prostata: diagnosis and treatment of localized and locally...

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

Oral abstracts

• Ten years final results of the TR.OG 03.04 (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.

Background

• Long term adjuvant AS is more effective

than short term neo-adiuvant AS

• 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

RTOG 92.02 (USA)

EORTC 22961 (Europe)

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

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

Results (1) PCSM: primary endpoint

A 29% reduction in distant progression was the main driver of the 30% reduction of PCSM

Results (2): Secondary endpoints

Cause of death by AS duration

Quality of life by AS duration

ZA vs no ZA: Oncological endpoints

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

Oral abstracts




Background

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

Characteristics of patients and treatment

Inclusion criteria • Intermediate and high risk localized prostate

cancer

• Total dose = 70-80 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)

Results

DFS: primary endpoint Biochemical recurrence: secondary endpoint

Toxicity: Secondary endpoints

Overall survival: Secondary endpoints

Conclusions Second cancer incidence: post hoc analysis

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

Oral abstracts




Background

AR amplifications/mutations are the most common actionable alteration in mCRPC

AR and AR-Activity (AR-A) is heterogeneus in mCRPC: strong

correlation between AR and AR-A

In primary localized prostate the significance of AR-activity diversity is unknown

Objective

To understand the biological and clinical relevance of AR- activity heterogeneity in localized prostate cancer

Methods

Identification of a distinct subclass of low AR-A adenocarcinomas

Results (1)

AR-A associated with distinct cancer hallmarks

Low AR-A tumors have increased immuno-stimulatory properties

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

Results (2)

Radiation sensitivity (PORTOS)

High AR and Low AR-A tumors have highest metastatic potential

Low AR-A tumors have increased rate

of distant metastasis

Results (3)

Clinically, tumors that develop CRPC have lower AR-A

Low AR-A tumors have unique drug sensitivities

Results (4)

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

Oral abstracts




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