While there are differences in each protocol, each trial aims to address different aspects of CRP in de novo HSPC. Therefore, the specific goals of each study and the limitations have to be taken into consideration when interpreting the results of these trials.

2. OBJECTIVE
• To review the ongoing randomised trials of
cytoreductive prostatectomy (CRP) in de novo
hormone-sensitive metastatic prostate cancer
(HSPC) in order to identify their goals and assess
their strengths and weaknesses.

3. METHODS
•PubMed, MEDLINE and clinical trials
websites searches were performed
to identify currently ongoing trials of
CRP in de novo HSPC.

4. Introduction
• Prostate cancer metastases are detectable at first presentation in ~15% of men in unscreened
Western
populations .
• Traditionally, systemic therapy with androgen-deprivation therapy (ADT) chemotherapy or second-
line hormone therapy was used, but the reported outcomes in men who present with metastatic
prostate cancer have not improved significantly over the last two decades .
• As such, attention has been focussed on multi-modal therapy, where treatment of the primary
tumour is combined with novel systemic therapy to improve the outcomes compared to systemic
therapy alone.

5. • The combination of radiotherapy (RT) and ADT treats the
primary tumour along with micrometastatic disease, reducing
the overall tumour burden.
• Although RT combined with ADT did not demonstrate any
survival benefit in men with prostate
• cancer with primary bone metastases in the HORRAD study ,
more recently, the subgroup analysis of the
• STAMPEDE Arm-H demonstrated a survival benefit from
treatment of the primary tumour in low-volume metastatic
prostate cancer with the addition of prostate RT .

6. Although RT avoids the
morbidity associated with surgery, the main
benefits of CRP compared to RT are …
1. The removal of the primary tumour source,
2. Reduction in the local tumour complications
3. Possibly the delayed need for ADT, reducing its associated
side-effects.

7. The Trials
•There are currently nine trials
investigating the effectiveness of CRP in
HSPC

8. (1)
Best Systemic Therapy or Best Systemic Therapy (BST)
Plus Definitive Treatment (Radiation or Surgery) trial
• Type of study : Phase 2 RCT
• Comparison : BST vs BST + CRP or RT to primary tumor
• Estimated date of completion : February 2020

9. (2)
Southwest Oncology Group (SWOG) 1802
trial
• Type of study : Phase 3 RCT
• Comparison : SST vs SST + definitive treatment (Sx or RT ) of primary
tumor in metastatic prostate cancer
• Estimated date of completion : October 2031

10. (3)
Surgery in Metastatic Carcinoma of Prostate
(SIMCAP) trial
• Type of study : Phase 2.5 RCT
• Comparison : BST vs BST + CRP
• Estimated date of completion : September 2022
• For the initial phase 2 portion of this study, the primary endpoint is failure-
free survival (FFS). If FFS shows a ≥30% improvement in the CRP + BST
arm at 2 years after randomisation, the study will be triggered to a phase 3
study and the OS will become the new primary endpoint.

11. (4)
Adjuvant Treatments to the Local Tumour for Metastatic Prostate
Cancer: Assessment of Novel Treatment Algorithms (IP2-ATLANTA)
trial
• Type of study : Three arm unblided RCT
• Comparison : SST vs MIAT vs Local RT
• Completed : August 2018

12. (5)
Testing Radical prostatectomy in men with prostate cancer
and oligoMetastases to the bone (TRoMbone) trial
• Type of study : Three arm unblided RCT
• Comparison : SST vs SST + CRP + ePLND
• Completed : August 2018

13. (6)
Impact of Radical Prostatectomy as Primary
Treatment in Patients with Prostate Cancer with
Limited Bone Metastases (g-RAMPP) trial
• Type of study : RCT
• Comparison : CRP + BST vs BST
• Closed early due to STAMPEDE results

