Randomized phase II trial in prostate cancer with hormone-sensitive OligometaSTatic relapse: Combining stereotactic ablative radiotherapy and durvalumab (POSTCARD GETUG P13): Study protocol

Highlights

• •POSTCARD is a randomized multicentric phase II trial.
• •Including patients with prostate cancer and hormone-sensitive oligometastatic relapse.
• •Treated with stereotactic body radiotherapy alone (SBRT) (Control group)
• •Or SBRT and Durvalumab (anti PD-L1) (Experimental group)
• •We expected longer life expectancy with acceptable toxicity in experimental group.

Abstract

Background

As in other solid tumors, increasing evidence indicates that patients diagnosed with a limited number of prostate cancer metastases, so-called oligometastases, have a better prognosis than patients with extensive metastatic disease. Stereotactic body radiotherapy (SBRT) is now considered an option in this population.

Programmed death-1 (PD-1) and its ligands (PD-L1) are targeted by immune checkpoint inhibitors. Preclinical studies have shown that the tumor immune microenvironment changes when combining radiotherapy with immunotherapy, especially with hypofractionated radiotherapy.

The oligometastatic setting appears to be the most relevant clinical situation for evaluating the immune response generated by radiotherapy and immune checkpoint inhibitors in patients with an intact immune system.

We hypothesize that durvalumab will enhance the immune response following SBRT targeting oligometastatic lesions. Our purpose is to demonstrate, via a randomized 2:1 phase II trial, that SBRT (3 fractions) with durvalumab in oligometastatic hormone-sensitive prostate cancer patients would improve progression-free survival in patients with prostate cancer with up to 5 metastases compared to patients who exclusively received SBRT.

Methods

This is a multicentric randomized phase II study in French academic hospitals. Patients with prostate cancer and up to 5 metastases (lymph node and/or bone) were randomized into a 2:1 ratio between Arm A (experimental group), corresponding to durvalumab and SBRT to the metastases, and Arm B (control group), corresponding to SBRT alone to the metastases. The study aims to accrue a total of 96 patients within 3 years. The primary endpoint is two-year progression-free survival and secondary endpoints include androgen deprivation therapy-free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response.

Discussion

The expected benefit for the patients in the experimental arm is longer life expectancy with acceptable toxicity. We also expect our study to provide data for better understanding the synergy between immunotherapy and radiotherapy in oligometastatic prostate cancer.

Introduction/rationale

As in other solid tumors, increasing evidence indicates that patients diagnosed with a limited number of prostate cancer metastases, so-called oligometastases, have a better prognosis than patients with extensive metastatic disease [1]. Survival of patients with three or fewer metastases was greater than that of patients with more than three lesions [2]. In a comparable study, patients with a single metastasis had 5-year cancer-specific survival of 90% compared with only 32% in patients with more than one metastasis [3]. These studies demonstrate that oligometastatic prostate cancer inherently has a less unfavorable disease course than prostate cancer with multiple metastases.

Stereotactic Body Radiotherapy (SBRT) consists in treating small tumor volumes using high-dose, highly-conformal hypofractionated radiotherapy. Several studies have investigated the use of SBRT alone or in combination with systemic treatment in oligo-recurrent prostate cancer patients. Already published data show benefits in terms of local and biochemical control with acceptable toxicity [4], [5], [6], [7]. Furthermore, SBRT may improve androgen deprivation therapy (ADT)-free survival [5], [8] and play a role in eliminating castrate-resistant clones, possibly also delaying progression to castrate-resistant disease [9]. For these reasons, SBRT is now considered an option in oligometastatic prostate cancer [10].

Programmed death-1 (PD-1) and its ligands (PD-L1 and PD-L2) are type I transmembrane glycoproteins of the CD28/CTLA-4 and B7 families, respectively [11]. Checkpoint inhibition (anti-PD-1/anti-PD-L1/anci-CTLA4) has demonstrated good efficacy in different immunologically “hot” tumors (eg. bladder and renal cell carcinomas) [12], [13]. However, immunologically “cold” tumors, with low somatic mutation frequency and few tumor-infiltrating T cells, such as metastatic castration-resistant prostate cancer (mCRPC), are considered relatively resistant to immune checkpoint therapy [14]. A recent phase II study (KEYNOTE-199) evaluating pembrolizumab in monotherapy on these patients revealed modest therapeutic activity (response rates of 5%) [15]. In the CheckMate 650 study, patients with mCRPC received a combination of ipilimumab (anti CTLA-4) plus anti-PD-1 therapies. The objective response rate was better, with ranges from 10% to 25%, but was associated with grade 3–4 adverse events, which occurred in about half of patients [16].

