Recent Advances in the Management of Hormone-Sensitive Oligometastatic Prostate Cancer

Figures & data

Table 1 Comparison Between Conventional and Next-Generation Imaging Methods in the Setting of OMPC

Type	Imaging Method	Strengths	Limitations
Conventional	Contrast-enhanced thoraco-abdomino-pelvic CT	> Allows for whole-body imaging^Citation21 > Widely available and affordable^Citation21	> Poor sensitivity and specificity for detection of LN mets (sensitivity < 40%)^Citation16,Citation18 > Suboptimal for detection of bone mets^Citation16,Citation21
	^99mTc-MDP bone scintigraphy	> Consistency for classification of M1 vs M0 disease^Citation21 > Most widely used method to detect BMs^Citation21 > Widely available and affordable^Citation17,Citation21	> Misses metastatic lesions in bone marrow^Citation21
Next generation	Fluciclovine (^18F)-PET	> As good as choline-PET^Citation12 > Identify both bony and soft tissue lesions^Citation12	> Accuracy depends on PSA levels^Citation12
	^18F/^11C-choline PET/CT	> Good specificity (92–95%) in LN mets^Citation77,Citation78	> LNs: Modest sensitivity in detecting LN mets (49.2–62%)^Citation12 > High false positive rates with reactive LNs^Citation12 > Reduced sensitivity with low PSA values^Citation12
	^68Ga-PSMA PET/CT	> Superior detection rates compared to other PET tracers^Citation12 > Able to identify small lesions at low PSA values^Citation12	> High false negative rates at low PSA values^Citation12 > Additional studies are needed to confirm results
	WB-MRI	> High sensitivity and specificity (>98%)^Citation12 > High inter-observer agreement^Citation21,Citation22 > No exposure to ionizing radiations^Citation11	> Long scanning time, inter-scanner variability, susceptibility to motion and other artefacts, high costs^Citation17 > Not widely used at present^Citation12

Abbreviations: 11C, carbon 11; 18F-NaF, 18F-sodium fluoride; 99mTc-MDP, technetium medronic acid; CT, computed tomography; LN, lymph node; met, metastasis; MRI, magnetic resonance imaging; PET, positron emission tomography; PSMA, prostate-specific membrane antigen.

Table 2 Summary of Some of the Most Promising New Target Therapies Emerging Either in Combination with or as an ADT Substitute in the Treatment of Hormone-Sensitive Oligometastatic Prostate Cancer

Drug(s)	Clinical Trials	Phase	Start-End Date	Status	N	Benefits	Limitations
Docetaxel	GETUG-AFU 15^Citation30 (Docetaxel + ADT) NCT00104715	III	2004–2011	Completed	385	> Improvement of b-PFS, c-PFS and PSA response	> No OS benefit for both low- and high- volume disease
	CHARTEED^Citation31 (Docetaxel + ADT) NCT00309985	III	2006–2015	Active, not recruiting	790	> Benefit in OS in high-volume disease	> No OS benefit in low-volume disease
Abiraterone	STAMPEDE (arm G)^Citation33 (Abiraterone + Prednisone + ADT) NCT00268476	II–III	2005–2024	Recruiting	1003	> OS gain both in the low- and in the high-risk and in the low- and high- volume	> Cost-effectiveness (compared to Docetaxel) > Side effects (hypertension, hypokalemia, elevated liver enzymes levels) > Some patients had synchronous disease
Enzalutamide	ENZAMET^Citation34 (Enzalutamide + ADT) NCT02446405	III	2014–2023	Active, not recruiting	1125	> Improvement of 3-yr OS for metachronous patients in the whole cohort > Augmented efficacy for the low-volume subset	> No clear OS benefit among men receiving concurrent Docetaxel in high-volume disease > Some patients had synchronous disease
	ARCHES^Citation36,Citation37 (Enzalutamide + ADT) NCT02677896	III	2016–2018	Active, not recruiting	1150	> Reduced risk of metastatic progression or death in low-volume disease and/or prior Docetaxel	> The use of rPFS instead of the more widely used OS index > Some patients had synchronous disease
Apalutamide	TITAN^Citation35 (testosterone suppression + Apalutamide) NCT02489318	III	2015–2020	Active, not recruiting	1052	> Benefit across all subgroups of patients	> Small size of certain patients’ subgroups
Durvalumab	POSTCARD (SBRT ± Durvalumab) NCT03795207	II	2019–2024	Recruiting	96 (estimated)	> Expected enhancement of immune response	> Results expected by 2024
Radium-223	RROPE (EBRT + Radium-223) NCT03304418	II	2018–2022	Active, not recruiting	20	> Expected delay of ADT start	> Results expected by 2022
	RAVENS^Citation42 (SABR ± Radium-223) NCT04037358	II	2019–2024	Recruiting	64 (estimated)	> Expected aadvantage of combining SABR and Radium-223	> Results expected by 2024
^177Lu-PSMA	PILOT STUDY^Citation43	I–II	2018–2019	Completed	10	> Feasible and safe treatment modality in patients with low-volume	> Low-volume disease could lead to unfavourable radioligand distribution to the organs at risk > Small cohort*
	BULLSEYE^Citation44 (^177Lu-PSMA) NCT04443062	II	2020–2024	Recruiting	58 (estimated)	> Validation of results obtained in the pilot study	> Results expected by 2024

Notes: *Results refer to a previously published prospective pilot study⁴⁰.

Abbreviations: ADT, androgen deprivation therapy; b-PFS, biochemical progression-free survival; c-PFS, clinical progression-free survival; EBRT, external-beam RT; OS, overall survival; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; r-PFS, radiographic progression-free survival; RT, radiotherapy; SABR, stereotactic ablative RT; SBRT, stereotactic body RT.

Table 3 Summary of Some of the Most Promising Biomarkers for the Identification of the True Oligometastatic Patient. Strengths and Limitations for Each of the Described Analytes are Reported

Biomarker	Definition	Strengths	Limitations
Circulating Tumor Cells (CTCs)	Cancer cell clones originating from a tumor site	> real time monitoring of metastases mutational content > in exploratory studies outperformed PSA as prognostic factor for oncological outcomes at 6 months^Citation57,Citation58	> rarity in the bloodstream^Citation59,Citation60 > difficult isolation^Citation62
Circulating Tumor DNA (ctDNA)	Originates from apoptotic and necrotic cells and comprises both genomic and mitochondrial DNA	> plasma concentration highly related to both tumor size and clinical stage^Citation64 > short half-life, suitable agent for disease real-time monitoring	> challenging measurement^Citation65 > choice of the main source is controversial (plasma vs serum)^Citation65
Micro Ribo-Nucleic Acid (miRNA)	Short non-coding transcripts of 17–25 nucleotides, participating in gene regulation	> high stability in biological fluids > baseline expression associated with CTCs and 28-weeks PSA response^Citation70 > several studies available on their role in PCa^Citation72^–^Citation75	> function can be controversial in different cancers^Citation67^–^Citation69 > a strong signature needs to be validated yet > lacking of standard procedures for isolation and storage

Abbreviations: CTC, circulating tumor cell; ctDNA, circulating tumor DNA; DNA, deoxyribonucleic acid; miRNA, micro ribo-nucleic acid; PCa, prostate cancer; PMPC, polimetastatic prostate cancer; PSA, prostate specific antigen.

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