Library Resources

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS): A Potpourri of Information

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The January 2026 issue of Neurourology and Urodynamics (45: 9-76) contains the individual committee reports. from a global consensus meeting on Interstitial Cystitis /Bladder Pain Syndrome (IC/BPS), which was held in April 2025 in Winston-Salem, NC, just prior to the annual meeting of the American Urological Association. The impetus to hold this meeting was initiated with NIDDK program officers and key opinion leaders representing all major societies dealing with this disorder to try to find commonality in defining best practices for assessment and management.

Continued Focus on Bone Metastases to Improve Outcomes and Patient Care in Prostate Cancer

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Bone metastases are at the center of advanced prostate cancer care, with over 90% of patients with metastatic prostate cancer expected to have bone involvement.1 These metastatic sites can be a cause of substantial pain in our patients, and they have been a key target for therapeutic development. Bone targeted agents have been developed to reduce fragility fractures and skeletal related events, and are now an integral part of the care of patients with metastatic prostate cancer,2,3 Further, radium-223 is a bone-targeted radiopharmaceutical that not only reduces pain burden but was also the first radiopharmaceutical to prolong survival in patients with prostate cancer. Over time prostate cancer studies have investigated the prognostic implications of bone metastases in comparison with other sites and helped us gain insight into the potential future progression or responsiveness of disease.4 Bone metastases have played a large role in the clinical care of patients with prostate cancer, and our approach to them continues to evolve.
  • Written by: Alicia K. Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
  • References:
    1. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000;31(5):578-83. doi: 10.1053/hp.2000.6698
    2. Saylor PJ, Rumble RB, Tagawa S, et al. Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline. Journal of Clinical Oncology 2020;38(15):1736-43. doi: 10.1200/jco.19.03148
    3. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-23. doi: 10.1056/NEJMoa1213755
    4. Halabi S, Kelly WK, Ma H, et al. Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer. J Clin Oncol 2016;34(14):1652-9. doi: 10.1200/jco.2015.65.7270 [published Online First: 20160307]
    5. Edward M. Schaeffer SS, Nabil Adra, Yi An, Daniel Barocas, Rhonda Bitting, Alan Bryce, Brian Chapin, Heather H. Cheng, Anthony Victor D’Amico, Neil Desai, Tanya Dorff, James A. Eastham, Thomas A. Farrington, Xin Gao, Shilpa Gupta, Thomas Guzzo, Joseph E. Ippolito, Micahel R. Kuettel, Joshua Lang, Tamara Lotan, Rana R. McKay, Todd Morgan, George Netto, Julio M. Pow-Sang, Robert Reiter, Mack Roach, Tyler Robin, Stan Rosenfeld, Ahmad Shabsign, Daniel Spratt, Benjamin A. Teply, Jonathan Tward, Richard Valicenti, Jessica K Wong. NCCN Guidelines Version 2.2023 Prostate Cancer. 2023 July 17, 2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
    6. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet 2020;395(10231):1208-16. doi: 10.1016/s0140-6736(20)30314-7 [published Online First: 20200322]

New PET Imaging Tracers and Targets for the Staging Biochemically Recurrent Prostate Cancer

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In December 2020, Gallium 68 PSMA-11 (68Ga PSMA-11) was approved by the U.S. Food and Drug Administration (FDA) for the staging of prostate cancer patients with suspected recurrence based on elevated serum prostate-specific antigen (PSA) levels.1 This was shortly followed by the FDA approval of 18F-DCFPyL (PYLARIFY®) in May 2021 for the same indication.2
  • Written by: Rashid K. Sayyid, MD MSc, University of Southern California, Los Angeles, CA & Zachary Klaassen, MD, MSc, Wellstar MCG Health, Georgia Cancer Center, Augusta, GA
  • References:
    1. FDA Approves First PSMA-Targeted PET Imaging Drug for Men with Prostate Cancer. https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer. Accessed on December 12, 2024.
    2. FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer#:~:text=FDA%20approved%20the%20first%20PSMA,at%20two%20sites%20in%20California. Accessed on December 12, 2024.
    3. U.S. FDA Approves Blue Earth Diagnostics’ POSLUMA® (Flotufolastat F 18) Injection, First Radiohybrid PSMA-targeted PET Imaging Agent for Prostate Cancer. https://www.businesswire.com/news/home/20230530005180/en/U.S.-FDA-Approves-Blue-Earth-Diagnostics%E2%80%99-POSLUMA%C2%AE-Flotufolastat-F-18-Injection-First-Radiohybrid-PSMA-targeted-PET-Imaging-Agent-for-Prostate-Cancer. Access on December 13, 2024.
    4. Afshar-Oromieh A, da Cunha ML, Wagner J, et al. Performance of [68Ga]Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer after prostatectomy-a multi-centre evaluation of 2533 patients. Eur J Nucl Med Mol Imaging. 2021; 48(9):2925-34.
    5. Vlachostergios PJ, Niaz MJ, Sun M, et al. Prostate-Specific Membrane Antigen Uptake and Survival in Metastatic Castration-Resistant Prostate Cancer. Front Oncol. 2021; 11:630589.
    6. Huynh TT, van Dam EM, Sreekumar S, et al. Copper-67-Labeled Bombesin Peptide for Targeted Radionuclide Therapy of Prostate Cancer. Pharmaceuticals (Basel). 2022; 15(6):728.
    7. Tolvanen T, Kalliokoski K, Malaspina S, et al. Safety, Biodistribution, and Radiation Dosimetry of 18F-rhPSMA-7.3 in Healthy Adult Volunteers. J Nucl Med. 2021; 62(5):679-84.
    8. Wurzer A, Di Caro D, Schmidt A, et al. Radiohybrid ligands: a novel tracer concept exemplified by 18F- or 68Ga-labeled rhPSMA-inhibitors. J Nucl Med. 2020; 61(5):735-42.
    9. Wurzer A, Parzinger M, Konrad M, et al. Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereo configuration on pharmacokinetics. EJNMMI Res. 2020; 10(1):149.
    10. Wurzer A, Kunert J, Fischer s, et al. Synthesis and preclinical evaluation of 177Lu-labeled radiohybrid PSMA ligands (rhPSMAs) for endoradiotherapy of prostate cancer. J Nucl Med. 2022; 63(10):1489-95.
    11. Jani AB, Ravizzini GC, Gartrell BA, et al. Diagnostic Performance and Safety of 18F-rhPSMA-7.3 Positron Emission Tomography in Men With Suspected Prostate Cancer Recurrence: Results From a Phase 3, Prospective, Multicenter Study (SPOTLIGHT). J Urol. 2023; 210(2):299-311.
    12. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic Performance of 18F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase 3, Multicenter Study. Clin Cancer Res. 2021;27(13):3674-82.
    13. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer. JAMA Oncol. 2019; 5(6):856-63.
    14. Fleming MT, Hermsen R, Purysko AS, et al. True-Positive 18F-Flotufolastat Lesions in Patients with Prostate Cancer Recurrence with Baseline-Negative Conventional Imaging: Results from the Prospective, Phase 3, Multicenter SPOTLIGHT Study. J Nucl Med. 2024; 65(7):1080-6.
    15. Nordquist L, Lengyelova E, Saltzstein D, et al. COBRA: Assessment of safety and efficacy of 64Cu-SAR-bisPSMA in patients with biochemical recurrence of prostate cancer following definitive therapy. J Clin Oncol. 2024; 42:Number 16_suppl.
    16. Baratto L, Jadvar H, Iagaru A. Prostate Cancer Theranostics Targeting Gastrin-Releasing Peptide Receptors. Mol Imaging Biol. 2018; 20(4):501-9.
    17. Beer M, Montani M, Gerhardt J, et al. Profiling gastrin-releasing peptide receptor in prostate tissues: clinical implications and molecular correlates. Prostate. 2012; 72(3):318-25.
    18. Faviana P, Boldrini L, Erba PA, et al. Gastrin-Releasing Peptide Receptor in Low Grade Prostate Cancer: Can It Be a Better Predictor Than Prostate-Specific Membrane Antigen? Front Oncol. 2021; 11:650249.
    19. Mapelli P, Ghezzo S, Gajate AMS, et al. 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI in Recurrent Prostate Cancer: Diagnostic Performance and Association with Clinical and Histopathological Data. Cancers (Basel). 2022; 14(2):334.
    20. Kurth J, Krause B, Joksch M, et al. Intraindividual comparison of [68Ga]Ga-RM2 and [68Ga]Ga-PSMA PET/CT in patients with mCRPC in a theranostic setting. J Nucl Med. 2023; 64(Supplement 1):1089.
    21. Nordquist LT, Lengyelova E, Iagaru A, et al. SABRE: Assessment of safety and efficacy of 64Cu-SAR-BBN in patients with PSMA-negative biochemical recurrent prostate cancer. J Clin Oncol. 2024; 42:Number 4_suppl.

