1 or 2 failed chemotherapies including docetaxel Abiraterone + P

Overall survival Time to SRE Time to pain progr.

Placebo + P


15.8 months

11.2 months

4.6 months (p< 0.0001)

301 days

150 days

151 days (p = 0.0006)

225

142

83 days (p = 0.0056)

•

Adverse events (% grade 3/4): • Fluid retention (2.3%), hypokalemia (3.8%), hypertension (1.3%), cardiac disorder (4.1%)

•

Other considerations: • In combination with prednisone De Bono et al. N Engl J Med. 364(21):1995-2000 (2011)

Enzalutamide (MDV3100) • A second generation antiandrogen

– Androgen receptor antagonist • Blocks binding of DHT to androgen receptor • Inhibits nuclear translocation of androgen receptor and binding to DNA DHT: dihydrotestosterone

Enzalutamide

Enzalutamide Phase III AFFIRM Trial Study Design

Scher et al. N Engl J Med 2012: 1187-97

AFFIRM Trial: Overall Survival

AFFIRM Trial: Time to SRE

De Bono et al. J Clin Oncol 2012;30(suppl.): abstr 4519 and accompanying presentation.

AFFIRM Trial: Adverse events Total events

Grade ≥ 3 events

Enzalutamide (n = 800)

Placebo (n = 399)

Enzalutamide (n = 800)

Placebo (n = 399)

Adverse events

98.1%

97.7%

45.3%

53.1%

Serious adverse events

33.5%

38.6%

28.4%

33.6%

Discontinuations due to adverse events

7.6%

9.8%

4.6%

7.0%

Adverse events leading to death

2.9%

3.5%

2.9%

3.5%

Cardiac disorders

6.1%

7.5%

0.9%

2.0%

Myocardial infarction

0.3%

0.5%

0.3%

0.5%

LFT abnormalities*

1.0%

1.5%

0.4%

0.8%

Seizure

0.6%

0.0%

0.6%

0.0%

Adverse events of interest

*Includes terms hyperbilirubinemia, AST increased, ALT increased, LFT abnormal, transaminases increased, Scher et al. J Clin Oncol 2012;30(suppl 5): abstr LBA1 and accompanying presentation. and blood bilirubin increased.

Summary: Enzalutamide •

Patients (n= 1199): • CRPC patients • 1 or 2 failed chemotherapies including docetaxel Enzulatamide

Placebo


Overall survival

18.4 months

13.6 months

4.8 months (p < 0.0001)

Time to SRE

16.7 months

13.3 months

3.4 months (p < 0.0001)

43%

18%

25% (p < 0.001)

Quality of Life improvement

•

Adverse events (% grade 3/4): • Less than placebo (45% vs. 53%)

•

Other considerations: • Can pass the bbb, lead to some seizures: (grade 3/4: 0.6%)

Wat betekent dit voor verpleegkundige? Orale therapie • • • •

Correct gebruik Compliance Interactie andere medicamenten ‘Andere’ bijwerkingen: hypertension, oedeem, elektroliet stoornissen, insulten (abi: zonder voedsel, enz: maakt niet uit)

(12 wk a 2 wk bij abi)

Verpleegkundige zorg Abiraterone • Inname: nuchter • 1000 mg (4 tabl) • Met prednison • Bijwerkingen: RR-Koedeem • Interactie: CYP2D6 metaboliseerders bijv metoprolol, pijnstillers (evt dosisverlaging)

Enzalutamide • Constante inname • 160 mg (4 tabl) • Zonder prednison • Bijwerkingen: insulten • Interactie: mn Cyp2C8 (gemfibrozil:minder werking enza); CYP3A4 metaboliseerders (mindere werkzaamheid)

Landschap: NU



Abirateron/ Enzalutamide/cabazitaxel: Abirateron progressie tijdens of na docetaxel1,2

Enzalutamide ONCOLOOG

UROLOOG Androgeen Deprivatie Therapie


lokale behandeling






Abiraterone Phase III COU-AA-302 Study Design

Phase III COU-AA-302: PFS

Phase III COU-AA-302: Overall Survival

*O’Brien-Fleming boundary used; †Data cut off 12/20/2011; ‡Nominal significance level 0.0008. Ryan et al. J Clin Oncol 2012;30(suppl.):abstr LBA4518 and accompanying presentation.

Phase III COU-AA-302: Adverse Events

Patients with Grade 3/4 adverse events (%)

Abiraterone

Placebo

Hypertension

3.9

3.0

Hypokalemia

2.4

1.9

ALT ↑

5.4

0.7

AST ↑

3.0

0.9

Ryan et al. J Clin Oncol 2012;30(suppl.):abstr LBA4518.

Summary: abiraterone before chemotherapy •

Patients (n = 1017): • Asymptomatic or mildly symptomatic metastatic CRPC with no prior cytoxic chemotherapy Abiraterone + P

Placebo + P


Overall survival

34.7

30.3 months

(p = 0.027)

Time to SRE

NA

NA

NA

12.3 months

10.9 months

P = 0.0053

Time to ECOG PS deterioration

•

Adverse events (% grade 3/4): • Fluid retention (3.9%), hypokalemia (2.4%), elevated ALT (5.4%), elevated AST (3.0%)

•

Other considerations: • In combination with prednisone (long term use may increase the risk on osteoporotic fractures) ESMO 2014; abstract

Phase III PREVAIL Trial Study Design

N Engl J Med 2014; 371:424-433July 31, 2014DOI: 10.1056/NEJMoa1405095

Clinicaltrials.gov identifier # NCT01212991.

