The TRACE-II trial: will this draw the path for radioguided surgery and androgen deprivation therapy combination, or not?

In 27–53% of cases, patients treated with curative intent for prostate cancer (PCa) will develop biochemical recurrence (BCR). After radical prostatectomy (RP) and external beam radiation therapy (EBRT), the most commonly used definitions for BCR are a prostate specific antigen (PSA) value >0.2 ng/mL and PSA nadir +2 ng/mL, respectively (1). The mainstay therapy for BCR without evidence for metastatic disease after RP has been salvage radiation therapy (sRT) to the prostatic fossa +/− pelvic lymph nodes +/− androgen deprivation therapy (ADT). While these therapies result in substantial disease control rates, toxicity is not negligible, both from sRT and from ADT (2). The evidence for other salvage therapies (e.g., surgery, high-dose rate brachytherapy, cryotherapy, high-intensity focused ultrasound and stereotactic body radiotherapy) for BCR after radiation therapy (RT) is less convincing till now (1).

The recommended management of BCR has undergone a significant transformation: personalized treatment based on risk stratification is now favored (3). Earlier and more precise identification of recurrent lesions is aided by advancements in imaging techniques like prostate specific membrane antigen positron emission tomography computed tomography (PSMA PET/CT). Performing such next generation imaging is advised in patients experiencing BCR if it impacts treatment decisions (1). With rising PSA levels, the likelihood of detecting metastatic disease increases; yet a considerable portion of PSMA PET/CT identified disease corresponds with local recurrences, either within the prostatic fossa or regional lymph nodes (4,5). In recent years, there has been a noticeable shift away from long-term systemic therapy (ADT + androgen receptor signaling inhibitor) in these patients towards salvage treatment modalities if feasible. In select cases, local relapses may be managed surgically (resection or salvage lymphadenectomy) or with radiotherapy. Salvage treatment modalities still aim to cure the patient. Yet, few trials are available regarding the optimal treatment management of patients with cN1 or pN1 disease in the primary setting (adjuvant versus salvage) (6-8). However, even fewer trials investigated how patients with metachronous lymph node disease should be ideally treated, leaving an important gap for future research.

A promising and intensively studied treatment option in this disease state is radioguided surgery (RGS). A recent systematic review by Berrens et al. nicely summarized the principles of PSMA-targeted surgery, including the published manuscripts about this topic (9). Since publication of this systematic review (only a year ago), two more randomized controlled trials (RCTs) investigating this treatment option have already been published (10,11).

In the current volume of BJU International, Zuur et al. present the study design of the single center, randomized TRACE-II trial, which is currently actively recruiting. PCa patients developing clinical loco-regional relapse after primary treatment, will be randomized between 6 months of ADT (Arm A, control arm) or 6 months of ADT supplemented by RGS (Arm B, experimantal arm). Inclusion criteria are a maximum of 2 pelvic nodes and/or locoregional relapse as defined on PSMA PET/CT (12). The primary endpoint is clinical progression-free survival at 24 months.

Any randomized trial in this clinical setting should be applauded, and the same goes without any doubt for the initiation of the TRACE-II trial. However, we are not convinced that the results of this trial will provide definitive answers to the question how these “oligorecurrent” patients should be treated at best and if they can be offered hope on definitive cure using RGS. We will try to constructively establish our concerns.

First, there is substantial room for interpretation concerning the criteria for patient inclusion and exclusion. It remains unclear from the protocol whether the trial includes patients with pathological N-stages (pNx, pN0, or even pN1) status at primary treatment. A large diversity in patients can possibly diminish the validity of the trial results and may be a source of criticism later-on. Let us consider following scenarios.

In case of pN1 disease at RP and pelvic lymph node dissection (PLND) specimen: according to the convincing data of Tilki et al. (13), patients with pN1 disease who were treated with adjuvant whole pelvis radiotherapy (WPRT) have better overall survival compared to patients receiving early salvage radiotherapy (esRT) or those who did not receive RT at all.

In case of pN0 or pNx disease, results are less straightforward. Again, Tilki et al. demonstrated that patients with adverse pathological features at RP specimen (Gleason score 8–10 and/or pT3a or higher) who were treated with adjuvant RT had a better overall survival when compared to esRT or no RT (13). Recent data of RADICALS-RT however, could not demonstrate a benefit of adjuvant RT over sRT (14). Nevertheless, the main message still holds true: when a biochemical relapse after RP occurs and there are no arguments for the presence of metastatic disease, RT to the prostate bed (15) or WPRT (16) is the gold standard treatment with curative potential for these patients.

We must raise a critical question concerning the inclusion criteria: “Have patients experiencing relapse after RP undergone (early) sRT or salvage WPRT?”. We believe that patients randomized in the control arm who did not receive s(WP)RT receive suboptimal treatment.