Preclinical studies have shown that the tumor immune microenvironment changes (ie. increased tumor-associated macrophages and dendritic cells, upregulation of PD-1/PD-L1 and CD8 + T-cells) when radiotherapy is combined with immunotherapy, especially hypofractionated radiotherapy [17], [18]. Furthermore, Philips et al. in a recent phase 2 prospective study (ORIOLE) identified a systemic immune response to stereotactic ablative radiotherapy (SABR) [4].

The oligometastatic setting appears to be the most relevant clinical situation for evaluating the immune response generated by radiotherapy and immune checkpoint inhibitors in patients with an intact immune system. We hypothesize that durvalumab will enhance the immune response following SBRT targeting oligometastatic lesions. We therefore propose a randomized 2:1 phase II trial of stereotactic body radiation therapy (3 fractions) with or without durvalumab in oligometastatic hormone-sensitive prostate cancer patients. Durvalumab will be started one month prior to SBRT to be able to evaluate PSA and immune response to the drug. It will be combined with SBRT and then given as an adjuvant for a total of 12 months.

Ancillary studies are associated:

• -Biological ancillary study which monitors immune response at 3 different time points during the treatment.
• -Biological ancillary study analyzing PD-L1 expression in circulating tumor cells.

Design

This is a multicentric randomized phase II study in French academic hospitals. Patients will be randomized in a 2:1 ratio between (Fig. 1):

• •Arm A (experimental group), corresponding to durvalumab and SBRT to the metastases
• •Arm B (control group), corresponding to SBRT alone to the metastases.

Fig. 1.

Study Design. SBRT: Stereotactic body radiotherapy; PET-CT: Positron Emission Tomography -Computed Tomography; MRI: Magnetic Resonance Imaging.

Two stratification factors at randomization are allowed: investigation center and number of metastases (1 vs 2–5).

The inclusion and exclusion criteria are detailed in Table 1.

Table 1.

Main inclusion and exclusion criteria for the POSTCARD GETUG P13 trial.

Inclusion criteria
1.Written informed consent obtained from the patient
2.Age > or = 18 years at time of study entry
3.Histologically proven diagnosis of prostate cancer (PCa)
4.PCa patients with a biochemical recurrence “Rising PSA” following treatment with curativeintent (radical prostatectomy, primary radiotherapy or a combination of both) as defined by the EAU guidelines
5.A maximum of 5 bone or lymph node metastases diagnosed on Ga-PSMA PET/CT, or a maximum of 3 bone or lymph node metastases diagnosed on FCH PET/CT ≤ 4 cm for bone metastases ≤ 2 cm for lymph node metastases
6.WHO performance state 0–1
7.Controlled primary tumor
8.If ADT has previously been administered to the patient, a minimum of 12 months must have elapsed between the predicted duration of the last injection and inclusion of the patient in the study.
9.Adequate normal organ and marrow function
10.Body weight > 30 kg
11.Life expectancy of > 24 months
12.Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
13.Social insurance
Exclusion criteria
1.Serum testosterone level less than 8.5 nmol/l
2.Vertebral metastases with a minimum distance of less than 5 mm between GTV and spinal cord
3.Lymph nodes>20 mm
4.Patient with PSA doubling time less than 3 months and with two metastases or more
5.Spinal cord compression
6.Any unresolved toxicity NCI CTCAE (5.0) Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
7.PSA rise while on active treatment (LHRH-agonist, LHRH-antagonist, anti-androgen, maximal androgen blockade, estrogen)
8.Lung, brain, liver or other visceral metastases
9.History of leptomeningeal carcinomatosis
10.Relapsed primary tumor
11.Perihilar lymph node metastases
12.Previous irradiation of the oligometastatic site using a dose > 20 Gy less than 5 years ago.
13.Previous treatment with a cytotoxic agent for PCa
14.Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids…)
15.Any prior immune therapy (CTLA-4, PD1 or PD-L1 inhibitor, including durvalumab)
16.Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab
17.Active or prior documented autoimmune or inflammatory disorders
18.History of active primary immunodeficiency
19.Active infection including tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus

Detailed description of the techniques to be used / treatments to be received

Durvalumab, AstraZeneca/MedImmune (MEDI4736)

Patients will receive 1500 mg of durvalumab (MEDI4736) via IV infusion every four weeks for up to a maximum of 12 months (up to 13 doses/cycle) with the last administration on week 48, or until confirmed disease progression, or unless there is unacceptable toxicity, or withdrawal of consent. In the event of an infusion reaction and/or immune-mediated adverse events, modification and toxicity management guidelines are available (supplementary).

