1. How best to manage patients with advanced prostate cancer presenting with high burden metastatic disease
Michiel Sedelaar

2. Disclosures
Amgen, Astellas, Ferring and Janssen

3. Introduction April 2013: Referral to local urologist (via GP):
49 year old man, married with 3 young children
Progressive micturition complaints (2 months)
Medical History: -
Medication: -
Referral to local urologist (via GP):
DRE: suspected T3/4 prostate cancer
PSA = 150 ng/dL
Prostate biopsy: 12/12 Gleason score 3+4=7
Bone scan: negative (no other imaging)
Treatment with 150 mg bicalutamide was started (possible prostate cancer and prostatitis?)
DRE, digital rectal examination; PSA, prostate-specific antigen; GP, general practitioner

4. Referral to University Center
The patient needed a second opinion
We saw him 2 weeks after bicalutamide treatment had started
Micturition problems improved slightly
PSA dropped to 94.4 ng/dL in 2 weeks
We did some additional investigations…

6. Referral to University Center
New investigations:
Additional MRI of prostate, nodes and bones:
Clear T4 (rectal wall and bladder)
Suspicious nodes (obturator and fossa)
Metastasis (os sacrum)
Re-evaluation of the biopsies:
Gleason score 8
Slight neuro-endocrine activity
New diagnosis: cT4N+M+Gl8 prostate cancer

9. Change of medication
Long discussions on the outcome of the diagnostic tests and the possible course of the disease
Palliative treatment may be successful for years, but not curative
We choose a GnRH antagonist (degarelix), because of the immediate effect on testosterone
August 2013: PSA = 3.9 ng/dL
November 2013:
PSA = 9.2. ng/dL
ALP = 70 units/L
Testosterone = 0.8 nmol/L
New imaging: no change, no new lesions
New treatment: addition of bicalutamide (MAB)
ALP, alkaline phosphatase

10. Some good news…
December 2013: PSA dropped to 2.9 ng/dL and testosterone dropped to 0.4 nmol/L
MAB is still effective:
February 2014: PSA = 0.6 ng/dL
May 2014: PSA = 0.9 ng/dL
The patient experienced the side effects of the hormonal treatment:
Hot-flushes (stellate ganglion block)
Weight-gain
Fatigue
Psychological problems (rollercoaster)
Intervention: diet, physiotherapy, personal trainer and counselling

11. First signs of CRPC? August 2014:
Rise in PSA (3.6 ng/dL) and ALP (163 units/L)
New sign: back pain; treated with tramadol/ibuprofen
New MRI:
Prostate: decreased tumour activity
Nodes: smaller nodes and decreased activity
Bones: strong progression of bone metastasis (C3/C4/Th1/Th7/Th11/L2/L4/L5/S1/S2; os sacrum, os ilium, acetabulum left and right)
Referral to radiation oncologist for local radiation S1/S2
CRPC, castration-resistant prostate cancer

12. May 2013
August 2014

14. New diagnostic tests
Because of the abnormal (short) effect of the hormonal treatment, our multidisciplinary board advised to do an additional prostate biopsy
Possibility of neuro-endocrine tumour?
Possibility of ductal carcinoma?
BRCA1/BRCA2 mutation?

15. New diagnostic tests
Prostate biopsy histology: mixed hormonal refractory adenocarcinoma, ductal type with urothelial differentiation and acinar adenocarcinoma with signs of hormone sensitivity
20% neuro-endocrine activity
No BRCA1/BRCA2 mutation

16. Referral to the medical oncologist
New CT scan did not reveal anything new, no visceral metastases
After consultation with colleagues abroad: chemotherapy with docetaxel+carboplatin was started, together with denosumab treatment
Four chemotherapy cycles in total:
Positive results at first: less pain, still able to work and travel abroad
December 2014: more pain complaints (back and left upper leg)
CT/MRI of bones and nodes: progression of bone metastases but no visceral metastases
Bone scan: +++
PSA = 11.0 ng/dL
ALP = 218 units/L

