SPARKLE: a new spark in treating oligorecurrent prostate cancer: adding systemic treatment to stereotactic body radiotherapy or metastasectomy: key to long-lasting event-free survival?

BACKGROUND: Metastasis-directed therapy (MDT) significantly delays the initiation of palliative androgen deprivation therapy (pADT) in patients with oligorecurrent prostate cancer (PCa) with a positive impact on patient's quality of life. However, it remains unclear whether the addition of ADT improves polymetastatic free survival (PMFS) and metastatic castration refractory PCa-free survival (mCRPC-FS) and how long concomitant hormone therapy should be given. A significant overall survival (OS) benefit was shown when an androgen receptor targeted agent (ARTA) was added to pADT in patients with metastatic hormone sensitive PCa (HSPC). However, whether the addition of and ARTA to MDT in the treatment of oligorecurrent PCa results in better PMFS and mCRPC-FS has not been proven yet. METHODS & DESIGN: Patients diagnosed with oligorecurrent HSPC (defined as a maximum of 5 extracranial metastases on PSMA PET-CT) will be randomized in a 1:1:1 allocation ratio between arm A: MDT alone, arm B: MDT with 1 month ADT, or arm C: MDT with 6 months ADT together with ARTA (enzalutamide 4 × 40 mg daily) for 6 months. Patients will be stratified by PSA doubling time (≤ 3 vs. > 3 months), number of metastases (1 vs. > 1) and initial localization of metastases (M1a vs. M1b and/or M1c). The primary endpoint is PMFS, and the secondary endpoints include mCRPC-FS, biochemical relapse-free survival (bRFS), clinical progression free survival (cPFS), cancer specific survival (CSS), overall survival (OS), quality of life (QOL) and toxicity. DISCUSSION: This is the first prospective multicentre randomized phase III trial that investigates 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 PMFS and/or mCRPC-FS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05352178, registered April 28, 2022.

Diverse Imaging Methods May Influence Long-Term Oncologic Outcomes in Oligorecurrent Prostate Cancer Patients Treated with Metastasis-Directed Therapy (the PRECISE-MDT Study).

Metastasis-directed therapy (MDT) has been tested in clinical trials as a treatment option for oligorecurrent prostate cancer (PCa). However, there is an ongoing debate regarding the impact of using different imaging techniques interchangeably for defining lesions and guiding MDT within clinical trials. Methods: We retrospectively identified oligorecurrent PCa patients who had 5 or fewer nodal, bone, or visceral metastases detected by choline or prostate-specific membrane antigen (PSMA) PET/CT and who underwent MDT stereotactic body radiotherapy with or without systemic therapy in 8 tertiary-level cancer centers. Imaging-guided MDT was assessed as progression-free survival (PFS), time to systemic treatment change due to polymetastatic conversion (PFS2), and overall survival predictor. Propensity score matching was performed to account for clinical differences between groups. Results: Of 402 patients, 232 (57.7%) and 170 (42.3%) underwent MDT guided by [18F]fluorocholine and PSMA PET/CT, respectively. After propensity score matching, patients treated with PSMA PET/CT-guided MDT demonstrated longer PFS (hazard ratio [HR], 0.49 [95% CI, 0.36-0.67]; P < 0.0001), PFS2 (HR, 0.42 [95% CI, 0.28-0.63]; P < 0.0001), and overall survival (HR, 0.39 [95% CI, 0.15-0.99]; P < 0.05) than those treated with choline PET/CT-guided MDT. Additionally, we matched patients who underwent [68Ga]Ga-PSMA-11 versus [18F]F-PSMA-1007 PET/CT, observing longer PFS and PFS2 in the former subgroup (PFS: HR, 0.51 [95% CI, 0.26-1.00]; P < 0.05; PFS2: HR, 0.24 [95% CI, 0.09-0.60]; P < 0.05). Conclusion: Diverse imaging methods may influence outcomes in oligorecurrent PCa patients undergoing MDT. However, prospective, head-to-head studies, ideally incorporating a randomized design, are necessary to provide definitive evidence and facilitate the practical application of these findings.

Prostate cancer-what about oligometastatic disease and stereotactic ablative radiotherapy?-a narrative review.

