ESMO 2023: Next Generation Imaging: How Does It Change the Evidence Seen in Trials?

(UroToday.com) The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20^th and 24^th, 2023 was host to a ‘Dissecting metastatic castration-sensitive prostate cancer (mCSPC) for optimal patient benefit’ session. Dr. Bernard Tombal discussed how the results of next generation imaging change the evidence from clinical trials in the mCSPC disease space.

Dr. Tombal began his presentation by providing an overview of the contemporary treatment landscape for prostate cancer in 2023 and highlighted the currently available early treatment intensification strategies for patients with mCPSC.

The major limitation of all these trials leading to the regulatory approvals is their reliance on conventional imaging (CT/MRI + bone scan), which has poor diagnostic performances compared to newer-generation imaging, mainly PSMA PET/CT. Additionally, we have relied on timing (synchronous versus metachronous) and volume of disease (CHAARTED high and low) to risk stratify patients based on prognostic, but not predictive, factors, and this clearly strongly impacts clinical decision making, as evidence by a survey of experts from the most recent Advanced Prostate Cancer Consensus Conference.

The limitations of conventional imaging are many, with numerous examples to this end. Dr. Tombal highlighted a 2016 report to exemplify these limitations. When whole body MRI was performed in addition to a bone scan for the assessment of metastatic spread in prostate cancer patients, 13/46 evaluable patients had evidence of novel, previously undetected oligometastatic disease on whole body MRI. Additionally, most of these lymph nodes were detected outside the standard treatment template, such as in the axillary nodes.¹

Further evidence highlighting the limitations of conventional imaging comes from the ProPSMA trial. This was a multi-center, two-arm randomized controlled trial of men with histologically confirmed prostate cancer who were being considered for curative intent radical prostatectomy or radiotherapy. To be eligible for inclusion, men must have had at least one high-risk factor including PSA ≥ 20 ng/mL, ISUP grade group 3-5, or clinical stage T3 or greater. Following enrollment, patients were randomly assigned in a 1:1 ratio to either conventional imaging consisting of bone scan and CT or ⁶⁸Ga-PSMA-11 PET/CT. The primary study outcome was the accuracy of first-line diagnostic imaging for identifying either pelvic nodal or distant metastatic disease. reference standard was a composite panel of histopathology, imaging, and biochemistry at 6-month follow-up.

Between 2017 and 2018, 302 patients were randomized to either conventional imaging (n = 152) or ⁶⁸Ga-PSMA-11 PET/CT (n = 150). With regards to the primary outcome, PSMA PET/CT had a 27% absolute greater AUC for accuracy compared to conventional imaging (95% CI for difference: 23 – 31%): 92% (95% CI: 88 – 95%) vs. 65% (95% CI: 60 – 69%). Conventional imaging had both a lower sensitivity (38% vs. 85%) and specificity (91% vs. 98%). Subgroup analyses by site of metastasis demonstrated the superiority of PSMA PET/CT for pelvic nodal (AUC: 91% versus 59%) and distant metastases (AUC: 95% versus 74%).

One likely implication of the increased adoption of PSMA PET/CT will be ‘transforming’ patients with high-risk localized or non-metastatic biochemically recurrent disease to low volume metastatic disease and low volume patients to high volume disease patients.

Although we have clearly established the improved diagnostic performance of novel imaging, including, PSMA PET, what is its clinical utility in practice? To this end, Dr. Tombal presented a case of a 63-year-old male who presented with Grade Group 5 disease in 5/12 cores, cT3a, PSA 14.6 ng/ml, who was found to have had a pelvic bone metastatic deposit on an MRI of the pelvis.

This patient was offered a whole body MRI; however, Dr. Tombal argued that this unlikely to change practice given that this patient has already demonstrated a metastatic bone deposit. He recommended that following the results of PEACE-1 and ARASENS, everybody in this setting should receive an androgen receptor pathway inhibitor (ARPI), and doublet therapy with docetaxel alone is no longer a recommended option. One may ask: If the patient has evidence of high disease volume on the MRI whole body scan, would this push the treating clinician to recommend docetaxel as well? Dr. Tombal argued that disease volume alone should not be used to decide whether docetaxel is indicated. As demonstrated by the recent STOPCAP meta-analysis of the GETUG-15, STAMPED, and CHAARTED trials,^3-6 it appears that the benefit of docetaxel for mCSPC patients is related to both volume and timing of disease, with all subgroups, except the low volume metachronous patients, likely benefiting from early docetaxel treatment intensification.

This is consistent with the current EAU guidelines, summarized below. The only treatment decision that is directly dictated by volume of disease is the decision to offer patients radiotherapy (low volume based on STAMPEDED Arm H and HORRAAD).^7,8

However, even this has come into question following the presentation of the PEACE-1 radiotherapy results at ASCO GU 2023, which failed to demonstrate an OS benefit for prostate radiotherapy in low-volume mCSPC patients.

