Vesa V. Kataja, MD, PhD

Professor of Clinical Oncology

Chief Medical Director

Central Finland Health Care District (KSSHP)

Jyväskylä, Finland

Medical Therapy of Castration

Resistant Prostate Cancer

(CRPC)

European Prostate Awareness Day

16 September 2015

European Parliament Brussels

Castration resistant prostate

cancer – what is it?

• The patient is surgically or chemically castrated

• The serum testosterone level is below 50 mg/mL

• AND

• Rising PSA and/or

• Disease progression evidenced clinically and/or by radiological and/or radio-isotope scanning

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• How does prostate cancer develop resistance to castration? Under intensive research!

History of medical treatment

• Earlier, castration resistance was considered as equal to hormone resistance

• All available chemotherapeutic cytotoxic medicines have been tested since late 1950’s

• Results have been rather disappointing with occasional successes only

• Mitoxantrone in combination with prednisone better than prednisone alone in palliation of symptoms(1)

• 30 % reduction in symptoms (mainly pain)

• No survival advantage

• Became standard treatment for symptomatic mCRPC

(1)Tannock IA, et al. 1996

Present medical treatment -

Chemoterapy

Docetaxel • Taxane chemotherapeutic agent developed first for

metastatic breast cancer (early to mid 1990’s)

• In two randomised trials showed modest survival advantage:

• In combination with estramustine compared to mitoxantrone + prednisone, median survival +1,9 mths(1)

• In combination with prednisone compared to mitoxantrone + prednisone, median survival +2,9 mths(2)

• Main problem: toxicity!

(1) Petrylak DP, et al. 2004

(2)Tannock IA, et al. 2004 and Berthold DR, et al. 2008

Present medical treatment -

Chemotherapy

Cabazitaxel

• Taxane chemotherapeutic agent improved from

docetaxel

• In randomised trial showed survival advantage in 2nd

line treatment (post-docetaxel):

• In combination with prednisone compared to

mitoxantrone + prednisone, median survival +2,4 mths(1)

• Main problem: toxicity!

(1) De Bono J, et al. 2010

Present medical treatment –

Hormonal therapy

Abiraterone (tabl 250 mg)

• Inhibitor of androgen biosynthesis (CYP17 - enzyme)

• In combination with castration, testosterone levels fall

beyond detection

CRPC reacts to hormonal manipulation, ie.

nearly total lack of testosterone in circulation

• Co-administration of prednisone needed to decrease

risk of hypertension, low potassium levels, peripheral

fluid retention and cardiac insufficiency

• Well tolerated; Serious adverse events very rare

Present medical treatment –

Hormonal therapy

Abiraterone (tabl 250 mg)

• Scientific proof of efficacy and base for FDA / EMA

approval

• COU-AA-301: Abiraterone+Prednisone vs. Prednisone post

docetaxel(1)

• Improvement in median survival +4,6 mths

• COU-AA-302: Abiraterone+Prednisone vs. Prednisone pre

docetaxel(2)

• Improvement in median survival +4,4 mths

• Postponement of chemotherapy +8,4 mths

(1) Fizazi K, et al. 2012; (2) Ryan CJ, et al. 2015;

Present medical treatment –

Hormonal therapy

Enzalutamide (caps 40 mg)

• Competitive inhibitor of the androgen receptor

prevents testosterone from ”sitting” in it’s chair (receptor), thus preventing the stimulatory effect for cancer cell growth

• Effective even with already testosterone-activated receptors

• Continued castration necessary, but no need for corticosteroid substitution

• Generally well tolerated, serious adverse events (epileptic seizures) rare (< 0,5 %)

• Most common (> 1/10) AEs: asthenia, fatigue, headache, hypertension, hot flushes

Present medical treatment –

Hormonal therapy

Enzalutamide (caps 40 mg)

• Scientific proof of efficacy and base for FDA / EMA

approval

• AFFIRM(1): Enzalutamide vs. placebo or prednisone post

docetaxel

• Improvement in median survival +4,8 mths

• PREVAIL(2): Enzalutamide vs. placebo pre docetaxel

• Improvement in median survival +2,2 mths

• Postponement of chemotherapy +17,2 mths

(1) Scher HI, et al. 2012; (2) Beer TM, et al. 2014

Present medical treatment –

Internal radiotherapy

Radium-223 • Intravenous radiation therapy for patients with CRPC

and symptomatic bone metastases, but no metastases in visceral organs

• Injected monthly, max. 6 times

• Selective for bone (mimics calcium)

• Emits alpha-particles; low energy with short range (< 100 μm = 10 cell diameters)

• Safe for surrounding tissue and environment

• Most common (> 1/10) AEs: thrombocytopenia, diarrhea, vomiting, nausea

Present medical treatment –

Internal radiotherapy

Radium-223 • Scientific proof of efficacy and base for FDA / EMA approval

• ALSYMPCA(1): Radium-223 vs. placebo

• Improvement in median survival +2,8 mths

• Postponing skeletal related events +5,8 mths

• Less skeletal related events, incl. fractures

• Less need for further treatment for pain

• Slower PSA-progression

(1)Parker C, et al. 2013

Present medical treatment –

Immunotherapy

Sipuleucel-T • Cell-based cancer immunotherapy

• Personalised treatment via programming a patient's own immune system to seek out cancer spreading in the body, and attack it as if it were foreign

• Must be prepared specifically for each patient

• FDA approved 2010 for asymptomatic or minimally symptomatic patients; EMA for 5 years in 2013

• The European Commission withdrew the marketing authorisation in EU in May 2015 due to the request of the marketing authorisation holder (discontinuation of marketing due to commercial reasons)

Present medical treatment –

Sequencing

Future medical treatment

• Better understanding of molecular biology improves treatment

• Personalised selection of therapy based on

• Molecular genetics of the tumour and/or

• Molecular genetics of the patient

AND

• Rational sequencing of therapy based on

• Response to previous treatment and/or

• Molecular genetics of the tumour

Future medical treatment • Galaterone

• Peroral, multi-target (CYP17 inhibition, receptor antagonism, receptor degradation)

• ARN-509 and ODM-201 • Receptor antagonists, extreme affinity to androgen receptor

• GWAX • ”Whole cell” vaccine

• Ipilimumab • Cytotoxic T lymphocyte associated protein 4

• Nivolumab and pembrolizumab • PD-1 and PD-L1 antibodies

• Olaparib • poly ADP ribose polymerase (PARP) inhibitor

• Orteronel • Non-steroidal lyase-inhibitor

Sequencing treatments in the

future?