19. Secondary hormonal manipulation
December 2014:
Disease progression during docetaxel/carboplatin chemotherapy: treatment was stopped
Treatment with abiraterone (1000 mg) + prednisone (5 mg twice daily) was started
↑ bone pain: treatment with fentanyl patch and oxycodone
January 2015:
↑ pain; PSA = 53 ng/dL; ALP = 565 units/L
Prednisone was changed to dexamethasone (1 mg twice daily)

20. QUESTION TO THE PANEL:
Would you give any additional medication for the pain?

21. Next steps
February 2015:
The patient was treated with samarium (Sm-153): after 1 week, there was an improvement in pain
PSA = 56 ng/dL; ALP = 283 units/L (↓)
After 2 weeks: the patient was feeling much better – he went on a skiing holiday with his family (!)

22. QUESTION TO THE PANEL:
How about hormonal responsiveness or AR activity?
How would you test this activity?
AR, androgen receptor

23. Next steps
Dihydrotestosterone (DHT)-PET-CT scan: surprisingly most bone metastases were DHT positive, indicating hormonal activity
Abiraterone and dexamethasone treatment was continued

24. DHT-PET-CT scan: imaging of the AR
Experimental studies in the Netherlands: PROCoMBO and FuTuRe studies

25. Abiraterone treatment side effects
April 2015:
Clinical improvement: PSA = 24 ng/dL; ALP = 564 units/L; testosterone < 0.1 nmol/L
Severe liver abnormalities
No evidence of liver metastases: liver toxicity was drug-induced
Abiraterone treatment was stopped and the patient was treated with enzalutamide and radium-223
Liver enzymes were normalised
↑ pain: the multidisciplinary team decided to adjust his pain medications
May 2015:
Slight clinical improvement due to the normalisation of liver enzymes and the new treatment: PSA = 10.7 ng/dL; ALP = 241 units/L

26. Enzalutamide and radium-223
June 2015:
Overall improvement: ↓pain, feeling good, looking forward to the summer holiday; PSA = 10 ng/dL; ALP = 206 units/L
September 2015:
New liver enzymes abnormalities
CT scan: progression of steatosis, hepatitis but no liver metastases
Enzalutamide and radium-223 (5 cycles) treatment was continued
October 2015:
Clinical progression; liver biopsy revealed severe steatosis but no metastases; PSA = 43 ng/dL
Re-challenge with abiraterone
Rapid clinical response: ↓ pain; PSA dropped to 20 ng/dL; no liver abnormalities

27. Abiraterone treatment
November 2015:
Severe headaches: brain metastases?
No intracranial abnormalities by CT scan, but the MRI revealed 2 small brain abnormalities (extradural space)
Clinical symptoms of brain metastases
Abiraterone treatment was stopped and metastases were treated with RT
December 2015:
Best supportive care, continue ADT, no more additional medication, no trials
The patient reported to have good days and bad days
February 2016: the patient is still alive
RT, radiotherapy

28. PSA levels over the last 2.5 years6. 1. 9. 8. 7. 2. 5. 3. 4.
Bicalutamide monotherapy
GnRH antagonist
MAB
4. PBx/docetaxel/carboplatin
5. Abiraterone + pred/dexa
6. Samarium
7. Enzalutamide/radium-223
8. Abiraterone
9. Stop abiraterone, BSC
BSC, best supportive care; PBx, prostate biopsy

29. ALP levels over the last 2.5 years6. 5. 4. 7. 8. 9. 3. 1. 2.
Bicalutamide monotherapy
GnRH antagonist
MAB
4. PBx/docetaxel/carboplatin
5. Abiraterone + pred/dexa
6. Samarium
7. Enzalutamide/radium-223
8. Abiraterone
9. Stop abiraterone, BSC

30. Lessons to be learnt
For every patient there is a personalised treatment
Personalised strategies should be used also for diagnosis and patient support
In case of abnormal reaction to treatment and repeated biopsies, personalised strategies can be useful for deciding appropriate treatment changes
Imaging techniques should be used in a personalised fashion
Patients should be treated:
By a multidisciplinary team: urologist, medical and radiation oncologist, palliative team, pathologist, radiologist and nuclear medicine specialist
With a holistic approach: see the person behind the patient, see the individual needs and wishes