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Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials - Beyond the Abstract

The management of metastatic disease with local therapies is a rapidly evolving paradigm. Historically, metastatic disease was viewed as a systemic disease state, and thus treated with systemic therapies alone. However, recent evidence has suggested metastasis represents a spectrum of disease typified on one end by a widely disseminated systemic process and on the other a localized discrete entity characterized by a few number of lesions.1 Those who present with a limited number of lesions, often defined as less than three to five, have been termed oligometastatic, which is a disease state postulated to behave biologically more akin to localized disease and less so a systemic process.1

An implication of an oligometastatic state, and an attenuated metastatic phenotype, is that local therapies to these lesions might result in durable disease control, forestalling of disease progression, and potentially cure.2 Indeed, a series of prospective trials of metastasis-directed therapy (MDT) confirmed the efficacy of local therapies in oligometastatic castration-sensitive prostate cancer (omCSPC).3-8 With an initial median follow-up of 36-months the STOMP trial demonstrated MDT, as compared to observation, was able to prolong androgen deprivation (ADT) free survival by delaying disease progression,4 and similarly the ORIOLE trial, with a median follow-up of 18.8-months, showed the use of stereotactic ablative radiation (SABR) prolonged progression free survival (PFS) within omCSPC.7 Additional prospective studies detecting benefits in PFS and overall survival (OS) with local therapies in oligometastatic disease of other histologies adds further evidence to the benefit of MDT.9-11

While mounting evidence supports consolidative therapies in oligometastatic disease, who most benefit from MDT, and conversely who would benefit from more intensified strategies, is not known. Genetic biomarkers hold promise in this realm by possibly providing both prognostic and predictive information regarding therapeutic interventions. Within metastatic castration-resistant prostate cancer (mCRPC), alterations of pathways involved in tumor suppression, DNA double strand break repair, and the cell cycle correlate with poor outcomes,12-14 and emerging evidence suggests similar findings in mCSPC.15-17 However, little is known regarding the prognostic and predictive role of genetics within omCSPC, especially following MDT. Thus, the goal of our recently reported study in the Journal of Clinical Oncology18 was to report long-term outcomes, as well as assess the prognostic and potentially predictive role of a high-risk mutational signature, by pooling the only two prospective randomized trials, STOMP and ORIOLE, of MDT versus observation in omCSPC.

Patients enrolled on STOMP and ORIOLE randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) calculated using the Kaplan-Meier method and stratified by treatment group and trial. Next generation sequencing (NGS) was performed to validate a high-risk mutational signature defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The Cox proportional hazards model was used to assess the prognostic and predictive values of high-risk mutational status.

Clinical outcomes following metastasis-directed therapy

One hundred and sixteen patients in total were included for analysis – sixty-two from STOMP (31 assigned to observation and 31 to MDT) and 54 patients were from ORIOLE (18 assigned to observation and 36 to MDT). Median follow-up for the whole group was 52.5 months (range, 5.8 – 92.0 months), compared to 36 and 18.8 months on initial reporting of STOMP and ORIOLE.
PFS was prolonged with MDT in both trials  with median PFS for the pooled cohort was 11.9 months (95% CI, 8.0 – 18.3 months) with MDT compared to 5.9 months (95% CI, 3.2 – 7.1 months) with observation. This corresponded with a pooled HR of 0.44 (95% CI 0.29 – 0.66, p-value < 0.001).   Toxicity outcomes showed a toxicity-free rate of 91.8% the observation group vs 61.2% in the MDT group (p = 0.001). In the MDT arm, the majority of events were low grade (grade 1: 35.8%, grade 2: 3%). No grade 3 or higher toxicities were seen.

Genetic features and impact on outcomes

A total of 103 patients (89%) had tissue available for sequencing and 70 patients (60%) had tissue that successfully underwent somatic NGS. Clinical characteristics of these 70 patients were similar to the entire cohort. In this population, the incidence of a pathogenic mutation in a high-risk gene of interest was 24.3% (n = 17). The most frequently seen alteration was TP53 at 52.9% (n = 9), followed by BRCA2 at 23.5% (n = 4).

In the entire population, the median PFS in those without a high-risk mutation was 11.9 months (95% CI, 7.0 – 16.3 months) compared to 5.9 months (95% CI, 5.8 – 11.1 months) in those with a high-risk mutation (HR of 0.57: 95% CI, 0.32 – 1.03, p = 0.06). In those without a high-risk mutation, median rPFS was 22.6 months (95% CI, 18.1 – 36 months) compared to 10.0 months (95% CI, 5.9 – 17.1 months) in those with a high-risk mutation (HR of 0.38, 95% CI, 0.20 – 0.17, p <0.01). Alterations in genes for other oncogenic pathways such as PI3K and the cell cycle did not associate with PFS outcomes in this cohort.

We then stratified patients by both treatment arms and separately based upon high-risk mutational status to assess differential magnitude of benefit of MDT. Both those with and without a high-risk mutation benefited from MDT, however, a potential larger magnitude of benefit was experienced in those with a high-risk mutation. Tumors harboring a high-risk mutation treated with MDT experienced a median PFS of 7.5 months (95% CI, 5.9 months – NR) compared to PFS of 2.8 months (95% CI, 2 months – NR) in those randomized to observation (HR of 0.05, 95% CI, 0.01 – 0.28, p < 0.01 1). In tumors without a high-risk mutation, median PFS in the MDT cohort was 13.4 months (95% CI, 7.0 – 36 months) compared to 7.0 months (95% CI, 4.0 – 15.4 months) in the observation cohort (HR of 0.42, 95% CI, 0.23 – 0.77, p = 0.01) with a p-interaction of 0.12. Differences in rPFS according to treatment were not seen when stratified by high-risk mutation status (high-risk mutation: HR 0.83, p = 0.74; no high-risk mutation: HR 0.82, p = 0.58, p-interaction: 0.40).

Within the MDT cohort alone the PFS was 13.4 months (95% CI, 7.0 – 36.0 months) in those without a high-risk mutation, compared to 7.5 months (95% CI, 5.9 months – NR) for those with a high-risk mutation (HR of 0.53, 95% CI 0.25 – 1.11, p = 0.09). Median rPFS following MDT was 25.3 months (95% CI, 17.0 months – NR) in those without a high-risk mutation, compared to 8.0 months (95% CI, 5.9 months – NR) in those with a high-risk mutation (HR of 0.43, 95% CI 0.20 – 0.95, p = 0.04).

Our study in the JCO (18) presents long-term outcomes and genomic predictors of response to MDT in omCSPC through a pooled analysis of the only two prospective randomized trials conducted: STOMP and ORIOLE. Herein we reported several important findings: 1) with long term follow up, MDT continues to be associated with benefits in PFS as compared to observation, 2) a high-risk mutational signature composed of pathogenic mutations in ATM, BRCA1/2, Rb1, or TP53 is prognostic for outcomes following MDT in omCSPC, and 3) the high-risk mutational signature described above also represents a potential predictive biomarker for differential response to MDT.

MDT is rapidly emerging as a therapy in the management of oligometastatic disease and long-term outcomes from this strategy are now being reported. Several other prospectively run trials of local consolidative therapy in oligometastatic disease, such as SABR-COMET19 and trials in lung cancer or colorectal cancer,10,20,21 have recently reported long term outcomes that demonstrate MDT remains associated with improvements in important disease specific outcomes. Here too we report that with long-term follow-up (median of 52.5 months) MDT remains associated with improvements in PFS in omCSPC compared to observation. Of note, when looking at long term follow up, PFS beyond four to five years was 15-20% in those treated with MDT, and thus a sizable proportion of patients will experience durable response to therapy. In men with biochemically relapsed prostate cancer, deferred ADT is an accepted treatment paradigm,22 however ADT with a LHRH agonist/antagonist is often considered standard of care in mCSPC, and recent evidence suggests the addition of androgen receptor signaling inhibitors also improves OS, thus raising the question of how to best integrate these therapies into a cohesive treatment paradigm with local therapies.23,24 While trials such as TITAN and LATITUDE demonstrated significant benefit to the addition of next generation antiandrogens, it is important to note the patient population enrolled in these studies, which skewed towards high volume de novo metastatic disease, represents a considerably different population, both in clinical and biological behavior than individuals with metachronous omCSPC enrolled on STOMP and ORIOLE. While more follow up is needed, the encouraging PFS results report here suggests that in well selected patients the use of MDT alone without systemic therapy can be a reasonable treatment option upfront in well-informed patients wishing to avoid potential side-effects of testosterone lowering drugs. However, future trials, which are planned or underway, will more rigorously study this question, and hopefully build upon both the clinical and biomarker findings reported here to provide a more definitive answer.

We noted the use of MDT to be associated with prolonged PFS, a composite endpoint of PSA and radiographic failure, over observation. In our overall cohort, MDT did not prolong rPFS, defined as development of a new lesion or death, over observation. There may be several reasons for this. First, patients in the observation arm of ORIOLE were allowed to cross over to MDT before development of new metastatic lesions potentially resulting in prolongation of rPFS in the observation arm. Second, in the ORIOLE trial patients with rapid PSA rise were often started on ADT prior to development of new metastases, thus potentially prolonging rPFS in the observation group. ORIOLE ablated lesions were based on conventional imaging and thus subclinical disease might have progressed in both arms given no ADT was used.  Finally, rPFS may not be different as also seen in the SABR-COMET trial,19 but many patients needed and did undergo subsequent rounds of MDT and this may ultimately result in a change in survival outcomes although we are still likely underpowered to observe this in out cohort.  However, it is encouraging that by using a genetic biomarker we can stratify patients who experience superior rPFS despite these confounding issues.  Future studies need to investigate whether MDT and this high-risk genetic biomarker can delay the time to development of new metastatic lesions.

In the continued quest for improved patient selection and personalization in oligometastatic disease,25,26 genetic biomarkers are likely to play a critical role.27-30 Emerging evidence within mCSPC suggests pathways of tumorigenesis including tumor suppressors, DNA repair proteins, cell cycle proteins, and developmental pathways are important in biological and clinical progression and can give insight into definitions of metastatic disease.15,17,31 We observed a high-risk mutational signature consisting of pathogenic alterations in ATM, BRCA1/2, Rb1, or TP53 is highly prognostic for outcomes in omCSPC regardless of treatment group. Utilizing this information, the high-risk mutational signature was able to provide additional stratification of outcomes: those treated with MDT without a high-risk mutation experienced the best outcomes with median PFS of 13.4 months while in the observation group those with a high-risk mutation experienced the poorest outcomes with median PFS of 2.8 months. This suggests individuals with omCSPC without a high-risk mutation might initially be treated with MDT alone and conversely highlights the need for novel treatment paradigms in those with a high-risk mutation who experience inferior outcomes. These novel paradigms are as of yet undefined, but may include SABR in combination with LHRH agonist/antagonists, androgen receptor signaling inhibitors (e.g., DART trial NCT04641078), radiopharmaceuticals (Radium – 223, e.g., RAVENS trial NCT04037358, Lutetium – 177),32 or other targeted agents. Moreover, in addition to its prognostic significance, the high-risk mutational signature also appeared to identify a differential response to treatment. Those with a high-risk mutation appeared to have a relatively larger benefit to MDT when compared to individuals without a high-risk mutation. Similar findings were noted with PSA doubling time such that the magnitude of benefit of MDT appeared larger in those with shorter doubling times. Taken together, these findings suggest those with aggressive disease also benefit from integration of MDT. However, despite this differential benefit, outcomes following MDT for individuals with a high-risk mutation still lagged, again underscoring the need for new treatment intensification strategies, such as combination with systemic therapies, to integrate MDT in this population. Future trials of treatment intensification should integrate these biomarkers to better understand their significance and role in treatment selection.

There are several limitations to this report. While these findings were evaluated in a cohort of patients randomized to MDT or observation, the prognostic and predictive role of a high-risk mutational signature was not a primary endpoint of these studies, and thus needs to be evaluated in future prospective trials. Additionally, sample size and small cohorts of some groups (i.e., high-risk mutation on observation) could have limited some analyses. However, these findings should still be of interest, especially given the unique population this represents – a cohort of patients randomized to MDT versus observation. With the reporting of these clinical results showing sustained responses to MDT alone, it is unlikely future trials will have randomization to an observation arm. Thus, this population likely represents the only opportunity to evaluate the role of such biomarkers.

In conclusion, long-term outcomes of the only two randomized trials suggest a sustained clinical benefit to MDT over observation in omCSPC. A high-risk mutational signature composed of alterations in ATM, BRCA1/2, Rb1, or TP53 appears to have prognostic and perhaps predictive value in this patient population suggesting genomic biomarkers should be evaluated in future studies to optimize patient selection.

Written by: Matthew P. Deek, MD1,2 Kim Van der Eecken, MD3 Piet Ost, MD, PhD4 Phuoc T. Tran, MD, PhD2,5,6,7

  1. Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University
  2. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
  3. Department of Pathology and Human Structure and Repair, University of Ghent, Ghent, Belgium
  4. Department of Radiation Oncology, Iridium Network, Antwerp, Belgium and Department of Human Structure and Repair, Ghent University, Ghent, Belgium
  5. Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
  6. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
  7. James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
Conflicts of Interest:
Piet Ost: Consultant for Bayer, Janssen, Curium; Research grant recipient from Varian, Bayer
Phuoc Tran: Consultant for Janssen-Taris Biomedical  and RefleXion, Personal fees from Noxopharm, Janssen-Taris Biomedical, Myovant and AstraZeneca; Holds a patent 9114158- Compounds and Methods of Use in Ablative Radiotherapy licensed to Natsar Pharm.

Funding: PTT was funded by an anonymous donor, Movember Foundation-Distinguished Gentlemen’s Ride-Prostate Cancer Foundation, Babara's Fund, National Capitol Cancer Research Fund and the NIH/NCI (U01CA212007, U01CA231776, and U54CA273956) and DoD (W81XWH-21-1-0296); and  the STOMP trial was supported by Kom op tegen Kanker, a Belgian non-profit organization.