New PET Imaging Tracers for the Primary Staging of Unfavorable Intermediate and High-Risk Prostate Cancer

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Introduction

In December 2020, Gallium 68 PSMA-11 (68Ga PSMA-11) was approved by the U.S. Food and Drug Administration (FDA) for the initial staging of prostate cancer patients at high risk of metastases,1 and this was shortly followed by the FDA approval of 18F-DCFPyL (PYLARIFY®) in May 2021.2 These positron emission tomography (PET) imaging modalities have since been endorsed by numerous international guidelines and have been widely adopted in clinical practice for the primary staging of unfavorable intermediate- and high-risk prostate cancer patients.

Bipolar Androgen Therapy: Rationale, Candidate Patients, and Latest Evidence for mCRPC Patients

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Androgen receptor inhibition remains the mainstay treatment of advanced prostate cancer. However, therapeutic resistance to androgen receptor inhibition is almost universal. Prostate cancer cells can develop resistance to androgen ablation through an adaptive marked upregulation of androgen receptors over time in response to low-androgen conditions. This upregulation can make these cells vulnerable to supraphysiologic testosterone exposure. Bipolar androgen therapy (BAT) has been proposed as an approach to overcome androgen receptor therapeutic resistance. Rapid cycling between polar extremes of supraphysiologic and near-castrate serum testosterone in asymptomatic men with metastatic castrate-resistant prostate cancer (mCRPC) has been proven safe and effective. There are five unique features to BAT:

IBCN 2024: Highlights

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The IBCN 2024 occurred in Bern, Switzerland, from September 19th to September 21st, 2024. The event featured a keynote lecture on Friday morning by Niko Beerenwinkel, Professor of Computational Biology ETH Zurich, on “Inferring Tumor Evolution from Single-Cell Data.” Dr. Beerenwinkel discussed the evolutionary process of cancer, which can be visualized through tumor phylogeny and cell lineage trees. Phylogenetic tree reconstruction can be performed by using single-cell sequencing from a tumor biopsy. This is a powerful tool applicable to bladder cancer that can help identify evolutionary biomarkers and patient subgroups with similar tumor evolution patterns.
  • Written by: Amanda Myers, MD, Urologic Oncology Fellow, University of Texas, MD Anderson Cancer Center, Houston, TX

Promoting BCAN’s 2025 Walks to End Bladder Cancer: Join the Fight Against Bladder Cancer

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Bladder cancer is one of the most common cancers in the United States, impacting approximately 83,000 Americans each year. It is a disease that shocks not only the individuals diagnosed but also their families, caregivers, and communities. For healthcare providers, medical researchers, and doctors, bladder cancer deserves significant attention due to its prevalence and the urgent need for better treatments and outcomes.

Highlights from ESMO’24 Presidential Symposium: Bladder Cancer in the Forefront

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In Barcelona this past September, we witnessed another major milestone in the rapid development of bladder cancer therapeutics. The practice changing data of the phase III NIAGARA trial showed that perioperative (neoadjuvant and adjuvant) durvalumab (anti-PD-L1) plus neoadjuvant gemcitabine/cisplatin improved both event-free survival (EFS) and overall survival (OS) vs chemotherapy alone, without jeopardizing the ability of patients to pursue curative-intent radical cystectomy.
  • Written by: Petros Grivas, MD, PhD, Associate Professor, Department of Medicine, Division of Oncology, Clinical Director, Genitourinary Cancers Program, Fred Hutch Cancer Center, University of Washington Medicine, Seattle, WA

Systemic Treatment in Bladder Cancer State of Art in 2024 and Challenges in Morocco

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l. BACKGROUND

Bladder cancer treatment has evolved from traditional surgery and chemotherapy to include immunotherapy, targeted therapies, and antibody drug conjugates. These therapeutic innovations, along with advances in surgical techniques and multimodal approaches, continue to reshape clinical practice and improve outcomes for bladder cancer patients. However, the high cost of these treatments poses a significant challenge in low-income countries such as Morocco.
  • Written by: Karima Oualla, MD, MSc, Mehdi Alem, MD, and Nawfel Mellas, MD

IBCG Retreat 2024

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The annual International Bladder Cancer Group (IBCG) Retreat was held in Houston, Texas, from August 23-24, 2024. Co-chaired by Drs. Shilpa Gupta, Roger Li, and Patrick Hensley, the event brought together over 90 international bladder cancer clinicians, scientists, and patient advocates, with IBCG representation spanning five continents.
  • Written by: Kelly Bree, MD, and Niyati Lobo, MD

Treatment Intensification for High-Risk Biochemically Recurrent M0 HSPC: EMBARK in the PSMA PET Era and Ongoing Trials

