Clinical trial NCT04641078: Stereotactic Body Radiotherapy With or Without Darolutamide for OligoRecurrent Prostate Cancer
Official title: Stereotactic Body Radiotherapy With or Without Darolutamide for OligoRecurrent Prostate Cancer: a Randomized Phase II Trial (DART)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Prostate Cancer
Prostate Cancer Recurrent
Prostate Cancer Metastatic
Metastatic Cancer
Oligometastasis
Keywords: Radiotherapy
Metastasis-directed therapy
Oligometastatic recurrent hormone sensitive prostate cancer
Lead sponsor: University Hospital, Ghent
Sponsor class: OTHER
First posted: 2020-11-23
Enrollment: 124
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The current trial will test the combination of darolutamide with SBRT, in oligometastatic recurrent hormone sensitive prostate cancer. We hypothesize that the addition of short-term darolutamide improves metastasis-free survival when added to SBRT without a detrimental impact on the QoL. Considering the large reluctance of both patients and physicians to be randomized to observation, we propose to use the historical data from previous reported randomized trials (STOMP and ORIOLE) as a comparator to explore as a secondary endpoint.

Detailed description: As of the 2018 EAU guidelines, PSMA PET-CT is now recommended for prostate cancer patients with a rising PSA following local therapy, resulting in an increase in patients with conventional imaging M0, but novel imaging M1-state. This creates a new class of patients for which no clear guidelines exist on the optimal management. It became clear that there is no real consensus nor data on how these patients should be treated.

In 1995, a new approach was proposed, hypothesizing that patients with a limited number of metastases (oligometastases) might benefit from eradication of metastases by means of local therapy, or metastasis-directed therapy. Stereotactic body radiotherapy (SBRT), a novel radiotherapy technique for metastatic and primary prostate cancer treatments, has emerged as a highly precise radiotherapy method able to eradicate small metastases with acceptable toxicity. Nevertheless, responses following SBRT were not always durable. To improve response rates and time to new metastases, additional steps should be taken balancing with potential added toxicity. One of the logical steps would be to combine SBRT with temporary androgen deprivation therapy (ADT) as this combination therapy is standard of care for primary PCa and locally recurrent PCa17. However, ADT, negatively impacts quality of life (QoL) even when used temporary. Anti-androgen or androgen receptor (AR) pathway inhibitors (ARpI) may circumvent these side effects by suppressing AR transcription by competitive inhibition of AR, without lowering systemic testosterone. The current trial will test the combination of darolutamide with SBRT, in oligometastatic recurrent hormone sensitive prostate cancer. We hypothesize that the addition of short-term darolutamide improves metastasis-free survival when added to SBRT without a detrimental impact on the QoL.

Eligibility criteria: Inclusion Criteria:

* Histologically proven initial diagnosis of adenocarcinoma of the prostate
* Biochemical relapse of PCa following radical local prostate treatment (radical prostatectomy (RP), primary radiotherapy or the combination of RP and prostate bed adjuvant/ salvage radiotherapy) according to the EAU guidelines 2018.
* Following RP, patients with a biochemical relapse are eligible in case a metastatic relapse is detected even in the absence of prior postoperative prostate bed radiotherapy (adjuvant or salvage). In the absence of prior prostate bed radiotherapy, prostate bed radiotherapy is mandatory for all pT3a or higher or patients with a positive margin at time of RP.
* For patients without prior RP that have a suspected local recurrence following primary radiotherapy, a biopsy should confirm local recurrence. Patients with a confirmed local recurrence and metastases are eligible in case they also undergo a local salvage therapy.
* Metastatic relapse on PSMA PET-CT with a maximum of 5 metastases (any M1a, M1b or M1c). Concomitant diagnosis of N1 disease is allowed as long as all lesions are treated with SBRT and the total number of lesions does not exceed 5. PSMA positive lesions will be scored using the MI-RADS scoring system with lesions scored 4 or 5 considered positive19.
* Asymptomatic for metastatic PCa
* Age \>= 18 years
* WHO class 0-1
* Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
* Before patient registration/randomization, written informed consent must be given in accordance with to ICH/GCP, and national/local regulations.

Exclusion Criteria:

* Local relapse in the prostate gland or prostate bed not suitable for a local salvage treatment
* Small cell carcinoma of the prostate
* PSA doubling time \>12 months
* Serum testosterone level \<50ng/dl or 1.7 nmol/L at time of randomization
* Currently receiving ADT or PSA rise while on active treatment with ADT (LHRH-agonist, LHRH-antagonist, anti-androgen or estrogen) within the past 6 weeks
* Spinal cord compression or impending spinal cord compression
* Metastases in previously irradiated areas precluding safe delivery of SBRT
* Contraindications to darolutamide
* Previous treatment with cytotoxic agent for PCa
* Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids,...)
* Other active malignancy, except non-melanoma skin cancer or other malignancies with a documented disease-free survival for a minimum of 3 years.

Primary outcomes:
measure: Metastasis-free survival
timeFrame: 2 year
Secondary outcomes:
measure: Clinical progression-free survival
timeFrame: 2 year
measure: Biochemical relapse-free survival
timeFrame: 2 year
measure: Time to next systemic therapy
timeFrame: 4 year
measure: Castrate resistant-free survival
timeFrame: 4 year
measure: Prostate cancer-specific survival
timeFrame: 4 year
measure: Overall survival
timeFrame: 4 year
measure: Toxicity: acute toxicity
timeFrame: 3 months
measure: Toxicity: late toxicity
timeFrame: 2 year
measure: Patient reported QOL as per EORTC-QLQ C30
timeFrame: 2 year
measure: Patient reported QOL as per EORTC-QLQ PR25
timeFrame: 2 year
Other outcomes:
Locations:
city: Aalst
country: Belgium
facility: OLVZ Aalst
city: Antwerp
country: Belgium
facility: GZA
city: Brugge
country: Belgium
facility: AZ St-Jan Brugge
city: Brussel
country: Belgium
facility: Institut Jules Bordet
city: Gent
country: Belgium
facility: AZ St-Lucas Gent
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Hasselt
country: Belgium
facility: Jessa Ziekenhuis
city: Kortrijk
country: Belgium
facility: AZ Groeninge
Study officials:
affiliation: University Hospital, Ghent
name: Piet Ost, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: