Veterans Affairs Seamless Phase II/III Randomized Trial of STAndard Systemic theRapy With or Without PET-directed Local Therapy for Oligometastatic pRosTate Cancer

Prostate Cancer Clinical Trial

— VA STARPORT  

Official title:

Veterans Affairs Seamless Phase II/III Randomized Trial of STAndard Systemic theRapy With or Without PET-directed Local Therapy for OligoRecurrenT Prostate Cancer (VA STARPORT)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04787744
• Other study ID #: ONCA-026-20S
• Secondary ID: CX002277-01
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: July 1, 2021
• Est. completion date: December 1, 2025

Study information

• Verified date: May 2024
• Source: VA Office of Research and Development
• Contact: Abhishek Solanki, MD MS
• Phone: (708) 202-8387
• Email: Abhishek.Solanki[@]va.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a prospective, open-label, multi-center seamless phase II to phase III randomized clinical trial designed to compare SST with or without PET-directed local therapy in improving the castration-resistant prostate cancer-free survival (CRPC-free survival) for Veterans with oligometastatic prostate cancer. Oligometastasis will be defined as 1-10 sites of metastatic disease based on the clinical determination of the LSI which incorporates all imaging, clinical, and pathologic data available.

Description:

Prostate Cancer is the most commonly diagnosed cancer among Veterans, comprising 30% of new cancer diagnoses in the VA. Eighty-five percent of men present with localized prostate cancer, which is typically treated with active surveillance or curative local therapy using surgery or radiation therapy. Unfortunately, twenty percent of Veterans undergoing curative local therapy will develop metastatic recurrence. These men typically receive palliative systemic hormonal therapy to control their disease. Despite this, over half of men will have cancer progression within 1-2 years and half will die within 5 years.

Two diverging paradigms have been studied in recent years to improve the survival of men with recurrent metastatic prostate cancer. First, a subset of patients has oligometastatic disease. These patients are hypothesized to have an intermediate clinical state in which ablative local therapy with surgery or radiation to all metastatic sites of disease (metastasis-directed therapy; MDT) can lead to durable disease control and potentially cure in select patients. Recent Phase II randomized trials have demonstrated improved long-term progression-free survival with MDT in the absence of systemic therapy.

Yet, 75% of patients receiving MDT for oligometastatic cancer develop progression in new areas, arguing that systemic therapy is needed to treat occult metastases. This is supported by data demonstrating that earlier palliative hormonal therapy is associated with improved survival. In fact, the second approach that has been studied in recent years, is whether escalating hormonal therapy by adding novel androgen receptor axis targeted agents or chemotherapy improves outcomes in men with metastatic prostate cancer. Multiple phase III randomized trials demonstrate that escalating hormonal therapy with these novel therapeutic agents improves progression-free survival and overall survival dramatically. Therefore, these agents have been integrated as an option into today's standard systemic therapy (SST) for metastatic prostate cancer.

Given the promise of MDT to induce long-term cancer control and the effectiveness of SST to prevent further cancer progression, there is an urgent need to determine whether adding MDT to SST improves disease outcomes further. Additionally, prior studies have excluded patients with local recurrence. However, these comprise a large proportion of Veterans with recurrent oligometastatic prostate cancer. The primary goal of our study is to determine if adding PET-directed local therapy (MDT and treatment of primary tumor [de novo] or primary tumor local recurrence on PET/CT if applicable) improves disease control compared to SST alone in Veterans with oligometastatic prostate cancer. This is a multi-institutional phase II/III randomized trial comparing SST with or without PET-directed local therapy. Other goals of the study are to determine any differences in patterns of cancer progression, survival, and quality of life. We also will determine if certain mutations present in tumor DNA can predict if Veterans will benefit from PET-directed local therapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 464
• Est. completion date: December 1, 2025
• Est. primary completion date: July 1, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Age 18 years. Ability to provide Informed Consent for participation in the study ECOG Performance Status 2 at time of enrollment. Prostate cancer, confirmed histologically or cytologically. If original documentation of histology and cytology are not available, documentation of prostate cancer satisfies these criteria. If recurrent, prior curative-intent local therapy to all sites of prostate cancer with either upfront radiotherapy or prostatectomy with or without post-operative radiotherapy.

If recurrent, PSA suspicious for biochemical recurrence after local therapy, with lab value(s) taken prior to start of SST (if current SST has already started) or within 90 days prior to enrollment if not already on SST, and meeting one of the three below categories:

PSA 0.2 ng/ml x 2 after prostatectomy +/- post-operative radiotherapy; Elevation of PSA 2 ng/ml above the nadir after definitive radiotherapy; Or Two consecutively elevated PSAs with evidence of metastasis on the imaging Studies.