There does however appear to be some value for prostate radiotherapy for delaying the time to serious genitourinary events, which was observed in the overall, and not only low volume, population.

What about the role of novel imaging to assist with treatment de-escalation, similar to what is performed with intermittent ADT in responders? Dr. Tombal presented the case of a 71-year-old male who presented with a PSA of 145 ng/ml and was found to have cT4 disease with Grade Group 5 disease. CT demonstrated cN1 disease, and the bone scan showed 4 bone metastases. The patient received triplet therapy with degarelix + docetaxel + abiraterone and had a PSA response of 0.1 ng/ml, albeit with side effects from his ADT and abiraterone. This patient was interested in de-escalating his treatment and was offered entry into a clinical trial.

Interestingly, when this patient had a repeat PSMA PET scan to evaluate disease response, he had a heterogenous, asymmetric response with some lesions disappearing and others increasing in size. What is clear is that this is not only limited to PSMA PET. In unpublished data from his group, Dr. Tombal presented the results of an analysis evaluating whole body MRI findings by PSA response. Among PSA complete responders, only 56% will exhibit a complete response, with 38% demonstrating a partial imaging response. A complete or partial MRI response was observed in 57% of PSA non-responders. He thus argued that novel imaging, whether PSMA PET or MRI, cannot currently be relied on solely to evaluate disease response confidently.

A meta-analysis published in 2021 further highlights this after it showed that the concordance between response assessment using PSMA PET and PSA levels following systemic treatment in mCRPC patients is only about 70 – 80%.⁹

Perhaps we should still rely mainly on PSA response to consider treatment de-escalation. Ad hoc analysis of the ARASENS trial clearly demonstrates that patients with undetectable PSAs with triplet ADT + docetaxel + darolutamide have better prognoses.¹⁰

What about novel imaging modalities to assist with decision for metastasis-directed therapy in the biochemically recurrent setting? Dr. Tombal presented the case of a 73-year-old male who underwent radical prostatectomy for Gleason 8 pT3bR1N0 disease and received salvage radiotherapy + 6 months leuprolide. His PSA has now increased to 2.5 ng/ml with a PSA doubling time of 8 months. His bone scan was negative, but a whole body MRI demonstrated 1 bone metastatic deposit. What is the current evidence for MDT in this setting?

There has been growing enthusiasm to offer metastasis-directed therapy for these patients, and this is mostly based on a limited number of phase II trials showing that it can delay the time to start of ADT. However, this benefit is only in the region of a few months, and not of significant relevance in the polymetastatic progressive cohort.

As such, Dr. Tombal argued that caution should be advised when offering these patients these modalities without systemic therapy, with the patient in this case example progressing to diffusely metastatic disease on his future imaging. This is particularly relevant given the emergence of enzalutamide monotherapy or combination with ADT for such patients, with the EMBARK trial allowing for treatment interruption in responders. As such, addition of MDT to the systemic therapy may prolong these ‘off treatment’ periods. This has been corroborated by the EORTC which does not recommend metastasis-directed therapy in place of systemic therapy at the current time.

This concept of adding metastasis-directed therapy to systemic therapy was evaluated in the ARTO trial in castrate-resistant patients which randomized 157 mCRPC patients to abiraterone alone versus abiraterone plus stereotactic body radiotherapy to all sites of metastatic disease. This demonstrated a progression-free survival for this combination.

Dr. Tombal concluded his presentation with the following take home messages:

• Whole-body MRI and PET-PSMA have demonstrated superior diagnostic accuracy.
• Do they change the evidence seen in the trials?
  • No, because the standard of care ADT + ARPIs is independent of the extent and locations of metastases. And docetaxel and radiotherapy indications extend bevond a simple assessment of volume
• Do they disrupt the care pathway beyond the trials?
  • Yes, and that is a concern because strategies such as metastasis-directed therapy, escalation, and de-escalation are largely unproven
• New imaging technologies are here to stay
  • In the end, they challenge our willingness to study rather than disseminate.
• Whether we are happily treating our patients on the acceptability of low impact data, it's entirely up to us.
  • But patients deserve definitive evidence and not conventional wisdom

Presented by: Bertrand Tombal, MD, PhD, Chairman of the Department of Surgery and Full Professor of Urology at the Université Catholique de Louvain, Ottignies-Louvain-la-Neuve, Belgium

Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023. 

References:

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2. 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):1208-1216.
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8. Boeve LMS, Hulshof MCCM, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410-418.
9. Han S, Woo S, Kim Y, et al. Concordance between Response Assessment Using Prostate-Specific Membrane Antigen PET and Serum Prostate-Specific Antigen Levels after Systemic Treatment in Patients with Metastatic Castration Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. Diagnostics (Basel). 2021;11(4):663.
10. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-1142.