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Introduction

In November 2023, the United States Food and Drug Administration (FDA) approved enzalutamide, with or without concurrent leuprolide therapy, for conventional imaging-defined non-metastatic hormone-sensitive prostate cancer (M0 HSPC) patients with biochemical recurrence at high risk for metastasis.1 This drug approval followed the publication of the EMBARK trial, a randomized phase III trial of biochemically recurrent patients who had high-risk disease, defined by a PSA doubling time (PSADT) ≤9 months and a PSA level of ≥2 ng/mL above nadir following radiation therapy or ≥1 ng/mL after radical prostatectomy, with or without postoperative radiation therapy. Patients in this trial were randomized 1:1:1 to combination enzalutamide + leuprolide, leuprolide monotherapy, or enzalutamide monotherapy. This trial met its primary endpoint of improved 5-year metastasis-free survival with the combination of enzalutamide + leuprolide (87.3% versus 71.4% for leuprolide alone; HR 0.42, p < 0.001). Similarly, enzalutamide monotherapy was associated with superior 5-year metastasis-free survival rates, compared to leuprolide monotherapy (80% versus 71%; HR 0.63, p = 0.005).2

However, the ‘elephant in the room’ is that patients in the EMBARK trial, who were enrolled between January 2015 and August 2018, were staged using conventional imaging, as opposed to prostate-specific membrane antigen (PSMA) positron emission tomography (PET), which has emerged as a standard of care imaging modality for biochemically recurrent patients, owing to its improved sensitivity for detecting metastatic disease in this setting.3,4 As such, many experts in the field have suggested that there is a ‘discord’ between the study design of EMBARK and contemporary practice.

In this Center of Excellence article, we will discuss the results of the EMBARK trial within the context of contemporary PSMA PET imaging and discuss ongoing trials of biochemically recurrent M0 HSPC patients.

PSMA PET Findings in an ‘EMBARK-like’ Cohort

Had trial participants in EMBARK undergone a PSMA PET at study inclusion, what would a PSMA PET scan have shown? At ASCO 2023, Armstrong et al. presented the results of a post-hoc, retrospective analysis of four prospective studies of PSMA PET conducted at UCLA between 2016 and 2021 that included high-risk biochemically recurrent prostate cancer patients who would have met the EMBARK trial eligibility criteria. The study cohort included 183 patients, with a median time from primary therapy to PSMA PET of 39 months. The median serum PSA level at PSMA PET was 2.8 ng/mL, and the median PSADT was 3.6 months.

Overall, 85% of patients were PSMA PET positive, with an average of 3.9 lesions per case. Pelvic nodal disease was present in 56% of patients, and 30% had evidence of extra-pelvic nodal disease. Bone lesions were present in 26% of patients, and 4.4% of patients had visceral metastases:

figure-1-HSPC-PSMA-PET.jpg

Overall, 23% of patients had evidence of nodal-only disease (i.e., TanyN1M0), 46% had distant metastases (TanyNanyM1), 37% of patients had oligometastatic disease, and 9% had polymetastatic disease (i.e., >5 M1 lesions).5 A visual distribution of the metastatic breakdown is shown below:

figure-2-HSPC-PSMA-PET.jpg

Metastasis-Directed Therapy or Systemic Therapy Intensification for ‘EMBARK-like’ Patients

One of the proposed treatment paradigms for the contemporary management of an ‘EMBARK-like’ patient is obtaining a PSMA PET scan and targeting PET-avid lesions with metastasis-directed therapy (MDT), particularly for patients with evidence of oligometastases (i.e., ≤5 lesions), to maximize the systemic therapy-free interval. There are, however, important differences between the EMBARK cohort and the three major phase II trials of MDT in oligorecurrent hormone sensitive prostate cancer: STOMP, ORIOLE, and EXTEND.6,7,8 The major difference is that patients in STOMP and ORIOLE had evidence of metastatic disease on non-PSMA PET imaging (STOMP: choline PET/CT; ORIOLE: conventional imaging [CT, MRI, and/or bone scan]), whereas those in EMBARK had no evidence of metastasis on conventional imaging.

It is important to note, however, that approximately 40% of patients of ‘EMBARK-like’ patients will have oligometastatic disease on a PSMA PET. There is evidence from the ORIOLE trial to support MDT targeting of all PSMA avid lesions. In this trial, pre-treatment 18F-DCFPyL-PET/CT was performed in all patients assigned to the MDT arm (n = 36), and the treating physicians and patients were blinded to the results of these scans. Sixteen patients (44%) had baseline PET-avid lesions that were not included in the MDT treatment fields and had significantly worse 6-month progression rates of 38% (95% CI 18.5–61.5%) compared to those without untreated lesions (5%; 95% CI 0–26.8%; p = 0.03). Furthermore, those with untreated sites of disease had higher rates of new metastases (per conventional imaging) at 6 months (62.5% versus 15.8%, p = 0.006) and worse median distant metastasis-free survival of 6 versus 29 months (HR: 0.19; 95% CI: 0.07–0.54, p < 0.001).6

figure-3-HSPC-PSMA-PET.jpg

What about the use of MDT with systemic hormonal therapy? The phase II EXTEND trial demonstrated that the addition of MDT to 6 months of intermittent hormonal therapy significantly improved eugonadal progression-free survival (HR 0.32, p = 0.03). However, similar to the ORIOLE and STOMP, patients had evidence of metastatic disease, mostly identified on conventional imaging (75%). Additionally, approximately 90% of patients had a serum PSA level <2 ng/ml at study entry, whereas the median serum PSA level in EMBARK was 5–5.5 ng/ml. Notably, only 72% of the EXTEND trial patients had undergone definitive local therapy to the prostate, whereas all patients in EMBARK had undergone a radical prostatectomy and/or pelvic radiotherapy, with 50% having undergone both treatment modalities. As such, there are clear differences between the two study cohorts that limit trial comparisons and the generalizability of results and treatment approach used in EXTEND to EMBARK trial participants.

