Metastasis-directed Therapy for Oligorecurrent Prostate Cancer (SPARKLE)

Universitaire Ziekenhuizen KU Leuven

Status and phase: Enrolling; Phase 3

Conditions: Metastatic Cancer; Oligometastatic Disease; Prostate Cancer Recurrent; Hormone Sensitive Prostate Cancer; Prostate Cancer Metastatic; Prostate Cancer; Oligometastasis

Treatments: Drug: Androgen receptor targeted therapy; Other: Radiotherapy (SBRT) and/or surgery (metastasectomy); Drug: Androgen deprivation therapy

Study type: Interventional

Funder types: Other

Identifiers

NCT05352178

2022-000066-18 (EudraCT Number)

S65935

Details and patient eligibility

About

The aim is to investigate whether the addition of short-term androgen deprivation therapy (ADT) during 1 month or short-term ADT during 6 months together with an androgen receptor targeted therapy (ARTA) to metastasis-directed therapy (MDT) significantly prolongs poly-metastatic free survival (PMFS) and/or metastatic castration-refractory prostate cancer free survival (mCRPC-FS) in patients with oligorecurrent hormone sensitive prostate cancer.

Full description

Metastasis-directed therapy (MDT) has broadened the therapeutic window in patients presenting with oligorecurrent prostate cancer as it postpones the initiation of palliative androgen deprivation therapy (pADT) and its substantial side-effects for several years. Also from a biological point of view, this might be beneficial as the (early) use of ADT promotes the development of the lethal castrate-resistant state, whereby metastatic progression is driven by androgen-independent pathways. Metastasis-directed therapy with stereotactic body radiotherapy (SBRT) or surgery has shown to be able to eradicate metastases with a significant advantage concerning the pADT-free survival compared to active surveillance. And the combination of SBRT with palliative systemic treatment significantly improved overall survival (OS) when compared tot systemic treatment alone.

One of the largest retrospective analyses (191 patients) on MDT for oligorecurrent prostate cancer has been conducted previously at UZ Leuven (doi: 10.3390/cancers12082271). Estimated median pADT-free survival was 66 months and estimated median mCRPC-free survival was not reached, but 83% of patients were still free of mCRPC at 10 years.

The addition of ADT to primary radiotherapy for intermediate of high risk prostate cancer or to salvage radiotherapy has shown to improve overall survival. Within the context of SBRT for oligorecurrent disease it is not yet known whether the addition of a certain period of ADT prolongs CRPC-free survival and if so, what should be the optimal duration of this ADT administration. Moreover, the addition of an androgen receptor targeted agent (ARTA) to ADT in men with metastatic hormone sensitive prostate cancer and a treated primary tumor resulted in significantly improved clinical outcomes, also in low-volume metastatic disease.

In this clinical trial the aim is to investigate whether the addition of short-term ADT during 1 month or short-term ADT during 6 months together with an ARTA to MDT significantly prolongs poly-metastatic free survival (PMFS) and/or metastatic castration-refractory prostate cancer free survival (mCRPC-FS) in patients with oligorecurrent hormone sensitive prostate cancer.

Enrollment: 873 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histologically proven initial diagnosis of prostate adenocarcinoma
• Priory treated and controlled primary tumor
• Biochemical recurrence defined by prostate-specific antigen (PSA) values >0,2 ng/ml (i.e., two consecutive increases) following radical prostatectomy + postoperative radiotherapy and a PSA value of 2 ng/ml above the nadir after high-dose RT.
• Oligorecurrent disease defined as a maximum of 5 extracranial metastases in any organ, diagnosed on PSMA PET-CT or PSMA PET-MRI reported according to the E-PSMA consensus guidelines for interpretation of PSMA-PET (26). Nodal (N1) disease can be included only when accompanied by M1a-c disease, provided that the total number of spots does not exceed 5.
• Serum testosterone level within normal range.
• WHO performance 0-2
• Age >= 18 years old
• Absence of psychological, sociological or geographical condition potentially hampering compliance with study protocol.
• Patients must be presented at the multidisciplinary board meeting and the inclusion in the trial needs approval by this board.
• Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures
• 2. Use of highly effective methods of birth control; defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated with the Trial treatment(s)) or commitment to a vasectomised partner.

Exclusion criteria

• Any disorder, which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol
• Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the Trial
• Participation in an interventional Trial with an investigational medicinal product (IMP) or device
• Serum testosterone level at castration level.
• PSA rise while on active treatment (LHRH-agonist, LHRH antagonist, anti-androgen, maximal androgen blockade, oestrogen)
• Presence of poly-metastatic disease, defined as more than 5 metastatic lesions.
• Active malignancy other than prostate cancer that could potentially interfere with the interpretation of this trial.
• Previous treatments (RT, surgery) or comorbidities rendering new treatment with SBRT impossible.
• Contra indications for intake of enzalutamide (seizure or any condition that may predispose to seizure; significant cardiovascular disease within the last three months including myocardial infarction, unstable angina, congestive heart failure, ongoing arrythmias of grade > 2 or a thromboembolic event).
• Not able to understand the treatment protocol or sign informed consent.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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873 participants in 3 patient groups

MDT alone

Active Comparator group

Description:

Metastasis-directed therapy alone

Treatment:

Other: Radiotherapy (SBRT) and/or surgery (metastasectomy)

MDT + 1 month of ADT

Experimental group

Description:

Metastasis-directed therapy plus one month of androgen deprivation therapy (gosereline 3.6 mg sc, leuproreline 7.5 mg sc, triptoreline 3.75 mg im)

Treatment:

Drug: Androgen deprivation therapy

Other: Radiotherapy (SBRT) and/or surgery (metastasectomy)

MDT + 6 months of ADT + anzalutamide

Experimental group

Description:

Metastasis-directed therapy plus 6 months of androgen deprivation therapy (gosereline 3.6 mg sc 1x/month or gosereline 10.8 mg sc or leuproreline 7.5 mg sc 1x/month or leuproreline 45 mg sc or triptoreline 3.75 mg im 1x/month or triptoreline 11.5 mg im 1x/3months or triptoreline 22.5 mg im) and enzalutamide (4 x 40 mg each day during 6 months )

Treatment:

Drug: Androgen deprivation therapy

Other: Radiotherapy (SBRT) and/or surgery (metastasectomy)

Drug: Androgen receptor targeted therapy