CASTRATE RESISTANT PROSTATE CANCER NEW PERSPECTIVE IN CASTRATE RESISTANT PROSTATE CANCER Ferry Safriadi Department of Urology Hasan Sadikin General Hospital Medical School of Padjadjaran University 7th URO-ONCOLOGY UPDATE, 18-20 Feb 2016

CRPC DEFINITION a rising prostate specific antigen level and/or radiographic evidence of prostate cancer progression despite medical or surgical castration. Cookson MS, et al. J Urol 2013 Heidenreich A, et al. Eur Urol 2014

PCa in 4 Hospital University (2006-2013*) (Jakarta, Bandung, Yogyakarta, Surabaya) National RSHS (2006-2013) N 1052 334 Mean Age 67.28 (23-94) 67.3 (17-94) Mean PSA 519,46 784.36 ng/ml

Staging Stage National RSHS 1 48 (4.6%) 21 (6.3%) 2 296 (28.1%) 116 (34.7%) 3 30 (2.9%) 10 (3.0%) 4 647 (61.5%) 177 (53.0%) N A 31 (2.9%) CRPC 160 25 Half of the patients is already metastases, it’s consequency to primary treatment.

NCCN 2016 V. 1

EAU Guidelines of Prostate Cancer 2015

EAU Guidelines of Prostate Cancer 2015

EAU Guidelines of Prostate Cancer 2015

AUA Guidelines 2015

AUA Guidelines 2015

Panduan Penatalaksanaan CRPC di Indonesia Kata Sambutan Kata Pengantar Daftar Isi Bab I. Pendahuluan I.1. Definisi Castrate Resistant Prostate Cancer I.2. Epidemiologi Castrate Resistant Prostate Cancer I.3. Patogenesis Castrate Resistant Prostate Cancer Bab II. Langkah Diagnostik Bab III. Klasifikasi Bab IV. Penatalaksanaan IV.1. Androgen Deprivation Therapy (ADT) IV.2. Pilihan Terapi Sistemik IV.3. Petunjuk Penatalaksanaan CRPC di Indonesia IV.4 Kesehatan Tulang Pada CRPC IV.5. Penatalaksanaan Metastasis Tulang IV.6. Terapi Paliatif IV.7. Pendekatan Tim Multidisiplin Spesialistik IV.8. Edukasi Pasien Bab V. Pemantauan V.1. Pemantauan Perkembangan Penyakit V.2. Pemantauan Efek Samping Obat dan Penanganannya KEPUSTAKAAN LAMPIRAN

Panduan Penatalaksanaan CRPC di Indonesia Indeks Pasien Gejala Metastatik Kemoterapi Status Performa Penatalaksanaan 1 - Baik Rekomendasi: dilakukan observasi serta tetap diteruskan pemberian terapi ADT 2 -/minimal + Standard: (A) Abiraterone + prednisone, (B) docetaxel 3 Standard : Docetaxel. Rekomendasi: Abiraterone + prednisone 4 Buruk Pilihan: dengan Abiraterone + prednisone, atau Ketoconazole + steroid, atau terapi radionuklida 5 Standard: Abiraterone acetate + prednisone, atau Cabazitaxel 6 Pendapat ahli: terapi paliatif abiraterone + prednisone, atau ketoconazole + steroid, atau terapi radionuklida

New updates in clinical trial and review article of CRPC and Abiraterone

Cougar-AA-302 Chemo naïve indication for Abiraterone is still off-label Ryan CJ. COU- AA- 302. Lancet Oncol 2015

Overall Survival Chemo naïve indication for Abiraterone is still off-label Ryan CJ. COU- AA- 302. Lancet Oncol 2015

Subgroup Analysis of OS Chemo naïve indication for Abiraterone is still off-label Ryan CJ. COU- AA- 302. Lancet Oncol 2015

Ryan CJ. COU- AA- 302. Lancet Oncol 2015 Safety Ryan CJ. COU- AA- 302. Lancet Oncol 2015

Efficacy of ABI in Asia chemo-refractory CRPC patients

Efficacy of ABI in Asia chemo-refractory CRPC patients Patients aged ≥ 20 years with m-CRPC and documented PSA and or image progression after docetaxel Abiraterone Acetate 1000 mg once daily and prednisolone 5 mg twice daily orally. 1 cycle is 28 days 30 Patients were enrolled Median Age 69 years Gleason score at diagnosis 8-10 = 70% Baseline PSA on first dose = 325.8 Wu T, et al. Urological Science. 2015

Wu T, et al. Urological Science. 2015 Overall Survival Median OS was 19.2 months. The PSA responders had better overall survival compared with PSA non-responders Patients with a Gleason score ≥8 and visceral involvement had no significant difference in overall survival with ones in the other group Wu T, et al. Urological Science. 2015

PSA response in Asian population Twenty-three patients (82.1%) had serum PSA levels start to decline after one cycle of abiraterone treatment. Among 28 patients who received one or more cycles of treatment, 15 (53.6%) men achieved PSA response. Both a high Gleason score and visceral involvement did not have a negative impact on the time-to-PSA progression Wu T, et al. Urological Science. 2015

Fizazi K, et al. Annals of Oncol 2015 Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? Fizazi K, et al. Annals of Oncol 2015

Method AA 1000 mg and Predisolone 5mg 2x1 1048 patients from trial COU-AA-301, post docetaxel & 996 patients from COU-AA-302, chemo naïve AA 1000 mg and Predisolone 5mg 2x1 Efficacy end points : PFS and OS Placebo and Predisolone 5mg 2x1 Gleason Score was similar in baseline between two groups Fizazi K, et al. Annals of Oncol 2015