BACKGROUND AND OBJECTIVE: Oligometastatic prostate cancer (OMPC) encompasses a heterogenous group of clinical entities defined by the timing of the development of metastases. These include de novo oligometastatic, oligorecurrent and oligoprogressive prostate cancer (PrCa). We describe the evidence supporting the use of stereotactic ablative radiotherapy (SABR) to the oligometastases to improve patient outcomes in each of these settings. METHODS: Published clinical trials relevant to 'OMPC' and 'SABR' where used for this narrative review. KEY CONTENT AND FINDINGS: The driving force behind this narrative review is the constantly evolving field of OMPC with an increasing number of salvage radiotherapy options changing the current treatment paradigm. We now have evidence to support that disease control can be optimised with SABR as shown in several practice changing trials including 'ORIOLE', 'STOMP' for PrCa and 'SABR-COMET' showing a survival advantage with a tumour agnostic salvage approach. We also describe the challenges with data interpretation and cost implications. Challenges include the small sample size for most reported trials, in combination with a lack of cost-efficiency analysis. CONCLUSIONS: SABR is a promising treatment approach for OMPC with a proven clinical benefit in some clinical settings and its use will expand in the future.

PSMA-PET Guided Treatment in Prostate Cancer Patients with Oligorecurrent Progression after Previous Salvage Treatment.

BACKGROUND: Prostate Specific Membrane Antigen-Positron Emission Tomography (PSMA-PET) is used to select recurrent prostate cancer (PCa) patients for metastases-directed therapy (MDT). We aimed to evaluate the oncologic outcomes of second-line PSMA-guided MDT in oligo-recurrent PCa patients. METHODS: we performed a retrospective analysis of 113 recurrent PCa after previous radical prostatectomy and salvage therapies with oligorecurrent disease at PSMA-PET (≤3 lesions in N1/M1a-b) in three high-volume European centres. Patients underwent second-line salvage treatments: MDT targeted to PSMA (including surgery and/or radiotherapy), and the conventional approach (observation or Androgen Deprivation Therapy [ADT]). Patients were stratified according to treatments (MDT vs. conventional approach). Patients who underwent MDT were stratified according to stage in PSMA-PET (N1 vs. M1a-b). The primary outcome of the study was Progression-free survival (PFS). Secondary outcomes were Metastases-free survival (MFS) and Castration Resistant PCa free survival (CRPC-FS). Kaplan-Meier analyses assessed PFS, MFS and CRPC-FS. Multivariable Cox regression models identified predictors of progression and metastatic disease. RESULTS: Overall, 91 (80%) and 22 (20%) patients were treated with MDT and the conventional approach, respectively. The median follow-up after PSMA-PET was 31 months. Patients who underwent MDT had a similar PFS compared to the conventional approach (p = 0.3). Individuals referred to MDT had significantly higher MFS and CRPC-FS compared to those who were treated with the conventional approach (73.5% and 94.7% vs. 30.5% and 79.5%; all p ≤ 0.001). In patients undergoing MDT, no significant differences were found for PFS and MFS according to N1 vs. M1a-b disease, while CRPC-FS estimates were significantly higher in patients with N1 vs. M1a-b (100% vs. 86.1%; p = 0.02). At multivariable analyses, age (HR = 0.96) and ADT during second line salvage treatment (HR = 0.5) were independent predictors of PFS; MDT (HR 0.27) was the only independent predictor of MFS (all p ≤ 0.04) Conclusion: Patients who underwent second-line PSMA-guided MDT experienced higher MFS and CRPC-FS compared to men who received conventional management.

EAU Biochemical Recurrence Risk Classification and PSA Kinetics Have No Value for Patient Selection in PSMA-Radioguided Surgery (PSMA-RGS) for Oligorecurrent Prostate Cancer.

OBJECTIVE: To assess the influence of biochemical recurrence (BCR) risk groups and PSA kinetics on the outcomes of radioguided surgery against prostate-specific membrane antigen (PSMA-RGS). Currently, neither BCR risk group nor PSA doubling time (PSA-DT), or PSA velocity (PSA-V) are actively assigned or relevant for counseling prior to PSMA-RGS. METHODS: We retrospectively analyzed PSMA-RGS cases for oligorecurrent prostate cancer between 2014 and 2023. BCR risk groups, PSA-DT, and PSA-V were analyzed as predictors for complete biochemical response (cBR, PSA < 0.2 ng/mL), BCR-free, and therapy-free survival (BCRFS, TFS). RESULTS: Of 374 included patients, only 21/374 (6%) and 201/374 (54%) were classified as low- and high-risk BCR (no group assignment possible in 152/374, 41%). A total of 13/21 (62%) patients with low- and 120/201 (60%) with high-risk BCR achieved cBR (p = 1.0). BCR classification was no predictor for BCRFS (HR:1.61, CI: 0.70-3.71, p = 0.3) or subsequent TFS (HR:1.07, CI: 0.46-2.47, p = 0.9). A total of 47/76 (62%) patients with PSA-DT ≤ 6 mo and 50/84 (60%) with PSA-DT > 6 mo achieved cBR (p = 0.4). PSA-DT was not associated with cBR (OR: 0.99, CI: 0.95-1.03, p = 0.5), BCRFS (HR: 1.00, CI: 0.97-1.03, p = 0.9), or TFS (HR: 1.02, CI: 0.99-1.04, p = 0.2). Consistent negative findings were recorded for PSA-V. CONCLUSIONS: The BCR risk groups and PSA kinetics do not predict the oncological success of PSMA-RGS performed at low absolute PSA values. Indolent low-risk BCR is rarely treated by PSMA-RGS.