-Serum testosterone obtained prior to randomization based on one of the criteria below:

For patients who have a history of a prior episode of therapy with SST agents for prostate cancer, a total testosterone 100 ng/dl after completion of the prior episode of SST and before the start of current SST or within 30 days of starting current SST if the patient has already started SST for recurrence.

For patients who have no prior history of an episode of therapy with SST agents and have already started SST for recurrence, this pre-SST testosterone is not required.

CT or MRI abdomen/pelvis performed prior to start of SST (if current SST has already started) or within 90 days prior to enrollment if not already on SST. The results from the CT component of the PET/CT can be used to fulfill this criterion. This is optional for patients who have a PSMA PET/CT. Yechnetium (Tc99m-MDP) or sodium fluoride (NaF) bone scan (sodium fluoride preferred) performed prior to start of SST (if current SST has already started), or within 90 days prior to enrollment if not already on SST. This is optional for patients who have a PSMA PET/CT. Prostate PET/CT (currently PSMA, Fluciclovine, choline) performed prior to start of SST (if current SST has already started), or within 90 days prior to enrollment if not already on SST.

1-10 lesions suspicious for nodal recurrence or metastasis from prostate cancer as determined by the investigator based on the above imaging studies.

Has already undergone NPOP sequencing or a plan is in place for NPOP sequencing for prostate cancer.

For participants on SST at the time of enrollment only:

Has been on SST for 180 days. For participants with local recurrence after curative-intent local therapy on imaging :

Patients with local recurrence in the prostate, SV, or prostate bed are eligible as long as there is at least 1 nodal or distant metastatic recurrence. Biopsy must confirm local recurrence for patients who have had prior curative-intent radiation to the prostate, SV, or prostate bed.

Candidate for salvage local therapy (refer to Section 10.4) as determined by a urologist or radiation oncologist (depending on the respective modality to be used to treat the local recurrence).

For participants with de novo prostate cancer:

Candidate for prostate-directed radiation.

Exclusion Criteria:

• Any current or prior evidence of castration-resistant prostate cancer, defined as two consecutive rises in serum PSA, obtained at a minimum of 1-week interval, with the final PSA value >/= 1 ng/ml, while having a total testosterone < 50 ng/dl).

• Prior malignancy, except the following:

• Adequately treated non-melanomatous skin cancer;

• Adequately treated Stage 0, I, or II cancer from which the patient is currently in complete remission; or

• Any other cancer from which the patient has been disease free for three years.

• Presence of a symptomatic metastasis that requires palliative radiotherapy.

• Any known brain metastases, presence of leptomeningeal disease, malignant spinal cord compression, or malignant cauda equina syndrome.

• Prior nodal, bone, or visceral metastasis after curative-intent therapy other than those identified on the enrollment imaging studies which make the patient ineligible for PET-directed local therapy (per investigator discretion).

• Prior radiation therapy to any sites requiring PET-directed local therapy or salvage local therapy that will lead to prohibitively high risk of toxicity from subsequent local therapy, as determined by the treating radiation oncologist (if radiation is intended as the study local therapy) or surgeon/urologist (if surgery is intended as the study local therapy).

• Any other previous or current condition, which, in the judgement of the LSI, is likely to interfere with any STARPORT treatments or assessments.

Related Conditions & MeSH terms

• Metastatic Prostate Cancer
• Oligometastasis
• Oligorecurrence
• Prostate Cancer
• Prostatic Neoplasms
• Recurrent Prostate Cancer

Intervention

Procedure:
• PET-directed Local Therapy using Surgery
Surgery will be used to treat metastases.

Radiation:
• PET-directed Local Therapy using Radiation
Radiation therapy will be used to treat metastases. Radiation options include: Stereotactic body radiotherapy (SBRT) using 1-10 fractions Conventionally fractionated radiotherapy using elective nodal radiotherapy and a simultaneous integrated boost to involved nodes The selection of the form of metastasis-directed radiotherapy for each metastasis will be determined using shared decision-making between the treating physician and the Veteran.

Other:
• Salvage Local Therapy for locally recurrent disease
For Veterans who have a local recurrence in addition to oligorecurrent metastatic lesions, they will undergo salvage local therapy using brachytherapy, SBRT, surgery, cryotherapy or HIFU. The selection of modality of salvage local therapy will be determined using shared decision-making between the treating physician and Veteran.