Even up till now, there is no general consensus about the number of positive lesions to qualify for ‘oligorecurrent PCa’. However, to the best of our knowledge, this is typically defined as the presence of ≤3 to 5 visible lesions (17). The rationale behind establishing a maximum of 2 PSMA-PET positive lymph nodes as an inclusion criterion is unclear in this regard. This strict cut-off is potentially included in the protocol as part of RGS feasibility, needed for randomization in the RGS arm. One of the largest benefits of RGS is the possibility to (potentially) remove (all) tumor foci without removing excessive non-tumoral tissues. A typical example hereof is removal of selective lymph nodes instead of performing a super-extended PLND. As we presume that in the TRACE-II trial only the isolated PSMA-positive nodes will be removed using RGS (study arm), we have to mention the preliminary results from the randomized PEACE V-STORM trial presented at ESTRO 2024 (18) which suggest that elective nodal pelvic radiotherapy for oligorecurrent nodal PCa results in a significantly better regional relapse-free survival when compared to metastasis-directed therapy on PSMA-PET positive lymph nodes alone. When extrapolating the data of PEACE-V to the current TRACE-II trial, there seems to be a substantial chance of higher pelvic relapse when only the PSMA-PET positive nodes are removed with RGS. In case complete PLND is performed [needed to calculate false negative rate of PSMA-RGS, which was already investigated in the TRACE-I trial (19)], the TRACE-II trial seems to be investigating “radioguidance augmented salvage surgery”.

If a locoregional pelvic relapse after primary radiotherapy occurs and if the patient’s life-expectancy is substantial, the ‘gold standard’ treatment in such situation is a local salvage treatment being salvage prostatectomy, salvage brachytherapy or salvage stereotactic body radiotherapy, the two latter treatment options possibly combined with a temporary castration (1). There is, in our opinion, no guideline-based evidence supporting the use of 6 months of ADT in monotherapy in these patients. In case of pelvic nodal relapse, we express similar concerns. These patients have still a chance on definitive cure, provided they receive an intensive treatment consisting of WPRT combined with a temporary castration from which the time may vary between 6 months and 3 years (20). Evidence supporting a synergistic or additive effect in patients undergoing surgery remains scarce (21). We hope the TRACE-II trial is not masking the true potential effect of RGS in this setting by combining with hormonal therapy.

Our research group recently published a large multicenter case series focusing on patients with a solitary local recurrence in the seminal vesicles following primary therapy (22). In this series, we documented short-term oncological outcomes. Even though frozen sections were not used, PCa was found in all patients. Although challenging, resection of local recurrences without RGS appears feasible in experienced centers. There was a substantial number of positive surgical margins (PSM) without PSMA-RGS. Radioguided-surgery trials, including TRACE-II trial, will provide proof of feasibility for salvage surgery for local recurrences, potentially facilitating the introduction of salvage surgery to a larger audience. We strongly believe TRACE-II might be able to show potential benefits in this patient population due to incorporation of RGS (e.g., significant reduction in PSM), leading to a better disease control. We noticed that the proportion of PSM is not included in this trial. However, this would be very interesting to look into as a secondary outcome for local recurrences. Minimally-invasive techniques already demonstrated less toxicity (23), but PSMA-RGS can potentially further improve these results.

The selected endpoints chosen by the authors are important and relevant. However, upon reviewing the published protocol of the TRACE-II trial, it appears that not all endpoints seem adequately addressed with the current trial design. It is unclear how the patients with repeated locoregional (including nodal) recurrence will be treated within this trial. Notably, patients with a local recurrence following treatment in Arm A have the option to cross-over to receive RGS. However, the protocol does not outline a similar provision for patients experiencing progression after receiving RGS in Arm B. It remains unclear whether repeated RGS is possible or if the final endpoint is reached at this time. Cross-over is an underrated inclusion in many trials. While we truly appreciate its incorporation into this trial design, we question its appropriateness here, as it may potentially diminish the perceived benefit of RGS. Further, apart from providing more compelling evidence that RGS is feasible in these patients, the cross-over might mask the true RGS results.

Even though this commentary might be critical of some parts of the TRACE-II trial, we truly want to congratulate the colleagues on starting this commendable trial and contributing valuable evidence on PSMA-RGS to the urological community. This underscores the significance of embracing all available new technologies to ensure optimal oncological outcomes for our patients, while avoiding the initiation of palliative ADT and its potential side effects. Salvage treatment options can often lead to unfavorable functional outcomes. However, the introduction of targeted surgical interventions, such as RGS, holds promise in potential cure, while decreasing morbidity. While the TRACE-II trial promises to provide valuable insights into the utility of RGS, it is essential to recognize that it represents just one facet of the broader landscape. Every trial, including this one, has its inherent limitations that must be considered when interpreting the final trial results.

We firmly believe that RGS is set to become an integral part of the urological future, both in primary and recurrent settings and we look forward to new trials that will continue to shape this path forward. But meanwhile, standard treatments should be respected in the control arms of such trials. And this is the major issue in TRACE-II: 6 months of ADT cannot be considered as standard of care (1).

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-104/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-104/coif). G.D.M. reports grant from European Scientific Grant by Rising Tide for phase 3 MEDCARE trial, payment for an oral presentation at the May 2024 Scientific Summits, support from Janssen Pharmaceutica for ASCO-GU 2024, and has leadership or fiduciary role in President Scientific Summits. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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