Node Oligorecurrence in Prostate Cancer: A Challenge.

Within the oligometastatic state, oligorecurrent lymph node disease in prostate cancer represents an interesting clinical entity characterized by a relatively indolent biology that makes it unique: it can be treated radically, and its treatment is usually associated with a long period of control and excellent survival. Additionally, it is an emergent situation that we are facing more frequently mainly due to (a) the incorporation into clinical practice of the PSMA-PET that provides strikingly increased superior images in comparison to conventional imaging, with higher sensitivity and specificity; (b) the higher detection rates of bone and node disease with extremely low levels of PSA; and (c) the availability of high-precision technology in radiotherapy treatments with the incorporation of stereotaxic body radiotherapy (SBRT) or stereotaxic ablative radiotherapy (SABR) technology that allows the safe administration of high doses of radiation in a very limited number of fractions with low toxicity and excellent tolerance. This approach of new image-guided patient management is compelling for doctors and patients since it can potentially contribute to improving the clinical outcome. In this work, we discuss the available evidence, areas of debate, and potential future directions concerning the utilization of new imaging-guided SBRT for the treatment of nodal recurrence in prostate cancer.

Radiotherapy in Oligometastatic, Oligorecurrent and Oligoprogressive Prostate Cancer: A Mini-Review.

Globally, prostate cancer is one of the most common malignancies affecting men. With the advent of advanced molecular imaging, an increasing number of men are found to have oligometastatic disease (OD) either at primary diagnosis or at the time of biochemical failure. No strict definition exists for OD, with historical and ongoing studies utilizing diverse criteria. There is mounting evidence from many different malignancies that patients with OD have improved outcomes compared to their widely metastatic counterparts. As such, treatment intensification of those with OD or oligoprogressive disease has become an area of intense interest and study. This article will review the biology, evidence and controversy behind the treatment of de novo oligometastatic, oligorecurrent and oligoprogressive prostate cancer.

Salvage radiotherapy in patients affected by oligorecurrent pelvic nodal prostate cancer.

PURPOSE: Metastasis-directed therapy (MDT) is an investigational treatment option in patients with oligorecurrent prostate cancer (PCa). The aim of this retrospective study is to report oncologic outcome and toxicity of elective nodal radiotherapy (ENRT) in PCa patients affected by pelvic nodal oligorecurrence. METHODS: 41 consecutive patients were treated with salvage radiotherapy. At biochemical recurrence after primary treatment, oligorecurrent disease was detected by positron emission tomography (PET) in 94% of the patients. Image-guided intensity modulated radiation therapy (IMRT) was delivered using tomotherapy. 83% of the patients received androgen deprivation therapy (ADT) in combination with ENRT. Survival analysis was performed with Kaplan-Meier method, log-rank test was used to analyze associations between survival end-points and clinical parameters. Multivariate analysis was performed using Cox proportional hazards regression models. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. RESULTS: The median at follow-up was 33.6 months. At 3 years, overall survival (OS), cancer-specific survival (CSS), and biochemical progression-free survival (b-PFS) were 89%, 92%, and 53%, respectively. At univariate analysis, all survival end-points were correlated with the number of positive pelvic lymph nodes at oligorecurrence (≤ 3 vs > 3). Biochemical-PFS was correlated with PSA (p = 0.034) and PSA doubling time (p = 0.004) at oligorecurrence. At multivariate analysis, no independent variable was statistically significant. No patient experienced grade ≥ 2 late toxicity after radiotherapy. CONCLUSIONS: The number of metastatic lymph nodes and PSA doubling time seems to be important prognostic factors in the pelvic oligorecurrent setting. Salvage radiotherapy combined with short-course ADT might be a valid treatment strategy.