What about the use of MDT with androgen receptor pathway inhibitors? To date, there are no randomized trials comparing the added benefit of combining one modality with the other (ARTO trial of abiraterone +/- stereotactic body radiotherapy [SBRT] was in the castrate-resistant setting) in this disease space.9 The only published trial of combination MDT with androgen receptor pathway inhibitors in oligorecurrent metastatic prostate cancer patients is the phase II SATURN trial, in which patients received six months of leuprolide + abiraterone acetate/prednisone + apalutamide and SBRT to all metastases, with or without radiotherapy directed to the prostate bed and pelvic lymph nodes, after the first month of systemic therapy. Overall, 50% of patients maintained a PSA <0.05 ng/mL six months after testosterone recovery (primary endpoint), and the median eugonodal progression-free survival was 11.4 months.10

One pragmatic approach to treating an ‘EMBARK-like’ patient that has PSMA PET findings of metastatic disease (ie. conventional imaging negative, PSMA PET positive for metastatic disease) is to treat these patients with enzalutamide + leuprolide, rather than enzalutamide monotherapy or leuprolide monotherapy. The rationale for such an approach is that these patients are more “ENZAMET/ARCHES-like” patients, where there is a proven therapeutic benefit of enzalutamide + ADT versus ADT alone in the mHSPC setting.11,12

In summary, the only available level one evidence to inform the treatment of high-risk, biochemically recurrent M0 HSPC patients staged with conventional imaging comes from the EMBARK trial, where both enzalutamide combination therapy with leuprolide and enzalutamide monotherapy have demonstrated metastasis-free survival benefits. Future randomized trials in this space may provide further answers to the question of optimal management of these patients who have PSMA PET positive disease. For the time being, however, similar to the mHSPC treatment paradigm which relies on conventional imaging volume findings to dictate treatment recommendations, high-risk, biochemically recurrent patients with conventional imaging-defined M0 HSPC should be recommended to receive systemic therapy with androgen receptor pathway inhibitors.

Ongoing Trials Utilizing PSMA PET in the High-Risk, Biochemically Recurrent M0 HSPC Space

ARASTEP

ARASTEP (NCT05794906) is an ongoing randomized, phase III, double-blind, placebo-controlled trial of prostate cancer patients with high-risk biochemical recurrence, defined by a PSADT <12 months with PSA ≥ 0.2 ng/mL after primary radical prostatectomy (+/- adjuvant radiotherapy/salvage radiotherapy) or PSA ≥2 ng/mL above nadir after primary radiotherapy only, ≥1 PSMA PET/CT-positive lesion of prostate cancer without visible lesions on conventional imaging, and serum testosterone >150 ng/dL.

Approximately 750 patients from 184 sites worldwide will be randomized to oral darolutamide 600 mg twice daily or placebo, both with ADT, for 24 months, unless there is earlier evidence of disease progression, unacceptable toxicity, or any other withdrawal criteria are met. Of note, patients will suspend treatment after 24 months if serum PSA levels remain undetectable (i.e., <0.2 ng/mL). Patients whose PSA values remain detectable (i.e., ≥0.2 ng/mL) will continue with the study treatment until PSMA PET/CT progression. The trial design for ARASTEP is as follows:

  image-3.jpg

The primary study endpoint is radiographic progression-free survival by PSMA PET/CT, assessed by a blinded independent central review. Key secondary endpoints include:

  • Metastasis-free survival by blinded independent central review
  • Time to CRPC
  • Overall survival
  • Quality of life
  • Safety
INDICATE

INDICATE (ECOG-ACRIN EA8191; NCT04423211) is a phase III trial that aims to evaluate the following in post-radical prostatectomy biochemically recurrent patients without evidence of metastases on conventional imaging:13

  1. Whether the addition of apalutamide to standard salvage radiotherapy plus short-term ADT improves survival in patients without extra-pelvic PET-detected lesions
  2. Whether the addition of MDT to the treatment intensification combination of salvage radiotherapy, short-term ADT, and apalutamide improves survival in patients with PET-detected lesions outside the pelvis

Eligible patients are those with biochemical recurrence post-radical prostatectomy, defined by a serum PSA level >0.5 ng/ml or >0.2 ng/ml, if detected within 12 months of the radical prostatectomy, and no evidence of extra-pelvic metastases on conventional imaging, who are candidates for standard of care salvage therapy (salvage radiotherapy to the prostate bed and pelvic node with concurrent short-term ADT). Of note, if a patient has a detectable PSA (≥0.01 ng/ml) at any time after radical prostatectomy and has a baseline PET that is positive for ≥1 lesion in any location, there is no minimum PSA requirement.

All patients will undergo baseline PET using one of the three FDA-approved tracers, at which point patients will be assigned to either Cohort 1 (PET negative for extra-pelvic metastases) or Cohort 2 (PET positive for extra-pelvic metastases). The study design is as follows:

  image-4.jpg

Patients in Cohort 1 (PET negative) will be randomized to either:

  • Arm A: Salvage external beam radiotherapy (EBRT) + short-term ADT (leuprolide or goserelin) OR
  • Arm B: Salvage EBRT + short-term ADT + apalutamide

Patients in Cohort 2 (PET positive for extra-pelvic metastases) will be randomized to either:

  • Arm C: Salvage EBRT + short-term ADT + apalutamide OR
  • Arm D: Salvage EBRT + short-term ADT + apalutamide + MDT (SBRT)

The primary endpoint in both cohorts is progression-free survival, defined as time from randomization to radiographic progression on conventional imaging, symptomatic disease progression, or death, whichever occurs first. Secondary endpoints include overall and event-free survival, toxicity, PET progression, and quality of life. The study accrual start date was October 2022, with an estimated primary completion date of December 2027.

Conclusions

Based on the current body of evidence, high-risk, biochemically recurrent patients without evidence of metastases on conventional imaging should be strongly considered for systemic therapy with enzalutamide combination therapy with leuprolide or monotherapy. Despite PSMA PET detecting extra-pelvic metastases in almost 50% of such patients, there is no high-level evidence, to date, to support the routine utilization of PSMA PET findings to direct treatment with SBRT. Ongoing trials will help address important remaining questions in this disease space, namely the value/utility of PSMA PET in patients with negative conventional imaging findings and the added benefit of PSMA PET-directed SBRT to systemic therapy intensification with androgen receptor pathway inhibitors in patients with PSMA PET/conventional imaging discordant findings.

Published November 2024 

Radium-223 in 2024 and Beyond: Resurrected and Disrupting the First-Line mCRPC Treatment Landscape

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Introduction

Radium-223 dichloride (radium-223) is a targeted alpha emitter that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha particles of short-range (<100 μm). Radium-223 acts as a bone-seeking calcium mimetic and binds into newly formed bone stroma, especially within the microenvironment of osteoblastic or sclerotic metastases. Double-stranded DNA breaks result secondary to the high-energy alpha-particle radiation.

ESMO 2024 Quick Take Insights: Prostate Cancer

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Introduction

At the ESMO 2024 annual meeting in Barcelona, Spain, the results of numerous practice-changing trials were presented, including those from three highly-anticipated clinical trials in the advanced prostate cancer space:

ESMO 2024 Quick Take Insights: A Focus on PEACE-3

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ESMO 2024 Quick Take Insights: A Focus on PEACE-3

The ESMO 2024 annual meeting in Barcelona, Spain, featured many practice-changing trials and hypothesis-generating data in genitourinary cancer. One of the most highly anticipated trials in the metastatic castration-resistant prostate cancer (mCRPC) disease space was the phase III PEACE-3 trial – the focus of this ESMO 2024 Quick Take Insights.

ESMO 2024 Quick Take Insights: A Focus on ARANOTE

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The ESMO 2024 annual meeting in Barcelona, Spain, featured many practice changing trials and hypothesis generating data in genitourinary cancer. One of the most highly anticipated trials in the metastatic hormone sensitive prostate cancer (mHSPC) disease space was the phase III ARANOTE trial – the focus of this ESMO 2024 Quick Take Insights.

ESMO 2024 Quick Take Insights: A Focus on SPLASH

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ESMO 2024 Quick Take Insights: A Focus on SPLASH

The ESMO 2024 annual meeting in Barcelona, Spain, featured many practice-changing trials and hypothesis-generating data in genitourinary cancer. One of the most highly anticipated trials in the metastatic castration-resistant prostate cancer (mCRPC) disease space was the phase III SPLASH trial – the focus of this ESMO 2024 Quick Take Insights.

Treatment Intensification for High-Risk Biochemically Recurrent M0 HSPC: Quality of Life and Sexual Function Considerations

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Introduction

In November 2023, the United States Food and Drug Administration (FDA) approved enzalutamide, with or without concurrent leuprolide therapy, for non-metastatic hormone-sensitive prostate cancer (M0 HSPC) patients with biochemical recurrence at high risk for metastasis.1 This drug approval followed the publication of the EMBARK trial, a randomized phase III trial of biochemically recurrent patients who had high-risk disease, defined by a PSA doubling time (PSADT) ≤9 months and a PSA level of ≥2 ng/mL above nadir following radiation therapy or ≥1 ng/mL after radical prostatectomy, with or without postoperative radiation therapy. Patients in this trial were randomized 1:1:1 to combination enzalutamide + leuprolide, leuprolide monotherapy, or enzalutamide monotherapy. This trial met its primary endpoint of improved 5-year metastasis-free survival with the combination of enzalutamide + leuprolide (87.3% versus 71.4% for leuprolide alone; HR 0.42, p < 0.001). Similarly, enzalutamide monotherapy was associated with superior 5-year metastasis-free survival rates, compared to leuprolide monotherapy (80% versus 71%; HR 0.63, p = 0.005).2

While both enzalutamide monotherapy and combination therapy with leuprolide have demonstrated promising efficacy outcomes for these high-risk patients, it is important to consider the safety profiles of these drugs and their impact on health-related quality of life measures. These patients have a prolonged natural history,3 and thus their survivorship care must remain of utmost importance.

In this Center of Excellence article, we will discuss the health-related quality of life effects of the different treatment arms of the EMBARK trial and highlight important functional outcomes considerations, particularly with regard to sexual function.

EMBARK

In the EMBARK trial, patient-reported outcomes were assessed at baseline and every 12 weeks thereafter until disease progression or completion of data gathering. For each patient-reported outcomes instrument, change from baseline (i.e., post-baseline value minus baseline value) was calculated for each assessment of a domain. Health-related quality of life was measured using Brief Pain Inventory–Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Prostate (FACT-P), Quality of Life Questionnaire–Prostate 25 (QLQ-PR25), and European Quality of Life 5-Dimensions 5-Levels health questionnaire (EQ-5D-5L) scores.4

At baseline, the questionnaire completion rates were ≥90% and remained high (≥85%) up to week 205. The baseline patient-reported outcome scores indicated low levels of pain and high health-related quality of life scores, suggesting that most patients were asymptomatic at baseline. However, sexual activity scores were low likely secondary to prior treatments received (50% radical prostatectomy and radiotherapy, 25% radical prostatectomy alone, 25% radiotherapy alone). Very few patients reported hormonal therapy-related symptoms at baseline, as only 31% had received prior hormones and none within the preceding nine months.

Overall, the patient-reported outcome scores remained stable throughout the trial for most patients in all groups, suggesting maintenance of the high baseline health-related quality of life and low baseline symptoms across all groups, with no clinically meaningful differences overall across the groups.

Key Outcomes: Worst Pain in Prior 24 Hours and Functional Status

There were no differences in either the time to first or confirmed clinically meaningful deteriorations in worst pain in the past 24 hours (BPI-SF item 3) or in functional status measured using FACT-P total score:
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FACT-P Subdomains

The FACT-P total score longitudinally worsened in all three arms, with no clinically meaningful differences between the three arms (leuprolide alone: -3.9; enzalutamide combination: -5.7; enzalutamide monotherapy: -6.4):
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Within the individual FACT-P domains, patients in both the enzalutamide combination and monotherapy arms had significantly shorter (i.e., worse) time to confirm clinically meaningful deterioration in the physical well-being score, compared to leuprolide alone. Time to confirmed clinically meaningful deterioration in physical well-being score was 49.8 months with leuprolide, compared to 24.8 and 27.6 months for enzalutamide combination and monotherapy, respectively (HRs 1.41 and 1.35, respectively).

Patients in the enzalutamide monotherapy arm had a significantly worse median time to first clinically meaningful deterioration in the prostate cancer subscale score (HR 1.21) and advanced prostate symptom index (HR 1.34), compared to leuprolide-only therapy. There were otherwise no significant differences observed in the times to first or confirmed clinically meaningful deteriorations for the other FACT-P domains, including social/family, emotional, and functional well-being and prostate cancer pain domains:
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Sexual Function and Hormonal Symptoms

With regards to QLQ-PR25, the time to confirmed clinically meaningful deterioration of composite sexual activity was significantly longer (i.e., better) with enzalutamide monotherapy, compared to leuprolide-only therapy (median: 5.6 versus 3 months; HR 0.76, 95% CI 0.62–0.94). The longitudinal changes in sexual function are summarized below, with enzalutamide monotherapy denoted below in blue:
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An individual item-level analysis of sexual function was presented at ASCO GU 2024 and demonstrated that enzalutamide monotherapy, compared to leuprolide monotherapy, was associated with significantly longer times to deterioration of sexual interest and sexual activity. Patients in the enzalutamide monotherapy arm had significantly higher satisfaction with their sexual life and ability to achieve and maintain erections. In the comparison of enzalutamide combination to leuprolide monotherapy, patients in the enzalutamide combination arm had significantly worse ability to achieve and maintain erections:5
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The time to confirmed clinically meaningful deterioration in hormonal treatment-related symptoms with enzalutamide combination was significantly worse compared to leuprolide alone (HR 1.19, 95% CI 1.01–1.40), although there were minimal differences in the median times to deterioration (2.86 versus 2.89 months):
figure-7-quality-of-life.jpg

Safety

No new safety signals were observed with the combination of enzalutamide and leuprolide. Grade ≥3 adverse events were observed in 43-50% of patients across the three arms. The most common adverse events (occurring in ≥10% of patients) in the enzalutamide combination group and the leuprolide-alone group were hot flashes (57–69%) and fatigue (33–43%). The most common adverse events in the monotherapy group were gynecomastia (45% versus 8–9% in the two other arms), hot flashes (22%), and fatigue (47%). Notable adverse events in the enzalutamide monotherapy group were nipple pain (15% versus 1–3% in the other two arms) and breast tenderness (14% versus 1% in the other two arms). Fractures were more common in the enzalutamide combination group (18.4%), compared to the leuprolide-alone group (14%) and the enzalutamide monotherapy group (11%).

