N.N. Alexandrov National Cancer Centre Chemotherapy in the Treatment of Locally Advanced Prostate Cancer (own experience). Sergey Polyakov, MD, PhD N.N. Alexandrov National Cancer Centre Minsk, Belarus

The Role of Chemotherapy in PCa DOCETAXEL×10-12 +1.9-2.4 months Localized PCa Locally-Advanced PCa mHormone-Naïve PCa mCRPC Historically the first evidence of CHEMO efficacy came from 2 trials 10-12 cycles of docetaxel provided survival benefit from 1.9 to 2.4 months compared to MITO TAX 327 (Tannock et al, 2004) SWOG 99-16 (Petrylak et al, 2004)

The Role of Chemotherapy in PCa DOCETAXEL×6 +10-13.6 months Localized PCa Locally-Advanced PCa mHormone-Naïve PCa mCRPC The next step was successful use of CHEMO in hormone naïve mPC Earlier use was more beneficial comparing to mCRPC – only 6 cycles gave survival increase by 10 to 13 months CAARTED (Sweeney et al, 2015) STAMPEDE (James et al, 2016)

The Role of Chemotherapy in PCa DOCETAXEL? Localized PCa Locally-Advanced PCa mHormone-Naïve PCa mCRPC The question that has remained unsolved today is – could CHEMO be given even more earlier in nonmetastatic hormone naïve patients as adjuvant chemotherapy As is used to be in breast or colorectal cancer The theoretical benefit of earlier us Possible synergism with primary hormones as it shown on mice model Decreased resistance of PC cells earlier in the course of tumour development And if the stem cell theory true this mean than earlier use of multimodal therapy may increase cure rate in high risk localised disease Theoretical Benefit: Possible synergism with primary hormones (Eigl et al. 2005) Decreased resistance earlier in the course of PCa (Marín-Aguilera, 2014) In line with stem cell theory

Questions Safety Efficacy The questions that we have to answer are 2

Questions Safety Efficacy Combination with RTx Drug Mitoxantrone AML Estramustine  Thromboembolism Safety is important as most patients will survive up to 7 to 10 years long term morbidity for them unacceptable Most issues in comb with radiotherapy as toxicities probably potentiate Some drugs may be particularly dangerous: For example SWOG 9921 trial assessing adjuvant mitoxantrone CHEMO after prostatectomy was closed prematurely after three cases of acute myelogenous leukemia (AML) were reported of a total of 487 patients in the mitoxantrone treatment arm. Estramustin (EMCYTE) was shown to markedly increase thromboembolic complications

Vinblastin/doxorubucin/ ММС Questions Safety Efficacy Combination with RTx Author Year N Scheme No of cycles G3-4 toxicity Khil et al 1997 65 EMP/vinblastin 1/w × 16 5% Ryan et al 2004 23 10 – 22% Bagley et al 2002 25 Vinblastin/doxorubucin/ ММС 1/3w × 6 65-76% neutropenia Swanson et al 2006 30 5-FU infusion 1/d × 8 w 30% Kumar et al 22 docetaxel 5-25 mg/m2 1/w × 8 25 mg/m2 2/2 diarrhea Perrotti et al 2008 20 docetaxel 20 mg/m2 no Combination of CHEMO with concurrent radiotherapy and AA was assessed in a number of phase 2 trials The toxicity was prominent And in case of weekly docetaxel the optimal dose was 20 mg per meter squared

Questions Safety Efficacy TAX-3501 (Schweizer et al, 2015) GETUG 12 (Fizazi et al, 2015) RTOG 0521 (Sandler et al, ASCO 2015) STAMPEDE (James et al, 2016) As for efficacy What we have is results of 4 trials which are TAX-3501 GETUG 12 (french) RTOG 0521 STAMPEDE (UK)

Studies with short follow up, low death numbers All this trials were combined in meta-analysis which was recently published in the Lancet Oncology As a result highly statistically significant benefit was shown for PFS, which translated in an 8% reduction in absolute failure rates at 4 years HR for OS was 0.87 that translated to a potential absolute improvement of 2%; however, the confidence intervals were wide, and the result were not statistically significant However most trials had short follow up and low death numbers that made impossible to come to definite conclusions on OS Lancet Oncol, 2016