Oncological Outcomes of Metastasis-Directed Therapy in Oligorecurrent Prostate Cancer Patients Following Radical Prostatectomy.

Several retrospective and a few prospective studies have shown that metastasis-directed therapy (MDT) could delay clinical progression and postpone the initiation of systemic treatment in oligorecurrent prostate cancer (PCa) patients. However, these endpoints are strongly influenced by variables such as concomitant use of androgen deprivation therapy (ADT) and follow-up imaging protocols. The aim of this manuscript was to assess palliative ADT- and metastatic castration-resistant prostate cancer (mCRPC)-free survival as long-term oncological outcomes in oligorecurrent PCa treated by MDT. We retrospectively identified consecutive post-prostatectomy oligorecurrent PCa patients treated by MDT (salvage lymphadenectomy, radiotherapy, or metastasectomy) at our tertiary referral center. Patients were eligible for inclusion if they developed recurrence following radical prostatectomy, had ≤5 metastatic lesions on imaging and had a serum testosterone >50 ng/dL or a testosterone suppression therapy-free interval of >2 years prior to the first MDT as an assumption of recovered serum testosterone (if no testosterone measurement available). Patients with castration-resistant or synchronous oligometastatic PCa at the time of first MDT were excluded. Repeated MDTs were allowed, as well as a period of concomitant ADT. Kaplan-Meier analyses were performed to assess palliative ADT-free and mCRPC-free survival. We identified 191 eligible patients who underwent MDT. Median follow-up from first MDT until last follow-up or death was 45 months (IQR 27-70; mean 51 months). Estimated median palliative-ADT free survival was 66 months (95% CI 58-164) and estimated median mCRPC-free survival was not reached (mean 117 months, 95% CI 103-132). In total, 314 MDTs were performed and 25 patients (13%) received ≥3 MDTs. This study demonstrated that (repeated) MDT is feasible and holds promise in terms of palliative ADT-free and mCRPC-free survival for patients with oligorecurrent PCa. However, these findings should be confirmed in prospective randomized controlled trials.

Exploring All Avenues for Radiotherapy in Oligorecurrent Prostate Cancer Disease Limited to Lymph Nodes: A Systematic Review of the Role of Stereotactic Body Radiotherapy.

CONTEXT: Stereotactic body radiotherapy (SBRT) is emerging as a treatment option in patients affected by oligorecurrent prostate cancer disease limited to lymph nodes, a subgroup of patients who would otherwise be treated only with androgen deprivation therapy (ADT). OBJECTIVE: To perform a systematic review of SBRT for oligorecurrent prostate cancer limited to lymph nodes. EVIDENCE ACQUISITION: We performed a systematic review of PubMed/Medline in October 2016 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). We searched for studies reporting on biochemical or clinical progression and/or toxicity or complications of SBRT. Reports were excluded if these end points could not be ascertained or separately analyzed, or if insufficient details were provided. EVIDENCE OF SYNTHESIS: A total of 363 patients from nine studies were collected. Of these patients, 211 were treated with SBRT for a total of 270 lymph nodes. With an alpha-beta ratio of 3 Gy, the biologically effective dose in fractionated SBRT was >100 Gy in all studies (range, 88-216 Gy). With a median follow-up of 19.23 mo, local control was achieved in 98.1% of patients. Median progression-free survival (defined as biochemical and/or radiological progression) was 22.5 mo (range, 11-30 mo). Information about ADT during SBRT was available in 281 patients, of whom 114 (40.5%) were on ADT during SBRT, and the duration of hormone therapy ranged from 1 to 17.5 mo. Median ADT-free survival was 32.8 mo (range, 25-44 mo). About toxicity, Common Terminology Criteria for Adverse Events toxicity scale was most used. Acute and/or late grade ≥2 toxicity was reported in only 5.6% of patients, and no patient developed grade 4 toxicity. CONCLUSIONS: SBRT seems to be promising in lymph node oligorecurrent prostate cancer, although there is a weak level of evidence to support such investigational treatment, which is currently based on retrospective studies of single-institution or pooled experiences. ADT-free survival is an interesting end point, which needs to be investigated. PATIENT SUMMARY: We performed a systematic review to assess outcomes and toxicity of stereotactic body radiotherapy (SBRT) for patients affected by oligorecurrent prostate cancer limited to lymph nodes. We concluded that SBRT is a promising therapy in this setting, but it needs to be validated in randomized controlled trials.