Treatment was discontinued due to adverse events in 21% of patients in the enzalutamide combination group, 10% of patients in the leuprolide-alone group, and 18% of patients in the enzalutamide monotherapy arm. The most common adverse event leading to discontinuation in all three arms was fatigue.

In a post-hoc analysis of outcomes stratified by age presented at ESMO 2024, serious adverse events were more common in patients aged ≥70 years vs <70 years for enzalutamide + leuprolide (45.0% vs 25.3%), leuprolide alone (36.2% vs 27.1%), and enzalutamide monotherapy (43.9% vs 30.4%). For clustered treatment emergent adverse events of special interest of any grade, musculoskeletal events, fatigue, and hypertension were common across all age and treatment groups.

Between-arms differences are summarized below (all comparisons are to leuprolide-only therapy):
  • Physical well-being score: Significantly worse time to confirmed clinically meaningful deterioration of physical well-being score for both enzalutamide combination and monotherapy arms (leuprolide: 50 months; enzalutamide combination/monotherapy: 25–28 months). These scores likely reflect the higher incidence of fatigue with enzalutamide combination (43%) or monotherapy (47%), versus leuprolide-only therapy (33%).
  • Prostate cancer subscale score and advanced prostate symptom index: Worse for enzalutamide monotherapy patients
  • Social/family, emotional, and functional well-being and prostate cancer pain FACT-P domains: No differences between the arms
  • Sexual function: Deteriorates in all three arms. Significantly longer time to confirmed clinically meaningful deterioration of composite sexual activity with enzalutamide monotherapy (5.6 versus 3 months). Patients treated with enzalutamide monotherapy reported superior sexual interest and activity and had higher satisfaction with their sexual life and ability to achieve and maintain erections. Enzalutamide combination therapy patients had significantly worse ability to achieve and maintain erections.
  • Hormonal treatment-related symptoms: Enzalutamide combination patients had a significantly worse time to confirmed clinically meaningful deterioration in hormonal treatment-related symptoms
  • Notable adverse events:
    • Hot flashes: More common in the enzalutamide + leuprolide and leuprolide-only arms (57–69% versus 22% for enzalutamide monotherapy)
    • Gynecomastia nipple pain, and breast tenderness: More common with enzalutamide monotherapy
      • Gynecomastia: 45% versus 8–9%
      • Nipple pain: 15% versus 1–3%
      • Breast tenderness: 14% versus 1%

Summary and Take-Home Messages

In this analysis of patient-reported outcomes from the EMBARK trial, the key take-home message is that the majority of trial patients maintained overall stable health-related quality-of-life outcomes throughout the study. However, there are notable differences between the study arms with respect to their relative impact on specific quality-of-life domains. A comprehensive understanding of these differences is key to engaging these patients in a shared decision-making process to strike a balance between maximizing oncologic benefits while maintaining quality-of-life measures that are most significant for the individual patients.

Published October 2024

Treatment Intensification for High-Risk Biochemically Recurrent M0 HSPC: ‘EMBARK’ing on a Novel Treatment Paradigm

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Introduction

Historically, the recommended management for biochemically recurrent prostate cancer patients following maximal pelvic therapy with no metastasis on conventional imaging has been disease monitoring, with androgen deprivation therapy (ADT) reserved for metastatic disease development. Studies of the natural history of such patients have demonstrated that the median time to development of metastases is approximately eight years, with 82% of patients remaining free of conventional imaging-defined metastasis 15 years following surgery.1

Metastasis-Directed Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: New Frontiers in Advanced Prostate Cancer

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Introduction


Classical theories of metastasis have followed ‘the seed and soil’ hypothesis, the Halstedian model, which proposes an orderly spread of disease from local to distant sites, with the presumption that cancer is an inherently systemic process even in the earliest cases. More contemporary spectrum theories now suggest that the propensity for distant spread exists along a ‘metastatic continuum’. Tumors with limited metastatic potential (i.e., oligometastases) represent a unique subset along this spectrum that could be potentially cured with local ablative therapy (i.e., metastasis-directed therapy [MDT]). This concept is not unique to prostate cancer and has been evaluated in other disease sites including non-small cell lung, colorectal, esophageal, and breast cancers.1

The majority of the evidence for MDT in the prostate cancer space, to date, has been for patients with recurrent, oligometastatic hormone sensitive prostate cancer. MDT has been evaluated both in lieu of, to avoid/delay the use of systemic therapy, and in combination with systemic therapy to potentially improve efficacy outcomes. In this Center of Excellence article, we discuss the evidence and practical applications for MDT in the recurrent oligometastatic hormone sensitive setting.

Trials of MDT versus Observation/Surveillance for Recurrent Oligometastatic Prostate Cancer

To date, three prospective phase II trials have compared MDT to observation for patients with recurrent oligometastatic hormone sensitive prostate cancer.

STOMP

The STOMP trial was a multicenter, randomized phase II trial that prospectively evaluated the effects of MDT for eugonadal men with evidence of oligometastatic disease on choline PET/CT (up to three extracranial sites) who had received prior treatment with curative intent and had evidence of biochemical recurrence. Between 2012 and 2015, 62 patients were randomized 1:1 to either surveillance or MDT, consisting of stereotactic body radiotherapy (SBRT) or metastasectomy. The primary endpoint was time to initiation of ADT (i.e., ADT-free survival). ADT was initiated for symptoms, progression beyond three metastases, or local progression of known metastatic disease

After a median follow up of 5.3 years, the five-year ADT-free survival was 8% in the surveillance arm compared to 34% for the MDT group (HR: 0.57, 95% CI: 0.38–0.84, log-rank p = 0.06). No differences were seen between groups when stratified by nodal versus non-nodal metastases:

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The secondary endpoint of 5-year CRPC-free survival was 53% in subjects under surveillance and 76% in those receiving MDT (HR 0.62, 80% CI: 0.35-1.09):2 

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ORIOLE

The ORIOLE trial was a randomized phase II trial of men with recurrent oligometastatic hormone-sensitive prostate cancer (up to three sites). Between 2016 and 2018, 80 men were screened, of which 54 men had 1 to 3 metastases detectable by conventional imaging and had not received ADT within 6 months of enrollment or 3 or more years total. These 54 men were randomized in a 2:1 fashion to receive SBRT or observation. The primary outcome was disease progression at 6 months, defined by a serum PSA increase, radiographic progression on conventional imaging, symptomatic progression, ADT initiation for any reason, or death. 