Trial Objective To assess safety and efficacy of addition of combination docetaxel- based chemotherapy (docetaxel + vinorelbine) to standard local ± adjuvant therapy in patients with locally-advanced PCa 2 trials depending on type of local therapy: Radiotherapy chemo-hormono-radiotherapy Surgery adjuvant chemotherapy At this point we would like to show results of our single center prospective RT Which was designed to assess safety and efficacy of addition of combination docetaxel-based chemotherapy (docetaxel + vinorelbine) to standard local therapy with or without adjuvant AD in patients with locally-advanced PCa 2 trials were designed depending on type of local therapy: The first assessed chemo-hormono-radiotherapy versus hormono-radiotherapy And the second adjuvant chemotherapy after surgery

Radiotherapy Population: Study Design PCa cT3-4 or N1 and M0 RPE not indicated Androgen deprivation + laparoscopic PLND ± TUR RANDOMIZATION Study arm 3D conformal EBRT + docetaxel AND vinorelbine × 4 - 1/2w Control arm 3D conformal EBRT on prostate and lymph nodes Primary: bNED Secondary: OS CSS PFS Toxicity In radiotherapy trial we included patients with locally advanced PCa without distant or bulky regional metastases in which RPe was not indicated All the patients underwent surgical or medical castration with laparoscopic PLND and were randomized into 2 arms In experimental arm 3D conformal EBRT was given with concurrent docetaxel AND vinorelbine combination chemotherapy In control arm standard 3D radiotherapy was administered Primary end point was biochemical recurrence free survival and secondary: OS, CSS, PFS and Toxicity

Therapy in the Study Group docetaxel 30/m2 + vinorelbine 15/m2 Lap PLND + castration 2-3 months Radiotherapy (3D CRT ): on prostate 78.6 Gy on lymph nodes 50.4 Gy 1.8 Gy per fraction 5 /w– 8.4 weeks The treatment protocol is shown on this slide Chemo was given every 2 weeks during course of radiotherapy The radiotherapy was 78.6 Gy on prostate and 50.4 Gy on lymph nodes with standard fractionating

Radiotherapy Population: Patients Characteristics Study arm, N (%) Control arm, N (%) Total, N (%) Patients no. 46 (100) 92 (100) Median age (min-max) 67 (51–76) 68 (50–84) cT сТ3a-b 29 (63) 36 (78) 65 (71) сТ4 17 (37) 10 (22) 27 (29) Median PSA (min-max) 30.0 (0.3-147) 25.2 (0.3-121) 27.1 (0.3–147) 0 - 9,9 ng/ml 5 (11) 6 (13) 11 (12) 10 - 19,9 mg/ml 14 (30) 11 (24) 25 (27) ≥ 20 ng/ml 26 (57) 28 (61) 54 (59) Gleason score 2-6 23 (50) 49 (53) 7 16 (35) 24 (26) 8-10 7 (15) 17 (18) pN1 20 (43) 37 (40) A total of 92 patients were included with 46 in each arm Median age 68 37-22% of T4 Median PSA 27 43-37% with lymph node metastases There were no significant differences between groups

Radiotherapy Population: Efficacy Results Median follow-up 7.5 years Study arm N (%) Control arm HR (95%CI)* p BCR progression 8 (17) 16 (35) 0.40 (0.17-0.95) 0.038 Clinical progression 7 (15) 10 (22) 0.64 (0.24-1.69) 0.37 Died 13 (28) 20 (43) 0.58 (0.29-1.18) 0.13 Died from PCa 5 (11) 0.43 (0.15-1.26) 0.12 * Stratification depending on regional lymph nodes status With median f-u of 7.5 years there were 16 vs 8 biochemical progressions 10 vs 7 clinical progressions More parents died in the control group including from PCa

