Introduction and Context
Biochemical recurrence (BCR) — a rising prostate-specific antigen (PSA) after definitive local therapy (radical prostatectomy and/or radiation) — has long been a clinical challenge because PSA changes often precede visible disease on conventional imaging. Over the last decade, prostate-specific membrane antigen positron emission tomography (PSMA PET) has dramatically increased the sensitivity for detecting small-volume recurrent disease. This shift exposes a previously unseen cohort of patients with imaging-only recurrence and raises questions about how to design rigorous clinical trials for this increasingly common and heterogenous state.
On November 13, 2024, the National Cancer Institute convened a working group (NCI BCR WG) of clinicians, trialists, imaging experts, and patient representatives to produce pragmatic recommendations for clinical-trial design in biochemically recurrent prostate cancer. The resulting consensus, published in JCO in late 2025 (Einstein et al., J Clin Oncol. 2025 Dec;43(34):3672-3683), provides definitions, baseline data standards, imaging and eligibility guidance, and suggested endpoints tailored to this distinct disease space.
Why this consensus matters now
– Widespread adoption of PSMA PET (proven to alter staging and management in randomized data such as the proPSMA trial) has created a patient group with disease visible only on advanced imaging (PSMA PET) but negative on conventional scans. – Most prior phase III prostate-cancer trials focused on metastatic disease defined by conventional imaging. Applying those designs to this new population risks misclassification, inappropriate endpoints, and over- or undertreatment. – Trialists need standardized nomenclature, baseline data elements, and realistic, patient-centered endpoints to design studies that inform practice and policy.
Key external context (select references)
– Hofman MS et al., proPSMA trial (Lancet 2020) demonstrated PSMA PET superiority to conventional imaging for staging recurrent prostate cancer. – PROSPER and SPARTAN trials (NEJM 2018) established metastasis-free survival (MFS) as a meaningful endpoint in non-metastatic CRPC, a precedent for endpoint selection. – Contemporary guidelines (NCCN, EAU) increasingly incorporate PSMA PET for staging and recurrence evaluation.
New Guideline Highlights
Major recommendations and themes from the NCI BCR WG
– New nomenclature: Define the distinct entity PSMA+BCR to describe patients with biochemical recurrence who have disease detectable only by PSMA PET and not by conventional imaging. This clarifies trial populations and avoids conflation with traditional metastatic hormone-sensitive prostate cancer. – Risk stratification: Define high-risk BCR as PSA doubling time (PSA-DT) ≤6 months regardless of PET status. This single, objective marker identifies patients at higher near-term risk of progression. – Baseline data and imaging: Recommend a minimum dataset and imaging standards to ensure consistent characterization across trials (detailed below). – Control-arm design: Neither systemic therapy nor metastasis-directed therapy (MDT) is mandatory in control arms; observation remains a valid comparator where appropriate. – Endpoint innovation: Encourage endpoint selection meaningful to patients and trial feasibility, including radiographic progression by conventional imaging, time to metastasis on conventional imaging, time to systemic therapy, progression-free survival adapted for BCR trials, and patient-reported outcomes. – Emphasize deintensification: Because many BCR patients have relatively indolent disease, the WG advocates for trials that test deintensification strategies to reduce toxicity without compromising outcomes.
Key takeaways for clinicians and investigators
– Use PSMA+BCR to label trial cohorts and to stratify enrollment and analyses. – Enroll high-risk BCR patients (PSA-DT ≤6 months) when trials aim to detect earlier progression events; include broader PSMA+BCR cohorts for exploratory or de-escalation studies. – Standardize imaging and baseline data to allow pooling and cross-trial comparisons. – Prioritize patient-centered endpoints and incorporate validated QoL instruments.
Updated Recommendations and Key Changes
What is new compared with prior practice and guideline thinking
– Explicit nomenclature: Prior guidelines referenced “PSA recurrence” or “biochemical recurrence” but did not formalize PSMA-based subtypes. The NCI WG’s PSMA+BCR is a clear innovation that aligns trial design to modern imaging. – Shift from conventional-imaging end points: Historically, trials used conventional imaging-defined metastasis or death; the WG recommends endpoints that recognize PSMA PET’s sensitivity while centering outcomes that remain clinically meaningful (e.g., metastasis on conventional imaging). – High-risk definition simplified: Multiple prior studies used varied PSA-DT cutoffs (e.g., ≤3, ≤6, ≤9 months). The WG recommends PSA-DT ≤6 months as the working definition for high-risk BCR for trial enrichment. – Control-arm permissiveness: The WG explicitly declutters trial control arms, noting that immediate systemic or MDT should not be mandated, enabling pragmatic trials with observation arms and more generalizable results.
Evidence driving the updates
– The sensitivity and impact of PSMA PET in restaging (proPSMA) and subsequent management changes drove the need for clearer nomenclature and new trial endpoints. – Natural-history data linking short PSA-DT to higher rates of progression and metastasis support using PSA-DT ≤6 months to enrich trials for event rates that make phase II/III evaluation feasible.
