Oligometastatic & Oligoprogression Disease and Local Therapies in Prostate cancer

Abstract

Our understanding of metastatic disease is rapidly advancing with recent evidence supporting an oligometastatic state currently defined by patients having a limited (typically five or fewer) number of metastatic deposits. The optimal management of these patients is also shifting towards increased integration of local therapies with emerging evidence suggesting metastasis-directed therapy (MDT) can improve overall survival (OS). Additionally, the use of stereotactic ablative radiation therapy (SABR) within castration-sensitive oligometastatic prostate cancer (OPCa) cohorts appears to forestall the need to initiate systemic therapy which have unfavorable side effect profiles, such as androgen deprivation therapy (ADT), while itself being associated with little toxicity. Herein we review the literature surrounding the use of MDT in the treatment of OPCa by reviewing the evidence for its use within three subgroups: de novo synchronous, oligorecurrent, and oligoprogressive disease.

Definitions of oligometastatic PCa

Definitions of oligometastatic prostate cancer (OPCa) have, for the most part, centered on numerical classifications¹. This is both for its simplicity in selecting patients and additionally due to evidence of its association with oncologic outcomes^2,3. As such, the majority of both prospective and retrospective reports on outcomes following metastasis directed therapy (MDT) in OPCa include patients with less than 3–5 metastatic foci^4–18. While purely clinical definitions predominate at this time in the future biological definitions should complement and might even supplant clinical variables in the characterization of OPCa and improve the selection of which men to treat with MDT¹⁹.

Several subgroups exists within OPCa. De novo (synchronous) oligometastaic disease represents patients found to have metastatic disease at the time of initial diagnosis. Oligorecurrent (metachronous) disease are patients initially treated with definitive therapy to cure their malignancy who subsequently develop limited metastatic disease recurrence. Finally, oligoprogressive disease represents patients with known metastatic disease who exhibit few isolated areas of progression in a background of otherwise stable disease. The role of MDT will be discussed for all three subgroups defined here.

Rational for treatment of oligometastatic PCa

The oligometastatic hypothesis was born from two opposing views of metastatic disease. One, the Halstead theory, believed cancer to spread in an orderly anatomically driven manner. The other, termed the systemic hypothesis, believed metastasis to be a systemic process at diagnosis and primary tumors to be an early manifestation of this subclinical systemic micrometastasis. The two theories were resolved by Hellman and Weichselbaum who proposed metastasis represented a continuum of these two hypotheses spanning from those with few metastatic lesions to widespread disease²⁰ (Figure 1). Built into this hypothesis is the idea of an oligometastatic state that is along this continuum and represents disease with a limited number of metastatic deposits. A consequence of this hypothesis is that individuals with a limited number of lesions might have disease amenable to local consolidation and could therefore experience prolonged disease-free survival or even be cured with aggressive therapy^19,21.

Figure 1:

Spectrum of metastatic disease

As the number of metastatic lesions increases the role of local therapy has historically been less important, however local therapy in oligometastatic disease appears to improve oncologic outcomes

Initial positive prospective randomized evidence regarding the role of MDT in oligometastatic disease stems from two trials on the role of consolidative local therapy in de novo metastatic Non-Small Cell Lung Cancer (NSCLC). Gomez et al. randomized patients with three or fewer metastases without progression of disease following initial systemic therapy to receive either consolidative local therapy or continue with maintenance/observation^22,23. The trial was closed early after the enrollment of 49 patients due to a benefit in progression free survival (PFS) with local consolidative therapy. Subsequent analysis of long term outcomes with a median of 38.8 months of follow up demonstrated the use of local consolidative therapy also resulted in improved overall survival (OS) (41.2 months vs 17.0 months). A similarly designed trial by Iyengar et al also reproduced these results documenting an improvement in PFS following consolidation of metastatic disease in de novo metastatic NSCLC²⁴ and was also closed early following the reporting of results from Gomez et al.

Systemic therapy in metastatic disease

In general ADT is initiated in men with symptomatic metastases for palliation of painful bone metastases or obstructive urinary symptoms²⁵ in addition to men who develop asymptomatic metastatic disease seen on conventional imaging. However, despite this being accepted as standard of care there still remain many questions regarding initiation of ADT in men with asymptomatic recurrent metastases as early initiation may modestly improve PCa specific survival, but a large portion of patients will not need ADT and it does not consistently improve OS^26–28. Additionally, there still remains debate about whether intermittent ADT can be considered once initiated, though some evidence suggests superiority of continuous therapy²⁹. The most commonly used agents are depots of luteinizing hormone releasing hormone agonists/antagonists which work on the pituitary axis to decrease production of testosterone by the testicles. The addition of non steroidal antiandrogens, which typically act peripherally to block the androgen receptor appears to add a small (2%) survival benefit through maximum androgen blockade³⁰.

Several studies have also assessed the benefit of adding additional systemic agents in the setting of castration-sensitive low volume metastatic disease (Table 1). The CHAARTED trial randomized men with castration-sensitive OPCa to ADT +/− docetaxel and found an OS benefit (57.6 vs 44 months) with the addition of chemotherapy. The benefit was much more pronounced in those with high volume (presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis) compared to low volume disease³¹. STAMPEDE arm C also looked at a similar question randomizing men with high risk locally confined or metastatic castration-sensitive PCa (majority 61% metastatic) to ADT, ADT + docetaxel, ADT + zoledronic acid, or ADT + docetaxel + zoledronic acid. The addition of docetaxel improved OS from 71 months with ADT to 81 months while the addition of zoledronic acid did not appear to impact OS. This benefit held up when looking at the subgroup of patients with metastatic disease (Hazard ratio 0.78)³² and those with low versus high-volume metastatic disease³³.

Table 1:

Studies of systemic therapy in metastatic hormone-sensitive prostate cancer indicating benefit in oligometastatic patients

Study	Population	Low volume	De novo	Recurrent	Outcome
STAMPEDE arm C	HSPC randomized ADT +/− docetaxel	34%	Yes	Yes*	Median OS (81 vs 71 months)
STAMPEDE arm G	HSPC randomized ADT +/− abiraterone	Not reported	Yes	Yes*	3 year OS (83% vs 76%)
TITAN	Metastatic HSPC randomized ADT +/− apalutamide	38%	Yes	Yes	2 year OS (82.4% vs. 73.5%)
ENZAMET	Metastatic HSPC randomized ADT +/− enzalutamide	48%	Yes	Yes	3 year OS (80% vs 72%)

HSPC – hormone-sensitive prostate cancer; OS – overall survival;

^*- ≤5% of men enrolled.

There also appears to be a benefit to adding supracastrating drugs in the upfront setting in metastatic castration-sensitive PCa. LATITUTE randomized men with newly diagnosed metastatic castration-sensitive PCa to ADT +/− abiraterone and noted improved median OS (not reached vs 34.7 months) with the addition of abiraterone, although the benefit to low volume metastatic patients was not assessed directly³⁴. STAMPEDE arm G also tested this hypothesis in a cohort of men with locally advanced or metastatic disease (majority 52%) and also found a survival benefit with the addition of abiraterone (3 year OS 83% vs 76%)³⁵. A large benefit was seen in those with metastatic disease, however the results for non-metastatic disease were not mature enough at time of publication. Two other trials have also looked at other supracastrating drugs in metastatic castration-sensitive PCa. The TITAN trial randomized men to ADT +/− apalutamide and found improved OS at two years (82.4% vs. 73.5%) with apalutamide³⁶ and the ENZAMET trial randomized men to ADT +/− enzalutamide and also noted improved OS at 3 years (80% vs 72%) with the addition of enzalutamide³⁷. Both these trial showed improvements in both low- and high-volume metastatic disease. Finally, a subset of these trials also enrolled patients with recurrent disease and demonstrated OS benefit whether de novo or recurrent (Table 1).

Local therapy in synchronous oligometastatic PCa

There is emerging evidence a primary tumor site not only leads to metastasis by dissemination of cancer cells through the lymphatics and circulation, but functions to prime the metastatic site and cause proliferation through secretion of endocrine factors^38,39. Additionally, pre-clinical data suggested that metastatic cancer cells could cycle back to the primary tumor resulting in cancer cells more competent for generation of macroscopic metastases termed the self-seeding hypothesis^40,41. This led to the concept that treatment of the primary tumor, even in the setting of metastatic disease, could halt the formation of new metastatic lesions and stop progression of already present lesions, which was in part supported by several retrospective studies demonstrating improvements in prostate cancer specific survival and OS with this strategy^42–44.

Several prospective randomized trials have since attempted to answer this question. The HORRAD trial⁴⁵ enrolled patients with de novo metastatic PCa with bone metastases and randomized to ADT +/− RT to the prostate primary. RT dose was 70 Gy/35 fractions or 57.76Gy/ 19 fractions three times per week. Of note the target volume was prostate plus any sites of extraprostatic extension and regional lymph nodes were not included. In total 432 patients enrolled with a primary endpoint of OS that was found to be not significantly different between the two groups (median 45 months vs 43 months). However, time to PSA failure was modestly improved with RT (15 months vs 12 months). While the trial was negative for the primary endpoint, there was a trend towards improved OS in those with five or less lesions treated with RT, in line with the findings of retrospective reports that patients with the best prognosis benefited most from therapy^44,46,47.

The STAMPEDE trial arm H⁴⁸ similarly enrolled patients with de novo metastatic PCa and randomized them to ADT +/− RT. However, based on the results of HORRAD, prespecified subgroups of high (four or more bone metastases with at least one outside the vertebrae/pelvis or visceral metastases) or low metastatic burden disease were defined. RT was either 36 Gy/6 fractions once per week or 55 Gy/20 fractions. 2,061 patients were enrolled and no difference in the primary endpoint of OS was found (46 months vs 48 months). However, in patients with low metastatic burden, RT improved three year OS (81% vs 73%), which was not the case for those with high metastatic burden. Similarly, prostate cancer specific survival was improved in the low metastatic burden group treated with RT, but not in the high metastatic burden group.

MDT in oligorecurrent PCa

The most common and best studied subset of OPCa is oligorecurrent disease. The longer natural history of PCa has made assessment of outcomes such as OS difficult, however some studies such as SABR-COMET⁴⁹, which included 16% PCa patients, help us extrapolate the impact of MDT. SABR-COMET was a phase II trial that randomized patients with oligorecurrent disease and five or less metastases to standard of care palliative treatments or standard of care plus SABR (stereotactic ablative radiation therapy) to consolidate all sites of metastatic disease. The addition of SABR to standard of care therapies resulted in improvements in median PFS (12 months vs 6 months) as well as median OS (41 months vs 28 months) and led to the follow-up phase III trial in an attempt to definitively confirm these results⁵⁰.

The long natural history of metastatic PCa has also resulted in interest to use unique endpoints for the application of MDT. The standard of care systemic therapy for hormone-sensitive metastatic PCa is androgen deprivation therapy²⁷ (ADT), which is associated with decreases in quality of life⁵¹ and has resulted in an interest at using local therapies to forestall the initiation of ADT. STOMP⁵² (Table 2) was a prospective randomized trial designed to test whether MDT could prolong time to initiation of ADT in men with hormone-sensitive oligorecurrent PCa. Patients with ≤ 3 metastases were randomized to MDT (SABR or surgical resection) or observation with a primary endpoint of ADT free survival (ADT-FS). Following MDT ADT was initiated for symptomatic progression, progression of treated lesions, or progression to greater than 3 lesions, however the trial did allow those who recurred with three or fewer lesions to be treated with additional MDT. In total 62 (31 in each arm) men were enrolled and the majority were treated with SABR as the mode of MDT (25/31). With a median of three years follow-up, MDT, as compared to observation, improved median ADT-FS from 13 to 21 months and also improved the median time to PSA progression from 6 to 10 months while not causing decrements in quality-of-life (QoL). Several other studies have since reported similar outcomes. POPSTAR⁵³ was a single arm prospective trial which enrolled both castration-sensitive and castrate-resistant oligorecurrent OPCa with three or less lesions and treated them with SABR using primary endpoints of feasibility, of which 97% of patients completed treatment within the specified time, and tolerability, of which only one patient (3%) experienced a Common Terminology Criteria for Adverse Events (CTCAE) grade three or higher toxicity. In total 33 patients (22 of which were castration-sensitive) were enrolled and treated to 50 lesions. The 22 men with castration-sensitive disease were not treated with ADT and two year ADT-FS was 48%. The authors additionally reported distant progression free survival rates of 58% and 39% and one and two years as well as local progression free survival of 97% and 93% at one and two years. The TRANSFORM trial⁵⁴ was also a prospective single arm study that enrolled oligorecurrent OPCa with five or less metastatic lesions treated with MDT with a primary endpoint of the proportion of patients not requiring treatment escalation at two years. In total 199 patients were treated with SABR and in those not treated with ADT 58.1% of patients were free of treatment escalation.

Table 2:

Prospective trials in oligometastatic prostate cancer

Study	Population	Outcome
Palma et al.	Oligorecurrent disease (≤ 5 metastases) Randomized SOC palliation +/− MDT	Median OS (41 vs 28 months)
		Median PFS (12 vs 6 months)
Ost et al.	Oligorecurrent HSPC (≤ 3 metastases), No ADT, Randomized MDT vs observation	Median ADT-FS (21 vs 13 months)
Siva et al.	Oligorecurrent HSPC and CRPC (≤ 3 metastases), Single arm SABR, No ADT for HSPC	One (58%) and two year (39%) DPFS
		Two year ADT-FS (48%)
Kneebone et al.	Oligorecurrent HSPC (≤ 3 metastases), Single arm SABR, PSMA scan used, No ADT	Median bDFS (11 months)
Bowden et al.	Oligorecurrent (≤ 5 metastases), majority HSPC; single arm SABR, no ADT for HSPC	Two year FFTE (51.7%)
ORIOLE	Oligorecurrent HSPC (≤ 3 metastases), Randomized SABR vs observation; No ADT	Pending
Boeve et al.	De novo metastatic PCa randomized to ADT +/− RT to prostate primary	Median OS (45 vs 43 months)
		Trend to improved OS with < 5 lesions
Parker et al	De novo metastatic PCa randomized to ADT +/− RT to prostate primary	Median OS (46 vs 48 months)
		Three year OS improved in low (81 vs 73%), but not high volume disease*

NSCLC – Non small cell lung cancer; LC – local consolidation; chemo – chemotherapy, OS – overall survival; PFS – progression free survival; MDT – metastasis directed therapy; SOC – standard of care; bDFS – biochemical disease free survival, FFTE – freedom from treatment escalation

^*High volume defined as four or more bone metastases with at least one outside the vertebrae/pelvis or visceral metastases

Advancements in molecular imaging modalities like prostate specific membrane antigen (PSMA)-targeted radiotracers has allowed for detection of recurrent disease at earlier time points compared to traditionally used conventional imaging techniques thus opening additional avenues for the integration of MDT in OPCa^55–58. Kneebone et al.⁵⁹ utilized PSMA positron emission tomography (PET) to stage a prospective cohort of castration-sensitive oligorecurrent PCa prior to treatment with MDT. Similar to the prior mentioned studies no patients received concurrent ADT and the primary endpoint was biochemical failure, which was defined as a PSA increase of 0.2 ng/mL above nadir following therapy. In total 57 patients were enrolled and treated to 73 lesions. The median time to biochemical failure was 11 months and the one- and two-year freedom from biochemical failure of 46% and 16%, respectively. The only factor that was associated with longer biochemical disease free survival was a pre-MDT PSA value less than 2 indicating intervention at earlier time points is preferable and underpinning the importance of integrating molecular imaging into the management of these individuals.

MDT in oligoprogressive disease

Oligoprogressive disease represents growth of few lesions in a background of otherwise controlled metastatic disease. The use of MDT in oligoprogressive disease represents an area of recent interest in light of evolving and improving systemic therapies such as targeted agents and immunotherapies that can often lead to long periods of disease control. The goal of MDT in these instances is to sterilize resistant cancer cell clones and thereby allow continuation of the systemic agent.

Several retrospective cohorts, all in castrate-resistant disease, have examined the feasibility and efficacy of such an approach. Berghen et al⁶⁰ reported on a cohort of 30 patients with castrate resistant PCa who experienced progression of three or fewer metastatic sites who maintained the same systemic therapy at time of MDT. With median follow up of 18 months the median time to next intervention was 10 months and the median PFS was also 10 months. Triggiani et al⁶¹ is the largest reported cohort of oligoprogressive castrate-resistant PCa and included 41 patients and 70 oligoprogressive lesions. At a median follow-up of 24 months, the one and two year distant progression free survival was 43.2% and 21.6%, respectively with median distant progression free survival of 11 months. Ten patients had oligoprogressive disease following SABR and were again treated with MDT. The median time to starting a new advanced systemic therapy in this cohort was 22 months. Yoshida et al⁶² reported on a cohort of 23 patients undergoing MDT for oligoprogressive castrate resistant PCa, however these patients were staged using whole body diffusion weighted magnetic resonance imaging. The median time to PSA progression, defined as PSA nadir + 2 ng/mL, was 8.7 months. Tumor diffusion coefficient appeared to be significantly associated with the risk of PSA failure. Deek et al reported on a cohort of 28 men with oligoprogressive CRPC and noted biochemical progression free survival and time to next intervention of 7.2 and 12.2 months respectively. The majority (67.9%) had a PSA response following therapy. Finally, Moyer et al reported on a cohort of 17 patients and documented distant progression free survival for 43% and 33% at one and two years, respectively. While retrospective evidence regarding the utility of MDT in oligoprogressive metastatic castrate resistant PCa is accumulating, prospective studies such as the FORCE trial ( NCT03556904), which is randomizing men with castrate-resistant OPCa to systemic therapy +/− RT will ultimately help answer whether this approach will be useful strategy in the future (Table 3).

Table 3:

Selected ongoing prospective trials in oligometastatic prostate cancer

Trial	Therapy
NCT03556904(FORCE)	SOC systemic therapy +/− RT in CRPC
NCT04037358(RAVENS)	SABR +/− Radium 223
NCT03940235	SABR + ADT
NCT03449719	SABR + abiraterone
NCT03477864	SABR + ipilimumab
NCT03795207	SABR + durvalumab
NCT03569241(PEACE V – STORM)	Oligocreccurent nodal disease treated with MDT and ADT +/− whole pelvis RT
SWOG 1802	Standard systemic therapy +/− prostatectomy or RT
GAP6	Molecular profiling

SOC – standard of care; SABR – stereotactic ablative radiation therapy, RT – radiation therapy, CRPC – castrate resistant prostate cancer, ADT – androgen deprivation therapy, MDT – metastasis directed therapy

Modes and patterns of failure

Specific guidelines for follow up after MDT are not well established, however can likely be extrapolated from those who undergo salvage RT for biochemical failure and men with metastatic disease treated with systemic therapy, which typically involves physical exam and PSA every 3–6 months with imaging as indicated for symptoms. We have classified modes of failure following MDT into broadly three classes: class I are men with long-term disease-free survival, class II are men with oligoprogressive disease who recur but in an isolated fashion with few lesions, and class III, which are men who have polymetastatic disease progression and development of numerous lesions (Figure 2).

Figure 2:

Classes of failure following metastasis directed therapy

Following metastasis directed therapy patients can be divided into those with long term control, oligoprogressors with limited number of recurrence sites, and polyprogressors with numerous sites of recurrence.

Getting an accurate sense of the breakdown for each class is difficult at this time due to small trials and limited follow up. However, in STOMP approximately 20% of patients had not progressed by PSA three years after treatment. Factors that appear to be associated with prolonged time to failure on multivariable analysis following MDT include castration-sensitive disease, the use of ADT, and smaller tumor volumes⁶. On the other hand, approximately 30% of patients in STOMP had polymetastatic progression following MDT requiring initiation of ADT. Patients with oligoprogressive disease represent an interesting subset of patients in that they can likely be re-treated with additional rounds of MDT. Decaestecker et al⁸ reported on a cohort of 50 men with oligorecurrent PCa treated with MDT alone, of which 75% of men with failure recurred with three or less lesions. A second and third course of SBRT was prescribed in 19 and 6 patients, respectively and was feasible with minimal toxicity and resulted in a median ADT free survival of 25 months. At this time, these modes of recurrence need to be better characterized, both clinically and molecularly. Little work has gone into describing these characteristics of oligometastaic disease, but some evidence does exist in colorectal cancer with liver metastases that combination of clinical and molecular factors can be used to group patients and predict outcomes following therapy, which can help towards decisions regarding who should optimally be treated with local therapies¹⁹.