SBRt

General recommendations

SBRT will be performed on Days 1, 3, and 5 (D1, D3, D5). For patients randomized in arm A (SBRT + durvalumab), SBRT will be delivered concurrently with the 2nd cycle of durvalumab (at week 4) and will begin on C2D1 after infusion of durvalumab.

Target volumes

Margins from gross tumor volume (GTV) or internal target volume (ITV) to planning target volume (PTV) are of 2–10 mm to account for set-up error and organ motion. For vertebral metastases: GTV, CTV and PTV will be defined according to the international consensus of radiosurgery [20].

Any organ that is traversed by all or part of a beam should be contoured so that the dose it receives can be assessed. Organs should be outlined by the treating radiotherapist. Organs at risk of dose constraints are adapted to the standard recommendations [21].

Dose prescription

Hypofractionated SBRT will be delivered with a biologic equivalent dose (BED) > 80 Gy.

There will be two levels of prescribed dose:

• -Non-vertebral metastases: the recommended dose and fractionation is 33 Gy in 3 fractions of 11 Gy.
• -Vertebral metastases: the dose will be reduced to 27 Gy in 3 fractions of 9 Gy.

The dose and fractionation shall however be adapted to normal tissue tolerance constraints: 30 Gy in 5 fractions of 6 Gy is tolerated for both non-vertebral and vertebral metastases.

The total dose (33 Gy or 27 Gy or 30 Gy) is prescribed for the isodose surface that covers an optimal percentage volume of the PTV. At least 90% of the PTV should receive the prescribed dose (33 Gy or 27 Gy or 30 Gy). Coverage of less than 90% of the PTV will be considered as Acceptable Deviation, and coverage of less than 80% of the target volume as Unacceptable Deviation. Adaptation should be made to remain within OAR tolerance. The maximum dose should be less than 140% of the prescribed dose and be located within the GTV.

Image guidance

The treatment set-up should use modern image guidance, most commonly with kilovoltage cone beam modern imaging guidance, such as on-board computed tomography or an ExacTrac® patient positioning platform.

Concomitant treatment

Concomitant treatment that are permitted or prohibited during the trial are available in supplementary.

Endpoints

The main objective is to assess the impact of durvalumab in addition to SBRT on progression-free survival (PFS) in patients with prostate cancer with 1 to 5 metastases compared to patients who exclusively received SBRT.

Primary endpoint

Primary endpoint is two-year progression-free survival. Three types of progression are defined, and definitions of progression are used and registered according to the recommendations of the prostate cancer clinical trials working group. Any patient who meets any of the progression criteria or death from any causes will be considered to have progressive disease. Calculation will start from randomization until progression or death.

• 1.PSA or biochemical progression: in case of decline from baseline: record time from randomization to first PSA increase (after at least 3 months) that is either: increase ≥ 25% and ≥ 2 ng/ml above the nadir; increase ≥ 25% and rises above the pre-treatment PSA value, and is confirmed by a second value 3 or more weeks later. In case of no decline from baseline: record time from randomization to first PSA increase that is ≥ 25% from baseline (after 3 months).
• 2.Local progression: each metastasis is a target lesion assessed independently for response using the RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 and iRECIST criteria [19]. In addition, metastases with a metabolic complete response on bone scintigraphy or ¹⁸F-choline (FCH) or ⁶⁸Ga-PSMA positron emission tomography/computed tomography (PET/CT) are scored as complete response in the absence of progression on CT scan.
• 3.Distant progression: appearance of new metastatic lesions.

Secondary endpoints

The secondary endpoints are as follows:

• 1.Quality of life scoring using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaires (QLQ): QLQ-C30 supplemented with QLQ-PR25 and evaluation of pain with the Brief Pain Inventory (BPI) and Visual Analogic Scale (VAS).
• 2.Androgen deprivation therapy-free survival: ADT will be started in both arms at time of polymetastatic disease, local progression of metastases (as defined above) or symptoms. In case of a metachronous oligometastatic recurrence, a retreatment with radiotherapy or surgery is allowed. Calculation will start from randomization until ADT is started.
• 3.Prostate cancer specific survival will be calculated from randomization until death from prostate cancer.
• 4.Overall survival (OS) will be calculated from randomization until death from any cause.
• 5.Time to first symptomatic event will be calculated from randomization until the event of symptoms due to metastatic disease.
• 6.Time to castration resistance.
• 7.Acute and late toxicity due to radiotherapy will be scored using the common toxicity criteria version 5.0.
• 8.Immune response monitoring.