References:

  1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1):8-10.
  2. Adson MA, van Heerden JA, Adson MH, Wagner JS, Ilstrup DM. Resection of hepatic metastases from colorectal cancer. Arch Surg. 1984;119(6):647-51.
  3. Kneebone A, Hruby G, Ainsworth H, Byrne K, Brown C, Guo L, et al. Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Detected via Prostate-specific Membrane Antigen Positron Emission Tomography. Eur Urol Oncol. 2018;1(6):531-7.
  4. Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol. 2018;36(5):446-53.
  5. Siva S, Bressel M, Murphy DG, Shaw M, Chander S, Violet J, et al. Stereotactic Abative Body Radiotherapy (SABR) for Oligometastatic Prostate Cancer: A Prospective Clinical Trial. Eur Urol. 2018;74(4):455-62.
  6. Tran PT, Deek MP, Phillips RM. Metastasis-Directed Therapy for Oligorecurrent Prostate Cancer-Not All That Glitters Is Gold-Reply. JAMA Oncol. 2020;6(10):1639.
  7. Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650-9.
  8. Glicksman RM, Metser U, Vines D, Valliant J, Liu Z, Chung PW, et al. Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis. Eur Urol. 2021;80(3):374-82.
  9. Gomez DR, Blumenschein GR, Jr., Lee JJ, Hernandez M, Ye R, Camidge DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672-82.
  10. Iyengar P, Wardak Z, Gerber DE, Tumati V, Ahn C, Hughes RS, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018;4(1):e173501.
  11. Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-8.
  12. Abida W, Armenia J, Gopalan A, Brennan R, Walsh M, Barron D, et al. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. JCO Precis Oncol. 2017;2017.
  13. Hamid AA, Gray KP, Shaw G, MacConaill LE, Evan C, Bernard B, et al. Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer. Eur Urol. 2019;76(1):89-97.
  14. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A. 2019;116(23):11428-36.
  15. Deek MP, Van der Eecken K, Phillips R, Parikh NR, Isaacsson Velho P, Lotan TL, et al. The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited. Eur Urol. 2021;80(5):632-40.
  16. Mateo J, Seed G, Bertan C, Rescigno P, Dolling D, Figueiredo I, et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J Clin Invest. 2020;130(4):1743-51.
  17. Stopsack KH, Nandakumar S, Wibmer AG, Haywood S, Weg ES, Barnett ES, et al. Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer. Clin Cancer Res. 2020;26(13):3230-8.
  18. Deek MP, Van der Eecken K, Sutera P, Deek RA, Fonteyne V, Mendes AA, et al. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials. J Clin Oncol. 2022:JCO2200644.
  19. Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020;38(25):2830-8.
  20. Gomez DR, Tang C, Zhang J, Blumenschein GR, Jr., Hernandez M, Lee JJ, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019;37(18):1558-65.
  21. Ruers T, Punt C, Van Coevorden F, Pierie J, Borel-Rinkes I, Ledermann JA, et al. Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann Oncol. 2012;23(10):2619-26.
  22. Parker C, Castro E, Fizazi K, Heidenreich A, Ost P, Procopio G, et al. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(9):1119-34.
  23. Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019;381(1):13-24.
  24. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-60.
  25. Onderdonk BE, Gutiontov SI, Chmura SJ. The Evolution (and Future) of Stereotactic Body Radiotherapy in the Treatment of Oligometastatic Disease. Hematol Oncol Clin North Am. 2020;34(1):307-20.
  26. Pitroda SP, Weichselbaum RR. Integrated molecular and clinical staging defines the spectrum of metastatic cancer. Nat Rev Clin Oncol. 2019;16(9):581-8.
  27. Lussier YA, Khodarev NN, Regan K, Corbin K, Li H, Ganai S, et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS One. 2012;7(12):e50141.
  28. Lussier YA, Xing HR, Salama JK, Khodarev NN, Huang Y, Zhang Q, et al. MicroRNA expression characterizes oligometastasis(es). PLoS One. 2011;6(12):e28650.
  29. Pitroda SP, Khodarev NN, Huang L, Uppal A, Wightman SC, Ganai S, et al. Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis. Nat Commun. 2018;9(1):1793.
  30. Wong AC, Watson SP, Pitroda SP, Son CH, Das LC, Stack ME, et al. Clinical and molecular markers of long-term survival after oligometastasis-directed stereotactic body radiotherapy (SBRT). Cancer. 2016;122(14):2242-50.
  31. Van der Eecken K, Vanwelkenhuyzen J, Deek MP, Tran PT, Warner E, Wyatt AW, et al. Tissue- and Blood-derived Genomic Biomarkers for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review. Eur Urol Oncol. 2021;4(6):914-23.
  32. Hasan H, Deek MP, Phillips R, Hobbs RF, Malek R, Radwan N, et al. A phase II randomized trial of RAdium-223 dichloride and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS). BMC Cancer. 2020;20(1):492.

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