Similarly, patterns of failure can also be informative in the quest to improve outcomes with MDT. Oligometastatic PCa appears to favor bone recurrence following MDT alone. In patients initially treated to an osseous site the vast majority of recurrences will occur in a new bony site^6,63. Similar patterns are seen with nodal lesions where many recurrences manifest as a new bone lesions or a combination of bone and other sites. This pattern informed the design of our institutions currently open and accruing RAVENS trial ( NCT04037358), enrolling patients with at least one bone metastasis to MDT with SABR +/− radium-223 in order to take advantage of the calcium mimetic properties of radium and possibly treat microscopic metastatic disease in bone sites.

Future directions

One of the most immediate needs within the realm of oligometastatic disease are more definitive confirmation of the results of recently published phase II trials by conducting randomized phase III trials, such as SABR-COMET −3 ( NCT03862911) and the phase III trial of local consolidative therapy in NSCLC following immunotherapy ( NCT03391869). Beyond confirmation of the efficacy of MDT future applications will need to find novel means to improve the outcomes for oligometastatic disease. One question that needs to be addressed is the biological definition of oligometastatic disease and what is the upper limit of lesions that can be consolidated and still lead to benefit. As discussed above, the current definition has empirically been determined to be 3–5 metastatic lesions up to this point, but whether patients with greater number of lesions will benefit from local consolidation is not clear. This question is being answered by the currently accruing SABR-COMET-10 ( NCT03721341), a phase III trial enrolling patient with oligorecurrent disease and 4 −10 metastatic lesions randomizing to standard of care systemic therapy +/− SABR to all metastatic deposits with a primary end point of OS⁵⁰.

Lastly, the Global Action Plan 6 (GAP6) being coordinated by the Movember Foundation is aiming to better study the biology of oligometastatic PCa by profiling metastatic sites to assess underlying biology and impact on oncologic outcomes following MDT.

An obvious next step in order to improve outcomes would be combination MDT and systemic therapy. Most work within castration-sensitive OPCa has attempted to use MDT to forestall the initiation of ADT and its associated side effects, however it is clear that for some men systemic therapy, such as ADT, might lead to improved outcomes and cure similar to the paradigm for men with high risk localized prostate cancer^64–67. Recent retrospective evidence suggests promising outcomes with this paradigm from a cohort of 28 men with castration-sensitive OPCa were treated with peri-RT ADT and MDT at Johns Hopkins Hospital. Median ADT treatment time after MDT in this group was 4.3 months and all had recovery of testosterone following treatment. At last follow-up (median, 33.5 months) 24-month biochemical progression free survival was 77% and at 24 months only 18% had needed to restart ADT⁶. In addition, other non-ADT systemic therapies may also be useful in this disease space. Several trials are attempting to answer this question with a variety of systemic agents including combining SABR with traditional luteinizing hormone releasing hormone agonists/antagonists ( NCT03940235), abiraterone ( NCT03449719), ipilimumab ( NCT03477864), and durvalumab ( NCT03795207).

Other important questions include the optimal radiation therapy volume and sequencing with other treatments. Pelvic nodal recurrences are being studied by PEACE V - STORM, which randomizes patients to MDT and ADT +/− whole pelvis RT ( NCT03569241). At Johns Hopkins Hospital the total eradication therapy (TET) trials are enrolling patients with de novo OPCa and treating them with neoadjuvant chemohormonal therapy + radical prostatectomy +/− post operative RT followed by consolidation MDT to the oligomeastatic sites of disease. Similarly, SWOG 1802 is enrolling men with de novo oligometastatic disease and testing whether standard systemic therapy +/− prostatectomy or RT to the prostate primary results in improved outcomes.

Conclusions

There is growing evidence that local therapies improve outcomes by lengthening PFS and OS in patients with OPCa while being associated with minimal side effects. The ideal integration of local therapies such as MDT is yet to be determined, but there appears to be benefit to treating the primary tumor in de novo metastatic disease as well as consolidating all sites of metastases in OPCa. Future trials will help to answer how aggressive one should be in treating metastatic sites in regards to number and volume and will similarly answer whether MDT can be used to prolong time to initiation or delay change in systemic therapy.