After a median follow-up of 19 months, disease progression at six months occurred in 19% of patients in the SBRT arm versus 61% of patients in the observation arm (p = 0.005). Patients in the SBRT treatment arm had superior median progression-free survival rates (median: not reached versus 5.8 months; HR: 0.30; 95% CI: 0.11–0.81; p = 0.002):

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Secondary to the blinding of the investigative team to the PSMA-targeted PET data during treatment planning, 16 of 36 men treated with SBRT had baseline PET-avid lesions that were not included in the treatment fields. The proportion of men with no untreated lesions with progression at 6 months was 1 of 19 (5%) compared with 6 of 16 (38%) for those with any untreated lesions (p = 0.03). The median progression free survival was unreached among men with no untreated lesions vs 11.8 months among participants with any untreated lesions (HR, 0.26; 95% CI, 0.09-0.76; p = 0.006):3

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As such, this was among the first data to suggest the importance of treating all PSMA PET-visible lesions for maximal oncologic benefit in the oligometastatic mHSPC space. 

ORIOLE + STOMP: Pooled Data

In 2022, pooled data from the ORIOLE and STOMP trials demonstrated that MDT improves progression free survival from 5.9 months to 11.9 months (HR: 0.44, p<0.001), however without any significant improvements seen in radiographic progression-free survival, time to castration-resistant disease, or overall survival:4

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SABR-COMET

SABR-COMET was a randomized, open-label phase II study of patients with oligometastatic disease (up to five sites) between February 2012 and August 2016. This trial was not restricted to patients with prostate cancer and also included lung, breast, and colorectal cancer patients. Of the 99 patients in this trial, 18 (18.2%) had prostate cancer. After stratifying by the number of metastases (1–3 versus 4–5), patients were randomized in a 1:2 fashion to receive either palliative standard of care alone or standard of care plus SBRT. 

At a median follow-up of 5.7 years, the primary outcome of overall survival was superior for SBRT-treated patients. The 8-year overall survival rates were 27% and 14% in the intervention and control arms, respectively (HR: 0.50, 95% CI: 0.30–0.84, p = 0.008). The 8-year progression-free survival estimates were 21% and 0%, respectively (HR: 0.45, 95% CI: 0.28–0.72, p < 0.001):

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The rates of grade ≥2 acute or late toxic effects were 30% versus 9% (p = 0.019), and the FACT-G quality of life scores declined over time in both arms, but with no differences in quality-of-life scores between the study arms.5 

Combination of MDT + Systemic Therapy for Recurrent Oligometastatic Prostate Cancer

EXTEND

The EXTEND trial was a single center, phase II randomized controlled trial of 87 oligorecurrent men, mostly with mHSPC (>90%), who were randomized 1:1 to intermittent hormone therapy +/- MDT (definitive radiation therapy to all sites of disease). All patients had ≤5 metastases, as defined by conventional imaging (75%) or fluciclovine PET/CT (25%). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. At a median follow-up of 22 months, progression free survival was improved in the combined therapy arm (HR: 0.25, 95% CI: 0.12 – 0.55, p < 0.001). Significantly, ‘eugonadal’ progression free survival was also improved with this combination approach (HR: 0.32, p = 0.03):6

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SATURN

SATURN is a phase II trial of 28 men with oligorecurrent extra-pelvic metastases on PSMA-PET/CT following initial treatment with radical prostatectomy. Patients were treated with 6 months of ‘androgen annihilation therapy’, defined as leuprolide + abiraterone acetate/prednisone + apalutamide. After the 1st month of this systemic therapy, patients received SBRT to all metastases with or without radiotherapy directed to the prostate bed and pelvic lymph nodes. Results of the primary endpoint, the percentage of patients who maintained PSA <0.05 ng/mL six months after testosterone recovery to ≥150 ng/dL, were presented at ASCO GU 2024. Overall, 50% of patients maintained a PSA <0.05 ng/mL six months after testosterone recovery. After a median follow-up of 20 months, the median progression free survival was 19.3 months. Moreover, 81% of patients recovered eugonadal testosterone levels, at a median of 9.4 months from the start of systemic therapy, and the median eugonadal progression free survival was 11.4 months. Grade 3 adverse events related to androgen therapy were observed in 21% of patients, and SBRT had 7.7% grade 2 and no grade 3 toxicity.9

Key Ongoing Trials of MDT + Systemic Therapy

There are several important ongoing trials combining systemic therapy with the site specific control offered by MDT. The ADOPT trial is an ongoing phase III trial that is randomizing 280 patients with evidence of recurrent oligometastatic disease (≤4 lesions) on PSMA-PET/CT 1:1 to either MDT (radiotherapy) alone or MDT + 6 months of ADT. The primary endpoint of this trial is 30 month metastases progression free survival, with key secondary endpoints including overall survival, adverse events, and quality of life outcomes:7

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NRG GU011 (PROMETHEAN) is a randomized phase II trial of SBRT with or without relugolix for early PET-detected recurrent oligometastatic prostate cancer. Eligible patients are those with biochemical recurrence following prior curative intent radiation or surgery for localized prostate cancer, PSA < 10 ng/mL, negative conventional imaging, and 1–5 PET-visible metastases (≥1 extra-pelvic). The primary endpoint is conventional imaging-based radiographic progression free survival. Key secondary endpoints include PET-based radiographic progression free survival, overall survival, and quality-of-life outcome measures:

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The VA STARPORT study is a phase II/III randomized trial that evaluates the value of adding PET-directed local therapy to standard systemic therapy for biochemically recurrent patients with evidence of ≤5 metastatic lesions on PSMA-PET/CT. PET-directed local therapy is defined as surgery or radiation to all visible metastases and any prostate/prostatectomy bed local recurrences. Systemic therapy will be administered indefinitely, consistent with current guidelines. The primary study endpoint is castrate-resistant prostate cancer-free survival. Key secondary endpoints include clinical and radiographic progression free survival, overall survival, toxicity, and quality of life outcomes:

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PERSIAN is a randomized phase II trial of recurrent oligometastatic, hormone-sensitive patients (<5 non-visceral lesions). Eligible patients will undergo 1:1 randomization to apalutamide + ADT +/- SBRT to all visible lesions. The primary outcome is 6-month complete biochemical response. The trial design and key secondary endpoints are illustrated below:

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The POSTCARD GETUG P13 is a French randomized phase II trial that is randomizing patients with recurrent oligometastatic disease following primary local therapy with curative intent to either SBRT alone (to all visible metastases) or SBRT + durvalumab. Oligometastasis is defined as ≤5 bone or lymph node metastases on 68Ga-PSMA PET/CT or ≤3 bone or lymph node metastases on 18F-choline PET/CT. The primary endpoint is two-year progression-free survival, with key secondary endpoints of androgen deprivation therapy free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response.8

Incorporating PSMA-PET/CT into the MDT Paradigm

The next ‘frontier’ of MDT trials is incorporating PSMA-PET/CT for staging oligometastatic patients and determining eligibility for MDT. Given the increased sensitivity of PSMA-PET/CT compared to conventional imaging,10 it is likely that this may lead to a ‘stage migration’ phenomenon, where future cohorts of oligometastatic prostate cancer patients, matched for the same number of metastatic lesions, have more favorable prognoses. However, there has been a shift away from defining the ‘upper limit’ of oligometastatic disease by the number of metastatic lesions. A recent survey of participants from the ESTRO-ASTRO consensus conference demonstrated that the majority of respondents concur that the ‘upper limit’ of oligometastatic disease should be defined by the ability to safely deliver curative intent metastasis-directed radiotherapy and not by the number of metastatic lesions.