14. (7)
Cytoreductive Prostatectomy vs Cytoreductive Prostate Irradiation
as a Local Treatment Option for Metastatic Prostate Cancer: a
Multicentric Feasibility Trial (LoMP II)
• Type of study : Phase 2 RCT
• Comparison : CRP + cytoreductive prostate RT
• Estimated date of completion : August 2022

15. (8)
Androgen Deprivation Therapy or Androgen Deprivation Therapy Plus
Definitive Treatment (Radiation or Surgery) (FUSCCOMPCa) study
• Type of study : Phase 2 RCT
• Comparison : ADT vs ADT + Sx or RT
• Completed : March 2020

16. (9)
Testing Radical Prostatectomy in Chinese Men With
Prostate Cancer and oligoMetastases to the Bone trial
• Type of study : RCT
• Comparison : CRP + SOC vs SOC
• Estimated date of completion : March 2021

17. The Definition of Metastatic Disease
• On the basis of volume of metastasis , metastatic disease has been
defined as ‘Oligometastatic disease’ and ‘Polymetastatic disease’.
• Oligometastatic disease : solitary or few (usually< 5) metastatic
lesions
• Polymetastatic lesions : > 5 metastatic lesions
• As better survival rates are demonstrated with ‘oligometastatic’ compared
with ‘polymetastatic’ disease , it is important to accurately differentiate
between these conditions in metastatic prostate cancer.

18. • Most of the CRP trials do not define the volume of metastases.
• SWOG 1802, IP2-ATLANTA and LoMP II trials include any T staging with
any volume of nodal, skeletal or visceral distant metastases, while the
SIMCAP trial defines the population as clinical T1–3M1a–b .
• TRoMbone is currently one of four studies investigating the role of CRP in
oligometastatic prostate cancer only. They defined the oligometastatic
disease as one to three skeletal metastases and do not include men with
visceral metastases. Any burden of lymph nodal disease is included.
• TRoMbone is currently one of four studies investigating the role of CRP in
oligometastatic prostate cancer only. They defined the oligometastatic
disease as one to three skeletal metastases and do not include men with
visceral metastases. Any burden of lymph nodal disease is included.

19. • In contrast, in the other oligometastatic studies, the g-RAMPP
included men with up to five skeletal metastases, while up to
three skeletal metastases are allowed in the Testing Radical
Prostatectomy in Chinese Men with Prostate Cancer and
oligoMetastases to the Bone trial,
• The FUSCC-OMPCa study includes up to five nodal or skeletal
metastases.

20. Identification of metastasis
• Conventional imaging modalities of CT and bone scan are gradually being
supplemented and possibly superseded by newer imaging modalities such
as MRI, choline positron emission tomography (PET) CT, prostate-specific
membrane antigen (PSMA) PET/CT, and Axumin PET/CT.
• The accurate determination of the metastatic volume currently is
challenging. PET scans have higher detection rates of metastases, with
PSMA-PET scans having a sensitivity of 80%, but with false-positive rates
of up to 14%. Therefore, in order to overcome the false positives, the
SWOG 1802 and SIMCAP studies have opted to biopsy these lesions.
• PET scans are currently not the SOC, not readily available worldwide, and
different countries use different tracers with different protocols. Therefore,
these studies will also need to take the imaging modality into account to
accurately determine the metastatic volume or have a predetermined
subgroup, such as in the IP2-ATLANTA trial, to avoid a heterogeneous
definition of metastases.

21. The SOC Definition and the Timing of Integration of
CRP to Systemic Therapy
• Until recently the SOC for metastatic prostate cancer has been ADT.
• The use of combined chemotherapy with docetaxel and newer androgen-
directed therapies, such as abiraterone and enzalutamide, are increasingly
becoming accepted as the SOC.
• All of these current trials investigate the effects of CRP against the
‘standard of care’, acknowledging that the BST or SST is likely to change
over time.
• The SWOG 1802 trial defines the ‘standard of care’ as per the current
National Comprehensive Cancer Network (NCCN) guidelines for
metastatic prostate cancer. This involves ADT, ADT with concomitant
abiraterone, or ADT plus docetaxel therapy for six cycles.