Evaluation and randomization

Prior to randomization, a complete history, physical examination, clinical laboratory tests and quality of life questionnaires (EORTC QLQ-C30 and EORTC QLQ-PR25) are required. Histologically, confirmation of malignancy is required with metastatic disease detected on imaging by FCH or Ga-PSMA TEP/CT. MRI is mandatory for patients with bone metastases. Imaging must be carried out a maximum of 2 months before treatment.

Once the patient's baseline assessment has been validated and the informed consent signed, patients will be randomized into the two treatment arms using a 2:1 ratio (SBRT + durvalumab: SBRT). Stratification will be made in relation to the investigation center and number of metastases (1 vs 2–5). Block randomization will be used to avoid any significant imbalance between the arms (more details available in supplementary). Treatment is to begin as early as possible after randomization, and at the latest 2 months after the date of randomization.

Follow-up

Each patient will be followed at least once every 4 months after the end of treatment (until 2 years after randomization) if no relapse event occurs, then twice a year (Table 2).

Table 2.

Follow-up.

	Screening (Max 2 months prior to treatment)	Radiotherapy Period			Treatment ARM A (durvalumab)	Follow-up
		D1	D3	D5	C1 to C13	At least 28 days after last treatment administration	Every 4 months after end of treatment (2 years after randomization or progression disease)	Every 6 months until end of study
Physical examination	X	X			X	X	X
Histological confirmation	X
QLQ-C30 and QLQ-PR25	X				X (a)	X	X (a)
Toxicity assessment		X			X	X	X	X
PSA	X					X	X (a)
Laboratory evaluation (3 days before treatment)	X				X (a)	X
Blood samples for ancillaries’ studies		X	X	X
MRI (a)	X	If suspicion relapse (b)
FCH or Ga-PSMA PET	X

(a) Every 2 months.

(b) Magnetic resonance imaging for patients with vertebral or pelvic bone metastases. Patients may continue to receive durvalumab beyond confirmed PD (confirmed PD = second imaging at least 4 weeks after the first one, iRECIST criteria) in the absence of clinically significant deterioration and if investigators consider that patients continue to receive benefit from treatment.

Clinical laboratory tests for PSA will be performed and quality of life questionnaires completed every 2 months.

In case of suspected relapse, imaging by MRI (for patients with bone involvement) and PET scan (FCH or Ga-PSMA) will be performed every 4 months until clinical progression is detected.

Two years after randomization, or after progression, patients will be followed at least once every year.

Biological ancillary studies

Immune response monitoring

For patients from the Institut de Cancérologie de l’Ouest randomized in the experimental arm, three blood samples will be analyzed (C1, C2 and C3) to determine the absolute values of the lymphocytic, monocytic, T-cell, regulatory T cell and myeloid suppressor cell subpopulations.

Analysis of PD-L1 expression in prostate circulating tumor cells (CTCs)

In blood samples from 64 patients enrolled in the experimental arm and at 3 times (before the first infusion of durvalumab, after one month of durvalumab, before SBRT and at 2 months after initiation of durvalumab), the aims are to isolate prostate CTCs, analyze PD-L1 expression in isolated CTCs, and analyze the correlation between PD-L1 expression and patient clinical status.

Statistical analysis

Sample size calculation

This is a randomized phase II trial. Two-year progression-free survival will be estimated. In Arm A (SBRT + durvalumab), an exact one stage design [22] will be applied to demonstrate that the 2-year progression-free survival is not less than 50% (null hypothesis H0: Π ≤ 50%) and could reach 70% (alternative hypothesis H1: Π ≥ 70%).

We wanted to be 95% (alpha = 5%) certain that any difference was not due to chance. We also wanted to be able to detect such a difference with 90% power (beta = 10%). With these alpha and beta, rejecting the null hypothesis H0: Π ≤ 50%, and accepting the alternative hypothesis H1: Π ≥ 70% required 53 evaluable patients in Arm A (SBRT + durvalumab). Around 20% of patients may be lost to follow-up before evaluation of progression at 2 years. To ensure that we retain at least 53 patients until this evaluation, it was necessary to recruit 53x1.2 = 64 patients in Arm A (SBRT + durvalumab) and 32 (64/2) in Arm B (SBRT), a total of 96 patients.

Primary endpoint analysis

Two-year progression-free survival will be estimated using RECIST 1.1 and iRECIST criteria and PSA response in both arms. PFS is the time measured from the date of randomization to the date of progression or death from any cause. Patients alive and free of progression at 2 years will be censored at the last assessment date. With alpha = 5% and power = 90%, rejecting the null hypothesis H0: Π ≤ 50%, and accepting the alternative hypothesis H1: Π ≥ 70%, will require 53 evaluable patients in Arm A (SBRT + durvalumab).