Existing evidence suggests that PSMA-PET/CT provides additional information in patients with evidence of recurrent oligometastatic disease on conventional imaging. In the ORIOLE trial, as highlighted above, pre-treatment 18F-DCFPyL-PET/CT was performed in all patients assigned to the MDT arm (n = 36). Of the 36 patients treated with SBRT, 16 (44.4%) had baseline PET-avid lesions that were not included in the treatment fields. These patients had significantly worse 6-month progression rates of 38% compared to those without untreated lesions (5%; p = 0.03). Furthermore, those with untreated sites of disease had higher rates of new metastases (per conventional imaging) at 6 months (62.5% versus 15.8%, p = 0.006), and worse median distant metastasis-free survival of 6 versus 29 months (HR: 0.19; 95% CI: 0.07–0.54, p < 0.001). These results highlight the importance of targeting all sites of disease, and the value of PSMA PET/CT for defining this with increased sensitivity compared to conventional imaging.3

A single arm phase II study evaluated the role of MDT (SBRT or surgery) in 37 patients with a rising PSA (0.4–3 ng/ml) following maximal local therapy (radical prostatectomy + adjuvant/salvage radiotherapy) who had not received prior salvage hormonal therapy and had negative conventional imaging, but evidence of oligometastasis on 18F-DCFPyL PET-MR/CT. Ten and 27 patients underwent surgery and SBRT, respectively. At a median follow-up of 16 months, the overall response rate was 60%, including 22% who had biochemical ‘no evidence of disease. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed.11

MDT for De Novo Oligometastatic Hormone-sensitive Prostate Cancer

There are numerous ongoing trials evaluating the role of MDT in combination with systemic therapy in the de novo oligometastatic hormone-sensitive setting. In this section, we will highlight key trials in this space.

SOLAR (NCT03298087) is a single arm phase II trial of 28 patients with de novo M1a/b disease and 1–5 radiographically visible M1 lesions (majority detected via PSMA PET-CT) who all underwent radical local treatment, intensified systemic therapy for six months (leuprolide, abiraterone acetate with prednisone, apalutamide), and metastasis-directed SBRT. Radical local therapy was either radical prostatectomy (n = 12) with lymph node dissection and postoperative radiotherapy (for ≥pT3a, N1, or positive margins) or radical radiotherapy (n=12) directed to the prostate, seminal vesicles, and pelvic lymph nodes. The initial results of this trial were presented at GU ASCO 2024. At a median follow-up of 30 months, 62% of patients completed all planned systemic therapy without dose modification. Of the 22 patients with >6 months follow-up after testosterone recovery, 86% remained free of any progression, defined as an undetectable serum PSA after radical prostatectomy or <2 ng/ml after radical radiotherapy. Grade 2 and 3 toxicities for primary tumor therapy were 46% and 4%, respectively. There were no grade 2–3 toxicities relating to SBRT.12

PLATON (NCT03784755) is a two-arm phase II RCT exploring sequential treatment with ADT +/- chemotherapy followed by cytoreductive prostatectomy or external beam radiotherapy and then SBRT for oligometastases in 410 men. The comparator arm consists of systemic therapy alone, although low-volume men will be allowed to receive conventional local prostate radiotherapy. The primary study outcome is failure-free survival:

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IP2-ATLANTA (NCT03763253) is a three-arm phase II randomized trial exploring sequential systemic, local, physical cytoreductive therapy and finally SBRT versus standard of care in 918 men with any-volume metastatic disease. All patients will receive doublet systemic therapy (ADT + docetaxel or enzalutamide or abiraterone). Patients in experimental arm 1 will receive minimally invasive ablative therapy +/- lymph node dissection, whereas those randomized to experimental arm 2 will receive local external beam radiotherapy +/- lymph nodes or radical prostatectomy +/- pelvic lymph node dissection. Patients in both experimental arms will further receive SBRT to oligometastases following receipt of of systemic and local treatment. Patients in the control arm will receive planned systemic therapy only, although patients with low-volume metastases will be eligible for prostate external beam radiotherapy:13

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Finally, TERPs (NCT05223803) is a phase II trial of patients with de novo oligometastatic disease (<3 on conventional imaging or <5 on PET/CT) who will be randomized 1:1 to best systemic therapy + primary prostate radiotherapy +/- MDT (SBRT). The primary study endpoint is two-year failure-free survival.14

Conclusions and Future Directions

MDT has emerged as a guideline-recommended treatment option for prostate cancer patients with oligometastatic disease. The evidence to date suggests that MDT can be used in lieu of systemic therapy to delay time-to-hormone therapy or in combination with systemic therapy as a consolidative measure. The latest NCCN guidelines recommend considering SBRT for MDT in oligometastatic patients when ablation is the goal or in oligometastatic patients with limited progression or limited residual disease on otherwise effective systemic therapy (i.e., consolidation), where progression free survival is the goal.

The next ‘frontier’ of clinical trials for MDT will be evaluating its efficacy and safety in patients with PSMA-PET/CT-defined oligometastases and defining its role in the de novo metastatic hormone-sensitive setting. The results of these exciting trials will become available over the next few years.

Published August 2024

American Society of Clinical Oncology (ASCO) 2024 Bladder Cancer Updates

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Patient-reported outcomes (PROs) from a Randomized, Phase 3 Trial of Enfortumab Vedotin plus Pembrolizumab (EV+P) Versus Platinum-Based Chemotherapy (PBC) in Previously Untreated Locally Advanced or Metastatic Urothelial Cancer (la/mUC)1

EV+P nearly doubled median PFS and OS versus platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer in the phase 3 EV-302 trial and is NCCN category 1 and ESMO guidelines preferred treatment option. PRO assessments included the
  • Written by: Shilpa Gupta, MD, Director of the Genitourinary Medical Oncology, Taussig Cancer Institute, Co-Leader of the Genitourinary Oncology Program, Cleveland Clinic, Cleveland, OH