22. • Similarly, the SIMCAP trial allows both docetaxel and
abiraterone as part of the BST regimen.
• The TRoMbone and g-RAMPP trials allowed for all treatments
including chemotherapy as determined appropriate by the
treating urologists/oncologists.
• the IP2-ATLANTA only has BST as its SOC and does not
differentiate SOC options based on metastatic burden. In
contrast, the oligometastatic trial FUSCCOMPCa investigates
ADT as the systemic treatment, while the other study from
Fudan University, Testing Radical Prostatectomy in Chinese
Men With Prostate Cancer and oligoMetastases to the Bone
uses ADT or other systemic therapy with CRP.

23. Interpreting the Outcomes of Different Studies
• The primary endpoints of these studies also differ.
• The primary aim in the SWOG 1802 trial is to assess any OS benefit from
treatment of the primary tumour over a follow-up period of 8 years.
• the SIMCAP and IP2-ATLANTA trials assess the direct outcomes of CRP
against SOC measures.
• The pilot phase of the IP2-ATLANTA trial aims to assess the feasibility of
randomisation between the SST vs SST + CRP + ePLND, the safety of
intervention, and the proportion of patients with complete pathological
response as defined by prostate biopsies at 6–9 months after SOC
systemic therapy.
• The LoMP II trial aims to assess the feasibility of randomisation between
CRP and RT in metastatic prostate cancer with a follow-up of 48 months,
thus directly comparing the outcomes of these modalities against each
other. Its secondary outcome measure is castration-resistant free survival.
Thus, this trial will allow direct comparison between CRP and RT in the
metastatic setting.

24. • The TRoMbone trial assesses the feasibility to randomize between
standard care vs standard care plus RP with ePLND measured at 3
months in the oligometastatic setting. The secondary endpoints measure
QOL and time to castration resistance at 6 weeks, 3 and 6.
• The g-RAMPP study assessed the CSS as the primary outcome, time to
castrate resistance, PFS, OS, and QOL as their secondary outcomes.
They aimed to follow-up patients for up to 5 years. However, the in light of
the STAMPEDE trial results, this trial has pre-maturely closed.
• The FUSCC-OMPCa trial assesses OS as the primary outcome, with time
to PSA progression and QOL as secondary outcomes in the
oligometastatic setting, with treatment of either CRP or RT with ADT.a

25. • The Testing Radical Prostatectomy in Chinese Men with
Prostate Cancer and oligoMetastases to the Bone trial
assesses the time to castration resistance as the primary
outcome, and QOL as the secondary outcome, after CRP with
SOC.
• These landmark studies aim to provide answers to some
important questions in the role of treating the primary with CRP
in metastatic prostate cancer. However, the aims of these
studies are very specific and the differences between individual
studies should be understood to avoid confusion.

26. Results
• Each study was different; assessing various primary outcome measures
including overall survival (OS), progression-free survival and feasibility to
randomise between standard therapy and CRP or between radiation
therapy and CRP in the metastatic setting.
• In the oligometastatic setting, the trials assess OS, feasibility to randomise
and time to castration resistance.
• Similarly, a number of secondary endpoints ranging fromcancer-specific
outcomes to quality-of-life outcomes are being investigated.
• The inclusion criteria in these trials also varied in terms of volume of
metastatic disease diagnosis of metastases, imaging modalities used as
well as outcomes and follow-up regimes.

27. Conclusion
In conclusion, the two pertinent questions that remain will be
answered by a combination of the aforementioned studies:
(i) does CRP also work as primary therapy for (oligo) metastatic prostate cancer? and
(ii) does treatment of the metastases themselves work in combination with best systemic
and primary- directed therapies for these men?

28. THANK YOU