Radiotherapy Population: Efficacy Results CCS CSS N0 CSS N1 There was benefit of chemo-radio-hormono-therapy in all end points, but statistically only and in CSS in patients with lymph node metastasis Biochemically no evidence of disease p=0.06 p=0.4 p=0.04

Prostatectomy Population: Study Design RADICAL PROSTA-TECTOMY pT3-4 or pN+ RANDOMIZATION CHEMO ARM DTX 70 mg/m2 + VRB 30 mg/m2  1 / 3 w × 4 Castration if N1 Salvage XRT if BCR CONTROL ARM Primary: bNED Secondary: OS CSS PFS Toxicity In surgery trial we included patients after radical prostatectomy with pathologically locally advanced or regionally metastatic disease The patients were randomized into 2 arms In control arm the patients underwent AA in case of lymph node metastases and were followed until biochemical recurrence In chemotherapy arm the same treatment was administered together with 4 cycles of adjuvant chemotherapy with docetaxel and vinorelbine Again primary end point was biochemical recurrence free survival and secondary: OS, CSS, PFS and Toxicity

Prostatectomy Population: Patient Characteristics Variable CONTROL arm, n (%) CHEMO arm, n (%) Total, n (%) No of patients 64 (100) 52 (100) 116 (100) Median age, years (range) 66 (51-76) 65 (44-78) 66 (44-78) Median PSA, ng / ml (range) 18 (2.1-130) 16 (1.7-85) 17 (1.7-130) PSA < 10 ng / ml 16 (25) 16 (3) 32 (27) 10 – 20 ng / ml 17 (27) 13 (25) 30 (26) > 20 ng / ml 31 (48) 23 (43) 54 (46) Gleason`s score ≤ 6 38 (59) 27 (51) 65 (56) 7 15 (23) 16 (30) 31 (26) ≥ 8 10 (16) 9 (17) 19 (16) pTN pT3aN0 23 (36) 39 (33) pT3bN0 20 (38) 43 (37) pT2-4N1 18 (28) 17 (32) 35 (30) A total of 116 patients were included with 64 in control and 52 in chemotherapy arm Median age 66 Median PSA 17 Roughly 1/3 was pT3a 1/3 was pT3b And 1/3 was N+ cases Again there were no significant differences between groups

Prostatectomy Population: Efficacy Results bNED PFS Median follow-up was 71 months There was significant benefit of chemotherapy in biochemical RFS with HR of 0.51 (p=0.046) And also not statistically significant benefit in PFS with HR of 0.59 Median follow-up 71 months HR 0.51 (95%CI 0.26-0.99) p=0.046 HR 0.59 (95%CI 0.22-1.58) p=0.30

Subgroup analysis of BCR risk Subgroup analysis of biochemical recurrence risk showed some improvement in efficacy in low grade cases and with higher PSA

Conclusions Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence There was also improvement in other end points: OS and CSS in radiotherapy trial PFS in surgery trial The study is underpowered to assess survival Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation Mature data from ongoing randomised studies is awaited In conclusion

Conclusions Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence There was also improvement in other end points: OS and CSS in radiotherapy trial PFS in surgery trial The study is underpowered to assess survival Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation Mature data from ongoing randomised studies is awaited

Conclusions Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence There was also improvement in other end points: OS and CSS in radiotherapy trial PFS in surgery trial The study is underpowered to assess survival Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation Mature data from ongoing randomised studies is awaited

Conclusions Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence There was also improvement in other end points: OS and CSS in radiotherapy trial PFS in surgery trial The study is underpowered to assess survival Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation Mature data from ongoing randomised studies is awaited

Conclusions Our results clearly indicate that the addition of docetaxel-based chemotherapy to standard treatment in locally advanced prostate cancer is associated with prolonged time to biochemical recurrence There was also improvement in other end points: OS and CSS in radiotherapy trial PFS in surgery trial The study is underpowered to assess survival Multimodal therapy with the addition of docetaxel-based chemotherapy represents new promising concept demanding careful evaluation Mature data from the ongoing randomised studies is awaited