Result PFS Post docetaxel OS Post docetaxel Showed benefit for OS and PFS in AA+P group regardless of the Gleason Score

PFS Chemo naïve OS Chemo naïve Showed benefit for OS and PFS in AA+P group regardless of the Gleason Score

Fizazi K, et al. Annals of Oncol 2015 Result The PSA response rate (≥50% decline in PSA from baseline) for patients with mCRPC post-docetaxel and chemotherapy naïve was greater in patients treated with AA plus P versus P regardless of Gleason score : - post chemo (<8: 34% versus 9%; ≥8: 26% versus 2%) - chemo naive (<8: 64% versus 24%; ≥8: 59% versus 22%) Gleason score had prognostic value on OS in both post-docetaxel (HR = 1.17; 95% CI 1.01–1.37, P = 0.04) and chemotherapy-naïve (HR = 1.20; 1.03–1.39, P = 0.0221) mCRPC patients. Fizazi K, et al. Annals of Oncol 2015

Chi KN, et al. Annals of Oncol 2015 A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel BACKGROUND : Recognizing the need for a prognostic tool that reflects outcomes from currently available treatments, we explored factors associated with OS in the abiraterone-prednisone arm of the COU-AA-301 study. Chi KN, et al. Annals of Oncol 2015

Chi KN, et al. Annals of Oncol 2015 There are 15 significant clinical and lab factors were found to be associated with OS using a univariate Cox model Chi KN, et al. Annals of Oncol 2015

Chi KN, et al. Annals of Oncol 2015

Chi KN, et al. Annals of Oncol 2015 Risk Grouping Risk Group Median OS Good 21.3 months Intermediate 13.9 months Poor 6.1 months Chi KN, et al. Annals of Oncol 2015

Chi KN, et al. Annals of Oncol 2015 Discussion The model was validated in the 398 patients of study COU-AA-301 and 286 patients of 11 centers in Canada. The result of the validation suggests that the prognostic factors are generalizable. Analysis of the validation set confirmed the ability of the model to prognosticate for OS. Hemoglobin, LDH and ALP, could potentially aid in prognostic stratification of patients with mCRPC, but their value in guiding treatment decisions is not well established. This model could be useful in clinical practice to aid in the determination of patient prognosis so that follow-up and monitoring may be planned accordingly, and may aid in patient stratification in clinical trials. Chi KN, et al. Annals of Oncol 2015

PSA Flare with Abiraterone Treatment

Background : we notified an important phenomenon that a small proportion of responders to abiraterone initially experienced a rise in serum PSA (PSA flare). Patients and methods = 103 patients of CRPC Serum PSA level was monitored every 4 weeks and CT Scan every 3 months

Characteristic of the PSA flare group In the PSA Flare group, 5 of 9 (55.6%) gained a PSA level decline ≥ 50% from baseline Median age of the PSA flare group = 78 years old 33% had a Gleason Score 8-10 89% patients had osseous disease 33% had visceral metastases 33% had received docetaxel with at least 1 more line therapy 55% patients PSA flare peak occurred after first cycle with the latest occurred after 3 cycles (1 patient) PSA Flare lasted a median of 28 days (range 28-112 days)

Median follow-up was 16.8 months Estimated median PFS all groups = 6.6 months Estimated median OS all groups = 18.6 months As many as 41,7% patients had an immediate PSA response (declined at least 50%) without initial flare up of PSA level 8.7 % patients had an initial PSA Flare

PSA Flare Group Non Flare Group Progression Free Survival 10.5 months (2.4-NR) 6.4 months (4.9-7.5) No difference in the median OS between PSA flare and those without PSA flare (P = 0.7681) or those with an immediate PSA response (P = 0 .2314). No difference in the median PFS (P =0 .2529) between PSA flare group and immediate PSA response group PFS = 10.5 vs 10.7 mo

Discussion PSA flare is a phenomenon related to tumor response. It is important to recognize this phenomenon to avoid early discontinuation of abiraterone treatment because of PSA flare. It remains unclear why only a small proportion of these patients experience the PSA flare phenomenon. The median PFS of the patients with PSA flare was similar to that of patients achieving an immediate PSA response but was higher than that in those who did not have a PSA flare. Patients are commonly aware of their PSA results and their prognostic/predictive value, they should be informed of this possible PSA flare phenomenon.

The panel included 41 prostate cancer experts from 17 countries, covering different specialties involved in research and treatment of men with APC Gillessen S, et al. Annals of Oncol 2015

Multidiscplinary specialists as panelist Gillessen S, et al. Annals of Oncol 2015

Highlight of #7 recommendation about monitoring and discontinuation of a treatment Gillessen S, et al. Annals of Oncol 2015

Gillessen S, et al. Annals of Oncol 2015

SUMMARY In CRPC there are a lot of updated clinical trials and review article with updates below : Combination of ABI and prednisolone can improve the overall survival in Taiwanese mCRPC patients who fail prior docetaxel chemotherapy. (Asian population) Abiraterone acetate conferred benefit to patients regardless of Gleason score (<8 versus ≥8) at initial diagnosis in CRPC Patients There are 6 strongest predictive factors model for assessing overall survival in CRPC patients = LDH, ECOG status, Liver metastases, ALP value, Hb value and Albumin value.

SUMMARY PSA Flare phenomenon in ABI treatment is possible in a small number of patients (8.7%) but did not significantly impact the median PFS compared with non PSA flare patients (10.5 months vs 6.4 months) A treatment should not be generalized to stop only from PSA progression alone. St. Gallen’s multidisciplinary consensus (82% of the panelist) agreed that at least two of 3 criteria's fulfilled to stop treatment (PSA progression, radiographic progression, and clinical deterioration).