Summary: enzalutamide before chemotherapy •

Patients (n = 1717): • Asymptomatic or mildly symptomatic metastatic CRPC with no prior cytoxic chemotherapy Enzalutamide

Placebo


Overall survival

32.4

30.2 months

(HR 0.71)(p<0.01)

Time to SRE

31.1

31.3

P<0.001

11.3 months

5.6 months

P = 0.001

Time to decline FACT-P

•

Adverse events (% grade 3/4): • hypertension (7%), Back pain (3%), cardiac event (3%), seizure (<1%)

Landschap: NU







lokale behandeling






Verpleegkundige zorg Abiraterone • Inname: nuchter • 1000 mg (4 tabl) • Met prednison • Bijwerkingen: RR-Koedeem • Interactie: CYP2D6 metaboliseerders bijv metoprolol, pijnstillers (evt dosisverlaging) • “botgezondheid”

Enzalutamide • Constante inname • 160 mg (4 tabl) • Zonder prednison • Bijwerkingen: insulten • Interactie: mn Cyp2C8 (gemfibrozil:minder werking enza); CYP3A4 metaboliseerders (mindere werkzaamheid)

Landschap: NU







lokale behandeling






Slide 24

Presented By Supriya Mohile at 2014 ASCO Annual Meeting

Botuitzaaiingen • Botuitzaaiingen komen voor in +/- 90% van alle mannen met CRPC

• Heeft negatief effect op overleving • Kan leiden tot serieuze morbiditeiten, zoals • Pijn

• Pathologische fracturen • Ruggemerg compressie • Beenmerg falen

Saad F et al. Eur Urol 2006, 49:429–440. Hotte & Saad .Curr Oncol. 2010; 17(Supplement 2): S72–

Huidige bot-specifieke therapiën • Pijnbestrijding – Beta-straling • Strontium • Samarium

• Uitstel van SRE’s – Bisfosfanaten – Denosumab

• Geen effect op overleving

Strontium/Samarium • Gefocust op plekken van Calciumbehoefte • Sterk effect op pijn • Geen (consistente) overlevingseffecten

• Leidt tot myelosupressie

Goyal et al. Cancer Letters 2012

Denosumab

Fizazi et al. Lancet 2011;377:813.

Denosumab: data after chemotherapy •

Patients (n= 1904): • Metastatic CRPC patients with no prior bisphosphonate use • ≥ 1 bone metastases Denosumab

Zoledronic acid


Overall survival

19.4 months

19.8 months

NA (p = 0.61)

Time to SRE

20.7 months

17.1 months

3.6 months (p = 0.008)

NA

NA

NA


•

Adverse events (% grade 3/4): • Renal (15%), hypocalcemia (14%), osteonecrosis of the jaw (2%)

•

Other considerations: • Denosumab is administered subcutaneously

Fizazi et al. Lancet 2011;377:813.

Landschap: NU







lokale behandeling






Radium 223 20

Ca

38

Sr 56

Ba 88

Ra

Korte introductie

Alpha vs. beta radiation

Nilsson S, et al. Presented at the American Society for Radiation Oncology annual meeting. 2010;

Poster 2385.

Radium-223 Mode of Action is Localized (Compared with β-emitters)

Range of β-particle (large volume)

Bone marrow Range of α-particle (small volume)

Tumor

Radium-223

Bone Bone surface

1. Henriksen et al. Cancer Res 2002;62:3120. 2. Nilsson et al. Presented at: American Society for Radiation Oncology annual meeting 2010; poster 2385.

Presentatie EAU

Radium 223 Phase III: ALSYMPCA

Parker C, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA4512.

Radium 223 ALSYMPCA: Overall Survival


ALSYMPCA: Overall Survival by Prior Docetaxel Use


Radium 223: ALSYMPCA: Time to SRE


ALSYMPCA: Adverse Events of Interest Patients with adverse events (AEs), n (%) All Grades

Grades 3 or 4

Radium-223 dichloride (n = 600)

Placebo (n = 301)

Radium-223 dichloride (n = 600)

Placebo (n = 301)

187 (31.2)

92 (31)

77 (13)

40(13)

30 (5)

3 (1)

13 (2)

2 (1)

69 (11.5)

17 (5.6)

39 (6.5)

6 (2)

Bone pain

300 (50)

187 (62)

125 (21)

77 (26)

Diarrhea

151 (25)

45 (15)

9 (1.5)

5 (1.7)

Nausea

213 (35.5)

104 (35)

10 (2)

5 (2)

Vomiting

111 (18.5)

41 (14)

10 (2)

7 (2)

108 (18)

64 (21)

6 (1)

4 (1)

Hematologic Anemia Neutropenia Thrombocytopenia Non-hematologic

Constipation


Radium 223 •

Patients (n= 921): • Symptomatic CRPC with ≥ 2 bone metastases • Previous docetaxel or unfit for docetaxel Radium 223

Placebo


Overall survival

14.9 months

11.3 months

3.6 months (p = 0.00007)

Time to SRE

15.6 months

9.8 months

5.8 months (p < 0.0001)

27%

18%

p < 0.05


•

Adverse events (% grade 3/4): • Thrombocytopenia (6%), neutropenia (2%)

•

Other considerations: • Radium can be given in combination with bisphosphonates • Radium showed less (serious) adverse events than placebo • Minimaal effect op PSA Parker et al. J Clin Oncol 2012;30(suppl.): abstr LBA4512.Parker et al. Poster 898PD ESMO 2012

Landschap: NU







lokale behandeling






E3805 – CHAARTED Treatment

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

OS by extent of metastatic disease at start of ADT

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

Landschap: NU







lokale behandeling




VRAGEN ?

Nieuwe ontwikkelingen bij de behandeling van mcrpc. F. van den Berkmortel Internist-Oncoloog Atrium mc Parkstad, Heerlen

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