Topic-by-Topic Recommendations
Below are the WG’s topic-by-topic recommendations summarized for trial designers and clinicians. Where possible, the WG framed guidance as “recommended” or “suggested” reflecting consensus strength.
1) Nomenclature
– Recommended term: PSMA+BCR = Biochemical recurrence with disease detectable by PSMA PET but negative on conventional imaging (CT and technetium bone scan or standard-of-care cross-sectional imaging). – Purpose: Separate these patients from (a) BCR with negative PSMA PET, (b) BCR with conventional imaging metastasis, and (c) metastatic hormone-sensitive prostate cancer.
2) Eligibility and risk stratification
– High-risk BCR: PSA doubling time (PSA-DT) ≤6 months (recommended for trials seeking faster accrual of clinical events). – Other stratifiers to record: Absolute PSA level, Gleason/ISUP grade group at diagnosis, initial stage, prior therapies including salvage radiation, ADT exposure and duration, time from definitive therapy to recurrence. – Inclusion of PSMA PET–positive sites: Specify whether PSMA-detected nodal or oligometastatic lesions are permitted and how MDT will be handled in study arms.
3) Baseline data capture (minimum dataset recommended)
– Demographics: age, performance status, comorbidities. – Cancer history: date of primary therapy, pathologic stage, Gleason/ISUP grade, margin status, PSA nadir. – PSA kinetics: PSA at enrollment and PSA-DT calculation method (preferably using validated calculators and ≥3 PSA values). – Prior systemic therapy: prior ADT exposures and durations. – Imaging: date and type of PSMA PET (radiotracer and scanner details), date and results of conventional imaging (CT chest/abdomen/pelvis ± bone scan), any prior PETs. – Prior local salvage interventions: salvage radiation, lymphadenectomy, or focal therapy.
4) Imaging considerations
– PSMA PET harmonization: Record radiotracer (68Ga-PSMA-11 vs 18F-DCFPyL/PYL), injected activity, timing, scanner type, and standardized reporting (e.g., PROMISE/miTNM). – Conventional imaging endpoint: The WG emphasized maintenance of conventional imaging (CT and bone scan) as an endpoint-defining modality for metastasis because regulatory and practice decisions often hinge on standard imaging. – Central review: Encourage central imaging review for pivotal trials to ensure consistency.
5) Interventions and control arms
– MDT and systemic therapy: WG did not mandate MDT (SBRT/surgery) or systemic therapy in control arms; these may be used per-protocol or allowed per investigator discretion but should be predefined and tracked. – Trial examples: Randomized trials can compare MDT ± short-term ADT versus observation, or early systemic therapy versus deferred therapy, depending on trial question and risk cohort.
6) Endpoints and follow-up
The WG suggested a hierarchy of endpoints, stressing clinical relevance and feasibility:
– Primary endpoints recommended for different trial types:
– Trials of disease control/deferred systemic therapy: Time to metastasis on conventional imaging (radiographic metastasis-free survival by standard scans) or time to initiation of systemic therapy.
– Trials testing MDT vs observation: Progression-free survival tailored for BCR (combining PSA progression, radiographic progression on conventional imaging, and initiation of systemic therapy), or time to conventional-imaging metastasis.
– Trials testing systemic therapies: Conventional metrics like radiographic PFS (on conventional imaging) if metastasis is a likely near-term event; otherwise, composite endpoints that include PSA-based progression with symptomatic and QoL measures.
– Secondary endpoints: PSA response, PSA-DT changes, PSMA PET response (exploratory), quality-of-life (QoL) measured with validated tools (EPIC-26, FACT-P), ADT-free survival, toxicity, and overall survival when feasible.
– Rationale: The WG recommended anchoring primary outcomes to conventional imaging to preserve clinical relevance and regulatory comparability even while collecting PSMA PET data as exploratory or supportive endpoints.
7) Quality of life and patient-reported outcomes (PROs)
– Use validated instruments: EPIC-26 for disease-specific domains (urinary, bowel, sexual, hormonal), FACT-P for cancer-specific QOL, and PROMIS or EQ-5D for general health. – Capture ADT-related symptoms proactively and incorporate PROs as co-primary or key secondary endpoints where toxicity tradeoffs are central to the question.
8) Special populations
– Prior salvage therapy: Trials should prespecify allowed prior salvage treatments and stratify on these variables (e.g., prior salvage radiation). – Patients with very low PSA-DT or biochemical persistence immediately post-prostatectomy may warrant separate trial cohorts or exclusion depending on the intervention tested.
