Oral Communications. Prostata: Diagnosis and treatment of localized and locally advanced prostate cancer

Transcription

1 Prostata: Diagnosis and treatment of localized and locally advanced prostate cancer Oral Communications Elisa Zanardi UOC Clinica di Oncologia Medica Ospedale Policlinico San Martino Dipartimento di Medicina interna e Specialità mediche (DiMI) Genova Milano, 02/03/2018

2 Oral abstracts Ten years final results of the TR.OG (RADAR) randomised phase 3 trial evaluating duration of androgen suppression +/- zoledronic acid for locally advanced prostate cancer. David J. Joseph et al. Daily versus weekly prostate cancer image-guided radiotherapy: a phase 3 randomised trial. R. de Crevoisier et al. Transciptomic eterogeneity of androgen receptor activity in primary prostate cancer: identification and characterization of a low-ar active subclass. Daniel Spratt et al.

3 Oral abstracts Ten years final results of the TR.OG (RADAR) randomised phase 3 trial evaluating duration of androgen suppression +/- zoledronic acid for locally advanced prostate cancer. David J. Joseph et al. Daily versus weekly prostate cancer image-guided radiotherapy: a phase 3 randomised trial. R. de Crevoisier et al. Transciptomic eterogeneity of androgen receptor activity in primary prostate cancer: identification and characterization of a low-ar active subclass. Daniel Spratt et al.

4 Background Long term adjuvant AS is more effective than short term neo-adiuvant AS RTOG (USA) EORTC (Europe) Prolonged AS is related to several complications: sexual dysfunction, gynaecomastia, hot flushes, weight gain, sarcopenia, loss of bone mineral density, fractures, anaemia, prolonged fatigue, prolonged hypogonadism, cognitive dysfunction, depression, the metabolic syndrome, myocardial infarctions

5 Objective To develop a treatment that: Has side effects no worse than «short course» AS Is as effective as «long course» AS An intermediate duration of AS (18 months) looked like a good option In association with Zoledronic Acid: A drug that increase bone mineral density Kills cancer cells in bone Has a low side effect profile

6 Trial demographics Eligibility T2-T4, N0, M0; ECOG <2 (T2a provided PSA 10 and Gleason Score 7 ) Enrolment 1071 men Median age 68.7 years Median follow up 10.4 years Risk classification (MSK): high (66%); unfav. intermediate (31%); fav. Intermediate (2%) End Points Main endpoint Prostate cancer-specific mortality Secondary enpoints Oncologic endpoints (PSA progression, sites of tumor progression; castratin resistance; secondary therapeutic intervention; all cause mortality) Quality of life Adverse treatment effects

7 Results (1) PCSM: primary endpoint A 29% reduction in distant progression was the main driver of the 30% reduction of PCSM

8 Results (2): Secondary endpoints

9 Cause of death by AS duration Quality of life by AS duration

10 ZA vs no ZA: Oncological endpoints

11 Conclusions In men with locally advanced prostate cancer: 18 months of AS is more effective than 6 months of AS The addition of 18 months of zoledronic acid provides no benefits Nabid et al. ASCO 2017

12 Oral abstracts Ten years final results of the TR.OG (RADAR) randomised phase 3 trial evaluating duration of androgen suppression +/- zoledronic acid for locally advanced prostate cancer. David J. Joseph et al. Daily versus weekly prostate cancer image-guided radiotherapy: a phase 3 randomised trial. R. de Crevoisier et al. Transciptomic eterogeneity of androgen receptor activity in primary prostate cancer: identification and characterization of a low-ar active subclass. Daniel Spratt et al.

13 Background Objective To compare the safety and the efficacy of daily versus weekly IGRT

14 Characteristics of patients and treatment Inclusion criteria Intermediate and high risk localized prostate cancer Total dose = Gy (+ ADT for high risk) 3DCRT o IMRT (PTV margins 1cm / 5 mm post) Pelvic lymph node not irradiated IGRT modalities = by direct (CBCT) or indirect proste visualization (fiducials + 2DkV imaing)

15 Results DFS: primary endpoint Biochemical recurrence: secondary endpoint

16 Toxicity: Secondary endpoints Overall survival: Secondary endpoints

17 Second cancer incidence: post hoc analysis Conclusions In men with locally advanced prostate cancer: Compared to weekly control, by improving targeting, daily control in prostate cancer IGRT significantly decrease the risks of recurrence and rectal toxicity but is associated with an increased risk of second cancer. Longer follow-up is however clearly needed to assess the rate of radiation-associated malignancies

18 Oral abstracts Ten years final results of the TR.OG (RADAR) randomised phase 3 trial evaluating duration of androgen suppression +/- zoledronic acid for locally advanced prostate cancer. David J. Joseph et al. Daily versus weekly prostate cancer image-guided radiotherapy: a phase 3 randomised trial. R. de Crevoisier et al. Transciptomic eterogeneity of androgen receptor activity in primary prostate cancer: identification and characterization of a low-ar active subclass. Daniel Spratt et al.

19 Background AR amplifications/mutations are the most common actionable alteration in mcrpc In primary localized prostate the significance of AR-activity diversity is unknown AR and AR-Activity (AR-A) is heterogeneus in mcrpc: strong correlation between AR and AR-A Objective To understand the biological and clinical relevance of AR- activity heterogeneity in localized prostate cancer

20 Methods Identification of a distinct subclass of low AR-A adenocarcinomas

21 Results (1) Low AR-A tumors have increased immuno-stimulatory properties AR-A associated with distinct cancer hallmarks

22 Results (2) Low AR-A tumors have decreased DNA repair and increased predicted radiation sensitivity Low AR-A tumors have increased NEPC expression and are more basal-like Radiation sensitivity (PORTOS)

23 Results (3) High AR and Low AR-A tumors have highest metastatic potential Low AR-A tumors have increased rate of distant metastasis

24 Results (4) Clinically, tumors that develop CRPC have lower AR-A Low AR-A tumors have unique drug sensitivities

25 Conclusions 1. AR-A is heterogeneuous in localized prostate cancer 10-15% of localized prosate adenocarcnoma have low AR-A 2. Low AR-A tumors have decreased DNA repair expression, a proimmune phenotype, and increased markers of NEPC 3. Clinically, low AR-A tumors are more likely to develop metastases 4. Low AR-A tumors appear more sensitive to XRT, PARPi, and platinum chemotherapy and less sensitive to taxanes and ADT Biomarker enhanced trials in development

26 Oral abstracts Ten years final results of the TR.OG (RADAR) randomised phase 3 trial evaluating duration of androgen suppression +/- zoledronic acid for locally advanced prostate cancer. David J. Joseph et al. Daily versus weekly prostate cancer image-guided radiotherapy: a phase 3 randomised trial. R. de Crevoisier et al. Transciptomic eterogeneity of androgen receptor activity in primary prostate cancer: identification and characterization of a low-ar active subclass. Daniel Spratt et al.