Drug:
• Goserelin, Histrelin, Leuprolide & Triptorelin
Androgen deprivation therapy (ADT) using an LHRH agonist
• ADT + Nilutamide, Flutamide, & Bicalutamide
ADT adding anti-androgen therapy to an LHRH agonist
• Degarelix & Relugolix
ADT using an LHRH Antagonist.
• ADT + Docetaxel +/- prednisone
Enhanced SST using chemohormonal therapy
• ADT + Abiraterone + Prednisone
Enhanced SST using Abiraterone + Prednisone
• ADT + Abiraterone + Methylprednisolone
Enhanced SST using Abiraterone + Methylprednisolone
• ADT + Apalutamide
Enhanced SST using ADT + Apalutamide
• ADT + Enzalutamide
Enhanced SST using ADT + Enzalutamide

Radiation:
• Prostate-directed Radiation for De novo oligometastatic prostate cancer
Veterans in ARM 1 will receive prostate-directed RT only and NO treatment to any nodal or distant metastatic sites. Acceptable dose/fractionations include 55 Gy in 20 fractions and 36 Gy in 6 fractions. Veterans in ARM 2 should receive prostate-directed local therapy using radiotherapy or radical prostatectomy in addition to PET-directed local therapy to metastases.

Locations

Country	Name	City	State
United States	VA Ann Arbor Healthcare System, Ann Arbor, MI	Ann Arbor	Michigan
United States	Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD	Baltimore	Maryland
United States	Bay Pines VA Healthcare System, Pay Pines, FL	Bay Pines	Florida
United States	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts
United States	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio
United States	Durham VA Medical Center, Durham, NC	Durham	North Carolina
United States	East Orange Campus of the VA New Jersey Health Care System, East Orange, NJ	East Orange	New Jersey
United States	Edward Hines Jr. VA Hospital, Hines, IL	Hines	Illinois
United States	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas
United States	Richard L. Roudebush VA Medical Center, Indianapolis, IN	Indianapolis	Indiana
United States	Kansas City VA Medical Center, Kansas City, MO	Kansas City	Missouri
United States	VA Long Beach Healthcare System, Long Beach, CA	Long Beach	California
United States	William S. Middleton Memorial Veterans Hospital, Madison, WI	Madison	Wisconsin
United States	Clement J. Zablocki VA Medical Center, Milwaukee, WI	Milwaukee	Wisconsin
United States	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota
United States	Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY	New York	New York
United States	Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA	Philadelphia	Pennsylvania
United States	Hunter Holmes McGuire VA Medical Center, Richmond, VA	Richmond	Virginia
United States	VA Greater Los Angeles Healthcare System, West Los Angeles, CA	West Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Castration-resistant prostate cancer-free survival (CRPC-free survival)	CRPC-free survival is a time-to-event outcome defined as the length of time from randomization to the first occurrence of failure. The following are forms of failure in the setting of a castrate testosterone level: PSA progression, radiographic progression, symptomatic skeletal event due to progression, and death.	4 years
Secondary	Radiographic progression-free survival (rPFS)	rPFS is a time-to-event outcome defined as the length of time from randomization to radiographic progression of prostate cancer or death.	4 years
Secondary	Clinical progression-free survival (cPFS)	cPFS is a time-to-event outcome defined as the length of time from randomization to radiographic progression on conventional imaging, symptomatic skeletal event due to progression, or death.	4 years
Secondary	Freedom from index lesion progression (FFILP)	FFILP is a time-to-event outcome defined as the length of time from randomization to progression of any of the enrollment index oligorecurrent lesions.	4 years
Secondary	New metastasis-free survival (MFS)	New MFS is a time-to-event outcome (MFS) defined as the length of time from randomization to the development of a new metastasis that was not present at the time of enrollment, or death.	4 years
Secondary	Prostate cancer-specific survival (PCSS)	PCSS is a time-to-event outcome defined as the length of time from randomization to death from prostate cancer.	4 years
Secondary	Overall survival (OS)	OS is a time-to-event outcome defined as the length of time from randomization to death from any cause.	4 years
Secondary	Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 toxicity	Toxicities will be evaluated based on system organ class and a higher number in the grading system is reflective of more severe toxicity.	4 years
Secondary	Patient-reported quality of life measured by the EORTC QLQ-C30 3.0	The QLQ-C30 is composed of 30 items. These include five functional scales, three symptom scales, a global health status/QoL scale, and six single items. Raw scores will be converted to standardized scores ranging from 0 to 100. A higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.	2 years
Secondary	Expanded Prostate cancer Index Composite Short Form (EPIC-26)	EPIC-26 contains 26 items in 5 domains (Urinary Incontinence, Urinary Irritative/Obstructive, Bowel, Sexual, and Hormonal). Raw scores are transformed linearly to a 0-100 scale, with higher scores representing better HRQOL.	2 years
Secondary	Patient-reported health-related quality of life measured by the EQ5D-5L	EQ5D-5l consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each dimension has 5 levels. The digits for the 5 dimensions is combined to describe the health state (higher total reflect a higher health state). There is also a vertical visual analogue scale to be used as a quantitative measure that reflects the patient's own judgement with the endpoints labelled as "The best health you can imagine" and "The worst health you can imagine."	2 years