Expert Commentary and Insights
Consensus opinions and controversies
– Consensus: PSMA PET redefines the landscape and requires rethinking trial design; PSA-DT ≤6 months is a pragmatic high-risk enrichment criterion; conventional imaging-based metastasis remains a meaningful and pragmatic primary endpoint. – Areas of debate: How to weight PSMA PET findings in primary endpoints (should PSMA PET progression count as a primary outcome?) The WG favored using PSMA PET primarily as a stratification and exploratory outcome rather than a primary regulatory endpoint at this time. – MDT role: While MDT (e.g., stereotactic radiotherapy to PET-avid lesions) shows promise in phase II trials, the WG stopped short of mandating or uniformly recommending MDT as standard, encouraging randomized evaluation. – Deintensification vs escalation: The WG strongly advocated for trials testing deintensification (e.g., observation vs early intervention) in appropriately selected low-risk PSMA+BCR patients to avoid unnecessary toxicities.
Representative expert perspectives (paraphrased)
– Imaging experts: Harmonization of PET protocols and reporting (PROMISE/miTNM) is essential for cross-trial comparison. – Clinical trialists: Anchoring primary endpoints to conventional imaging keeps results interpretable by regulators and clinicians while PSMA PET results can be analyzed hierarchically. – Patient advocates: Preserve quality of life as a central outcome; many BCR patients prioritize delaying ADT and its side effects.
Practical Implications
How these recommendations will change practice and trial design
– Trialists designing BCR studies should adopt PSMA+BCR nomenclature, collect the recommended baseline dataset, and prespecify how PSMA findings will be used in randomization and analyses. – Regulatory design: By recommending conventional-imaging–based primary endpoints with PSMA PET as exploratory, the WG provides a pathway to both clinically meaningful and regulatory-usable results. – Clinical care: The WG’s emphasis on deintensification may encourage clinicians to consider observation or limited interventions for selected PSMA+BCR patients within trials rather than reflexive systemic therapy.
Vignette: Applying the guidance
John Carter, 68, underwent radical prostatectomy 5 years ago (Gleason 4+3, pT3a). He now has a rising PSA to 1.2 ng/mL with three serial PSAs showing a PSA-DT of 4 months. A PSMA PET scan shows a single 1.2-cm pelvic nodal focus; CT and bone scan are negative. Under NCI WG guidance, John meets criteria for PSMA+BCR and is considered high-risk (PSA-DT ≤6 months). He would be eligible for randomized trials comparing metastasis-directed SBRT to the PET-avid node versus observation, with primary endpoint of time to metastasis on conventional imaging and co-primary or key secondary PROs (EPIC-26) to measure sexual and urinary function and ADT-free survival.
Looking Ahead: Research Needs and Conclusion
Priority research questions highlighted by the WG
– Can PSMA PET–directed MDT delay conventional imaging metastasis or the need for systemic therapy, and does this translate into improved QoL or survival? – What is the prognostic significance of different PET radiotracer uptake patterns and lesion burden in PSMA+BCR? – Which patients can safely undergo deintensification without compromising long-term outcomes? – How should PSMA PET–derived endpoints be validated and standardized for regulatory use?
Conclusion
The NCI BCR Working Group provides an important, pragmatic framework for clinical trials in biochemically recurrent prostate cancer in the PSMA PET era. By defining PSMA+BCR, recommending PSA-DT ≤6 months as a high-risk cutoff, and prioritizing conventional-imaging–based primary endpoints while collecting PSMA PET data as exploratory, the WG aims to make trials both clinically meaningful and feasible. Equally important is the WG’s call to test deintensification strategies and to center patient-reported outcomes — an approach that balances the sensitivity of new imaging with the need to avoid overtreatment in a population where quality of life often matters as much as disease control.
References
– Einstein DJ, Abel ML, Aragon‑Ching JB, et al. National Cancer Institute’s Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations. J Clin Oncol. 2025 Dec;43(34):3672‑3683. doi:10.1200/JCO‑25‑01693. PMID: 41129763.
– Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate‑specific membrane antigen PET‑CT in patients with high‑risk prostate cancer before curative‑intent surgery or radiotherapy (proPSMA): a randomised, open‑label, phase 3 trial. Lancet. 2020;395(10231):1208‑1216.
– Hussain M, Fizazi K, Saad F, et al. Enzalutamide in nonmetastatic, castration‑resistant prostate cancer. N Engl J Med. 2018;378(26):2465‑2474. (PROSPER)
– Smith MR, Hussain M, Saad F, et al. Apalutamide and metastasis‑free survival in prostate cancer. N Engl J Med. 2018;378(15):1408‑1418. (SPARTAN)
– National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Latest version 2024.
– European Association of Urology. EAU Guidelines on Prostate Cancer. 2023 update.
– Wei JT, Dunn RL, Litwin MS, et al. Development and validation of the Expanded Prostate Cancer Index Composite (EPIC) for comprehensive assessment of health‑related quality of life in men with prostate cancer. Urology. 2000;56(6):899‑905.
– Cella D, Yount S, Brucker PS, et al. Development and validation of the Functional Assessment of Cancer Therapy‑Prostate (FACT‑P). Support Care Cancer. 1993;1(1): [original FACT references].
Note: Trial designers and clinicians should consult the full JCO working‑group publication and current institutional/IRB/regulatory guidance when operationalizing these recommendations.
