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

Disclosures Amgen, Astellas, Ferring and Janssen

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

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…

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

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

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

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

May 2013 August 2014

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?

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

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

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)

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

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 (!)

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

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

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

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

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

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

PSA levels over the last 2.5 years 6. 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

ALP levels over the last 2.5 years 6. 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

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