If, of the 53 evaluable patients, 33 patients or more are alive and free of progression at two years, H0 will be rejected.

Planned timeline

The study has been submitted to, and approved by, the regulatory authorities (ANSM, date of approval: 23/02/2018) and ethics committee (SUD-MEDITERRANEE III. NIMES; date of approval: July 16, 2018). The project has been extensively discussed and approved by the GETUG and opened on March 21, 2019. The analysis of the primary endpoint should be completed by the end of 2023.

Ethical consideration and study registration

The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable regulatory requirements, including patient data protection:

• -European Directive (2001/20/CE),
• -Jardé Law (n° 2012–300) of March 5, 2012, relating to research involving humans.
• -Law of health orientation (Lois n° 2004–806 of August 9, 2004, and 2006–450 of April 18, 2006).
• -Law No. 78–17 of January 6, 1978, relating to computing, files, and freedoms, modified by law n° 2018–493 of June 20, 2018,
• -Regulation (EU) 2016/679 of the European Parliament and the Council of April 27, 2016.
• -Act No. 2004–800 August 6, 2004, in bioethics.
• -Decision of November 24, 2006, laying down the rules of good clinical practice for biomedical research on medicines for human use.

An Ethics Committee (CPP SUD-MEDITERRANEE III. NIMES; date of approval: July 16, 2018) approved the final study protocol, including the final version of the Informed Consent Form and any other written information and/or materials to be provided to the patients. Before enrolment of any patient into the study, the final study protocol, including the final version of the Informed Consent Form, was approved by the national regulatory authority (ANSM).

More details about consent, changes to the protocol and audits and inspections are available in supplementary.

Data safety monitoring board (DSMB)

A DSMB will be organized under the supervision of the coordinating investigator and composed of people well trained in the field of clinical research in oncology not directly involved in the current trial. The DSMB will meet after the first 15 patients are enrolled in Arm A (SBRT + durvalumab), then after 32, 48 and 64 patients are enrolled in the study. The role of the DSMB is to advise on the safety of the trial, and to give advice regarding the continuation of the study. In case of disagreement between the DSMB and the investigators, the ANSM will be informed and will receive meeting reports. More details about study monitoring are available in supplementary.

Data management

Data management will be performed by the sponsor.

Clinical Data Management Systems used for trial allows study design, consistency tests, medical coding, data import (in ASCII format) and export in compliance with regulatory authorities and Good Clinical Practices.

The data will be validated as defined in the Data Management Plan. Quality control procedures will be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. All clinical data are collected by the investigator or the investigators' designated representatives with eCRF.

A dedicated Clinical Research Associate will be in charge by the sponsor to verify, on the investigational site, that the e-CRF are correctly filled in by the investigators or its representatives.

Ethics approval and consent to participate

An Ethics Committee (SUD-MEDITERRANEE III. NIMES; date of approval: July 16, 2018) approved the final study protocol, including the final version of the Informed Consent Form and any other written information and/or materials to be provided to the patients. Before enrolment of any patient into the study, the final study protocol, including the final version of the Informed Consent Form, was approved by the national regulatory authority (ANSM).

Ethics Committee Name: CPP SUD MEDITERRANEE III (Nîmes) Ref Ethics Committee: 2018.03.07 ter.

Consent for publication

Each patient provides signed and dated informed consent (written) before conducting any procedure specifically for the study.

Availability of data and materials

They are available from the corresponding author upon request.

Fundings

The POSTCARD GETUG P13 study received funding from Astra Zeneca. AstraZeneca funded the study, provided the investigational product (Durvalumab), reviewed the methodology and ensures pharmacovigilance.

Authors' contributions

YP, PS, EM, US, AH, ER, GB, AR, MQ, MC, IL, EM, VG, PP, TL, PR, AL, AG, LC, OS, FD, VL, ABL and SS participated in the elaboration of the study protocol.

YP, PS, EM, US, AH, ER, GB, AR, MQ, MC, IL, EM, VG, PP, TL, PR, AL, AG, LC, OS, FD, VL and SS are investigators in the different centers involved in the enrolment of patients for this study.

ABL is the statistician in charge of the project.

MR and SS have written the first version of this article.

All authors have read and approved the final manuscript.

Trial registration

ClinicalTrials.gov NCT03795207. EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) 2017-003827-31 Registered on January 7, 2019. Ongoing study.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following are the Supplementary data to this article: