Journal Issue

PCa Commentary | Volume 186 – February 2024

ACTIVE SURVEILLANCE: Patient Selection, Outcome and Monitoring for Gleason Grade Progression.
Question: Why not be treated at initial diagnosis of prostate cancer— and hope for cure?
Answer: Because all treatments are associated with unwelcome adverse effects that most men would prefer to avoid. Who should receive immediate treatment, and which men may safely delay treatment, preserving quality of life, — and with careful monitoring and timely intervention experience a similar outcome as if treated initially. That is the subject of this Commentary: patient selection for active surveillance (AS) and new techniques for monitoring for progression during AS.

Currently, eligibility for AS is based on clinical/pathological and biomarker features that define low- or favorable intermediate-risk prostate cancer: Gleason score 3+3 (Grade Group1) and Gleason score 3+4 (Grade Group 2); < 20% Gleason pattern 4; less than 50% positive biopsy cores and having only one NCCN intermediate risk factor (i.e., PSA 10-20 ng/ml, Gleason score 7 and cancer limited to the prostate). A PSA Density of <.15 and an MRI PIRAD score of 1 or 2 support AS. Although Gleason Grade Group 1 is to a small extent heterogeneous, the behavioral heterogeneity of Gleason score 7 grouping has led to a sub-classification into “favorable (Gleason 3+4; Gleason Grade Group 2) and unfavorable intermediate-risk cancer (4+3; Gleason Grade Group 3), the latter not advised for AS. The concern regarding the extent of Gleason pattern 4 in Gleason score 3+4 is based on the understanding that prostate cancer cells with pattern 4 characteristics have the potential to invade and metastasize. Patients with <5% pattern 4, are deemed satisfactory for AS, whereas a rise toward 20% increases the advisability for early intervention. The NCCN guidelines “prefer” AS as opposed to initial treatment for low-risk patients and allows consideration of AS for men with favorable intermediate-risk cancer with low PSA density (< .15) and low tumor volume ( i.e., < 2 positive cores), low genomic risk score and low percentage of Gleason pattern 4, i.e., <5%. Brief Summary of Outcome of Trials of Active Surveillance in Patients with Gleason Grade Groups 1 and 2: An extensive current review (Mukherjee et al., Journal Clinical Medicine, Dec. 2023) of outcomes for men with localized cancer (low-risk and favorable intermediate-risk) was based on a review of 712 studies from which 25 provided sufficient detail. Two representative studies will be briefly summarized: Courtney et al., (J.NCCN. 2022): Men on AS [8726 low-risk (LRPC) and 773 favorable intermediate-risk (FIRPC)] patients were followed for a median of 7.6 years. Metastasis-free survival at 10 years was 98.5% vs 90.4%; cancer-specific survival was 99% vs 96%, respectively. Mukhergee et al., (Eur. Urol. Open Sci., 2023): For men on AS (276 LRPC and 96 FIRPC) with median follow-up of 4.5 years. “… there was no significant difference in the median duration of AS between the two groups (32.5 months for IRPCvs 36 months for LRPC, p=0.53.” During the course of AS 30% had disease progression and were offered active treatment. The overall survival probability at 5 years for LRPC and FIRPC was 93% for both, and at 10-years 90% vs 83%s respectively. Studies from John Hopkins and Toronto report 98-99% cancer-specific survival in carefully selected and monitored men with low- and favorable intermediate-risk cancer despite 36% to 50% conversion to treatment during AS due to Gleason grade progression (Data from NCCN 2022 guidelines). The excellent survival figures in all these studies point to the effectiveness of treatment in those men who progressed during AS. The equivalence of outcome at intervention for carefully selected and monitored men on AS compared to those men treated with surgery at diagnosis has been multiply reported. Epstein, Carter et al., (Journal Urology, 2017) reported, ”Patients on active surveillance reclassified to grade group 2 or greater are at no greater risk for treatment failure than men newly diagnosed with similar grades.” Genomic Classifiers (Decipher, Prolaris, OncotypeDx) provide greater prognostic accuracy than standard clinical/pathological classifications (cited above) for estimating progression in men with localized prostate cancer considering AS. At the 2023 meeting the Society of Urologic Oncology Sheng et al. (Abst 237) reported that in a study of 235 men, Decipher Genomic Classifier (range of increasing concern for metastases and mortality extend from 0 -1.0) was associated with an upgrade to adverse pathology in men with a scores above 0.4 (p=.002) and above 0.6 (p=.006) - both values not suitable for men considering AS. A second study by Khandaker based on data from the Miami Active Surveillance Trial reported similar findings: Decipher scores >0.4 and increasingly above 0.6 were associated with adverse Gleason grade progression which would signal early intervention as opposed to AS.

The Next Step Forward: Predicting Future Progression Dynamically During AS as Opposed to Predictions Made Only at Baseline.

The clinical/pathological classification systems cited above offer prognostic (as opposed the predictive) information to guide patient selection but are not patient-specific. For example, a Decipher score of, say, 4.3 establishes a concerning level of risk but leaves the patient and physician a significant management decision about how to incorporate that extent of risk in a management plan. Studies using statistical analysis (see Cooperberg below) and artificial Intelligence (see Lee and Nayan below) provide dynamic patient-specific predictions of adverse grade progression during the course of AS.

Cooperberg et al.,(JAMA Oncol, Aug 2020) addressed this issue in “Tailoring Intensity of Active Surveillance for Low-risk Cancer Based on Individualizing Prediction of Risk Stability.”
The Canary Prostate Active Surveillance Study (PASS) involves 9 academic medical centers and based their study on 850 very explicitly followed patients for at least 5 years following enrollment. Their product provided an individualized prediction at the time of diagnosis or during AS of ‘non-reclassification’ at 4 years – i.e., information that might guide continued participation in AS or a switch to intervention. “The Canary model was built to be calculable at any given landmark time or event in the course of active surveillance.” Their findings suggest that “based on an individual’s risk parameters, that many men may be safely monitored with a substantially less intensive surveillance regimen.”

Two other studies employed AI to predict grade progression during AS [Lee et al. (Nature Prostate Journal, Digital Medicine, Aug 2022) and Nayan et al. (Urol Oncol. Apr 2022)]. Both provided a guideline regarding future progression. Using AI and incorporating interval monitoring data (PSA, MRI and biopsies) each study estimated an ongoing “real life” prediction at any time during AS of the risk of future Gleason grade reclassification, information that could influence the decision to withdraw from AS and switch to active intervention.

BOTTOM LINE:

Active Surveillance is the preferred management option for men with low- and favorable intermediate-risk prostate cancer and has been shown to yield excellent outcomes. Genomic classifiers are further refining patient selection. Statistical analysis and artificial intelligence provide dynamic risk assessment for grade progression during the ongoing course of AS.

Read More

PCa Commentary | Volume 185 – January 2024

Background

Oligometastatic prostate cancer (omPC) designates the status of having 3 to 5 metastatic lesions at diagnosis with an untreated primary or a similar extent of spread at recurrence after primary therapy. Metastasis directed therapy (MDT) focuses radiation to those several lesions. This situation is increasingly prevalent due to the more frequent use of PSMA PET imaging and in 2018 the incidence of hormone sensitive metastatic PC prostate cancer (mHSPC) at diagnosis was 8.2% (Vandenberg et al. Prostate Cancer and Prostatic Diseases, 2023), occurring mainly in men with high-risk cancer. Metastatic hormone sensitive PC can be found in men studied by PET imaging whose PSA is rising following primary therapy, converting non-metastatic HSPC to metastatic hormone resistant PC (mHRPC).

In their study of 200 men with rising PSA values after primary therapy before hormone intervention, PSMA PET scans identified metastases beyond the prostate in 55% of men, pelvic nodal disease in 20% and local recurrence in 24% (ibid). Studies comparing the genomics of denovo mHSPC with recurrent mHRPC have found — likely due to the delay in diagnosis allowing time for mutations to develop — that the cancer in the recurrent state is more aggressive.

Focal radiation therapy (e.g. with CyberKnife radiation) achieves >95% local control of oligometastatic lesions, but the major deficiency of MDT is the subsequent emergence of un-imaged polymetastatic disease. Metastatic prostate cancer is biologically heterogeneous with some metastatic sites remaining indolent and others rapidly progressing to polymetastatic spread. The current research challenge is to identify biologic markers and molecular signatures to predict metastatic behavior and guide therapy based on which men would benefit from MDT.

Three treatment options for oligometastatic prostate cancer were reviewed in PCa Commentary Vol. #182. In brief, MDT without ADT, MDT with ADT, and MDT combined with intermittent Xtandi. All had improved overall survival as compared to ADT only. However, in those studies patients were selected based on CT and technetium bone scans, not the more sensitive PSMA PET imaging, which detects metastases earlier at diagnosis and at recurrence. Current patient selection is based arbitrarily on the number and location of treatable metastatic lesions.

Conventional Predictors of Progression Following MDT for Oligometastatic Prostate Cancer

Analysis of early trials comparing MDT with no ADT (Deek, JCO 2022) found that men with mutations in the DNA damage repairs genes, i.e. BRCA 1, 2 and ATM, were at high risk for early failure. Radiographic progression-free survival for those without deleterious mutations compared to those with mutations was 22.6 months vs 10 months, respectively.

Another analysis found that the size, location of metastatic lesions and PSA doubling time in men with oligorecurrent disease affected outcome (Franzese, Clin & Experimental Metastases, 2022). In their study with PSMA PET imaging the median size of metastatic lesions was 4 cm.

Local control at 1 and 2 years was 94% and 92%; progression-free survival at 1 and 2 years, 80% and 69%, with a median time to progression of 33.7 months. The best outcomes were associated with pelvic nodal disease, followed by extra-pelvic nodal spread or metastases to bone. The take-away from these data is the need for more accurate predictors based on molecular features to guide selection of men who will benefit most from MDT.

Liquid Biopsy

The current quest is to identify a molecular signature to predict the aggressiveness of oligometastatic lesions to determine the likelihood of rapid progression to polymetastatic disease.

Tumor cells circulate (CTC) in the blood pre-diagnosis and increasingly as the disease progresses. Cell Search, an FDA approved test, has established that 5 or more CTC in 7.5 cc of blood augers a poor prognosis and less than 4 is associated with a better prognosis. Sophisticated genomic sequencing – usually referred to as ‘next generation sequencing,’ can analyze the DNA and identify the associated mutations of these circulating cells. The analysis of DNA debris from these cells – referred to as circulating tumor DNA (ctDNA) summarizes the contribution of ctDNA of the entire malignant population, an advantage since the genomes of various metastatic lesions may differ, rendering a biopsy of one site a limited representation of the overall metastatic burden.

Most circulating free DNA is shed from normal cells; in cancer patients only 0.01 – 5% of the circulating free DNA is derived from tumor cells. After the primary prostate tumor has been removed or treated, ctDNA characterizes the totality of micro- or macro metastases – and it is this ctDNA that is being evaluated for clues as to the aggressiveness of the oligometastatic lesions to guide the appropriateness of MDT.

A Major Effort

“Stratification of Oligometastatic Prostate Cancer by Liquid Biopsy: Clinical Insights from a Pilot Study,” Colosini, Triggiano et al, Biomedicines, 2022. In their earlier abstract (GU Cancers Symposium, 2018) they described the background of their study: “oligometastatic prostate cancer (OPC) may represent the initial stage of an unfavorable, rapid progression to a polymetastatic state, or the expression of a real oligometastatic phenotype related to a condition of stable disease for a long time.” They studied 28 men with hormone naive OPC, imaged with 11C-Choline PET CT, sequencing a panel of 37 prostate cancer relevant genes in circulating free DNA and microRNA. The genomic analysis was repeated frequently to evaluate the evolution to disease progression. The commonest adverse mutations were ATM, 50%, BRCA2, 39% and BRCA1 21%.

Having established the pre-MDT genomic characteristics of the men, their goal is in the subset follow-up to relate the molecular biomarker to outcome. The study is immature for analysis, but it is hoped that the outcome will provide guidance for patient selection to MDT.

BOTTOM LINE

Metastasis directed therapy prolongs survival in men with oligometastatic prostate cancer. It is hoped that genomic analysis with liquid biopsy will provide guidance for improved patient selection.

Read More

PCa Commentary | Volume 184 – December 2023

Background

Some men with low- or intermediate-risk localized prostate cancer will present on MRI imaging with a lesion sufficiently small and apparently well-delineated to warrant targeted focused therapy. This is termed “focal therapy” and can be accomplished with heat probes (laser ablation), radioactive seeds (brachytherapy), freezing (cryotherapy) or highly focused radiation (stereotactic ablative radiotherapy with, i.e., CyberKnife). The goal is total eradication of the cancer with the associated benefit in quality of life by better preservation of erectile function and urinary continence as compared to whole gland treatments. It might be considered a “middle ground” between active surveillance and radical treatment and is particularly appropriate for favorable intermediate-risk cancers.

Currently, the mpMRI is the imaging tool to select patients for focal therapy. The concept of focal therapy is the irradiation of the “index” lesion as visualized on the mpMRI. Therefore, the accurate location and definition of intraprostatic cancer is essential. Since disease often extends unseen 5-10 mm beyond the MRI “area of interest,” the fully treated field is often “hemi-gland.” Appropriate candidates for focal therapy are those men with PSA less than or equal to 15ng/mL, clinical/radiological tumor stage limited to 1/2 of the prostate ( less than or equal to T2b) and Gleason Grades 2-3. A recent study (Geboers et al. BJU Int, Oct. 2023) addressed focal therapy and patient selection and reported that the sensitivity and negative predictive value for MRI imaging for excluding more advanced cancer were 79% and 77%, respectively.

Their study found that the addition of a PSMA PET scan for patient selection provided some improvement. However, the major shortcoming of focal therapy is unidentified cancer extending beyond the chosen treatment margins or subtle multifocal disease. These states are the “Achilles Heel” that decreases the effectiveness of all forms of focal therapy based on the conventional MRI.

In the 1970s pioneers in the management of breast cancer developed the “lumpectomy” procedure (local excision of cancer with breast preservation) and this strategy has become standard of care in the treatment of early breast cancer. Potentially, focal therapy of prostate cancer could achieve a similar accomplishment. The two most common forms of focal therapy for prostate cancer are brachytherapy and cryotherapy.

Focal Brachytherapy

In 2022 Langley et al. (Brachytherapy) reported the findings of the ‘Hemi-Ablative Prostate Brachytherapy Trial’ comparing low-dose-rate I-125 hemi-gland BT treatment, 30 men, vs 362 men, whole-gland “to control unilateral localized prostate cancer and reduce treatment-related toxicity at 2 years post-implant.” Bowel, bladder, erectile function and quality of life was evaluated by a combination of standard questionnaires. Symptoms were significantly less troublesome for men receiving hemi-gland vs whole-gland brachytherapy.

Findings: “The mean time to PSA nadir was 4.2 and 4.8 years in HG and WG, respectively.” Treatment failure occurred in 6.7% HG patients and in 5.5% WG patients. “Five-year relapse-survival was 97% in both groups (P=.07).”

Focal Cryotherapy

A small and carefully performed protocol of focal cryotherapy was reported by Tan et al, The Prostate, March 2023. Twenty-eight men were studied, and all underwent a 12-month follow-up biopsy. Patient eligibility required a single MRI lesion with volume less than or equal to 3 cm or two lesions each less than or equal to 1.5 cm; PSA less than or equal to 20 ng/mL; and Gleason Grade Group less than or equal to 4. The lesions were treated with 5 mm margins. The median PSA at onset was 7.3 ng/mL and was reduced to a median of 4.6 ng/mL, a 60.4% reduction.

Findings: At the 12-month MRI-based biopsy 22 patients (78.6%) had no detectable prostate cancer while 6 men had cancer with < Gleason Grade Group 2. Within the treated field 7.1% were biopsy positive and 10.7% had cancer beyond the treated field; one man had both. Four men had repeat cryotherapy, one surgery, and one with low-volume GG2 cancer entered active surveillance.

Urinary and sexual domains both demonstrated “acute deterioration at one month with recovery at 3 months.” “Ablation to the adjacent neurovascular bundle delayed recovery of sexual function for 6 months”, otherwise there was “no deterioration in sexual function.” Since focal therapy does not ablate the entire prostate, residual serum PSA remains, rendering inapplicable the usual PSA thresholds indicating post-treatment biochemical recurrence. A study of HIFU therapy by Mattlet et al, (Prostate, 2023) of 343 men found a failure rate of 23% based on clinically significant cancer on post-therapy biopsy.

The best criteria for predicting failure were “PSA nadir + 1 ng/mL at 12 months or PSA nadir + 1.5 ng/mL at 24-36 months.”

Artificial Intelligence to Treat the “Achilles Heel”

The in-field persistence of disease noted above in both types of focal treatments is likely the result of insufficient radiation dose or inherent resistance of the cancer in the treated focus. But out-of-field untreated disease is due to inaccurate targeting. Avenda Heath, a biotech company, has addressed this deficiency by creating a multimodal AI model, ‘Unfold AI,’ that produces a color-enhanced 3-D depiction of cancer within the prostate.

In their article, “Prediction and Mapping of Intraprostatic Tumor Extent with  Artificial Intelligence,” Priester, Marks et al, (European Urology Open Science, August 2023) contend that compared to their UnFold model, tumor delineation of intraprostatic tumor based on magnetic resonance imaging (MRI) significantly underestimates the extent of prostate cancer, which “complicates the definition of focal treatment margins.” Their AI-based platform is multimodal in that it combines patient-specific data (MRI, PSA, biopsy, and pathology) and artificial intelligence to create a “3-D cancer estimation map” showing the cancer’s extent and margins. Based on evaluation of 50 prostatectomy specimens from men with intermediate-risk cancer the mean sensitivity of cancer mapping was higher for AI estimated margins, 97%, than for MRI-based contours at 37%. This difference remained significant even when comparing the conventional treatment margins of 10 mm surrounding the MRI-identified tumor.

The authors’ conclusion: “This approach could help improve and standardize focal treatment margins, potentially reducing cancer recurrence rates.”

BOTTOM LINE

Focal therapy for prostate cancer is increasing. An Artificial Intelligence-based model, ‘UnFold’, more accurately defines intraprostatic tumor extent and margins compared to MRI-based estimates and can improve the efficiency of focal treatment.

Read More

PCa Commentary | Volume 183 – November 2023

Background

A forceful sea change is roiling in the management of this disease: artificial intelligence (AI) is coming into prominence benefiting cancer diagnosis, risk stratification, and the prediction of response to therapy for individual patients. Multimodal AI (using deep learning) draws upon increasingly large stores of clinical and outcome data and digital histopathology to identify patterns that can predict therapeutic benefits for personalized treatment. The reference datasets might be extensive information generated from large clinical trials, a repository of annotated pathology specimens or imaging datasets (such as those of MRIs). In recent years, the literature has reported an impressively extensive body of studies of AI applications. This Commentary will offer four examples that could inform clinical practice.

Guiding the Use of Androgen Suppression Adjuvant to Radiation Therapy:

Two published pace-setting studies on this subject were covered in previous PCa Commentaries.

PCa Commentary #180: Dr. Dan Spratt and colleagues (NEJM Evidence, June 2023) developed an AI program identifying a biomarker, derived from 1719 patients in 5 large clinical trials, that predicts the marginal benefit of adding short-term hormone therapy to primary radiation for a man with localized prostate cancer. By applying the AI-derived model, the 15-year estimate for developing distant metastases for biomarker-positive patients treated with ADT was 4% v 14.4% for biomarker-negative ADT patients. This test is commercially available at ArteraAI Prostate Test where it is fully explained.

PCa Commentary #181: The second study was presented in abstract form by Armstrong et al. at ASCO 2023:
“Development and validation of an AI-derived digital pathology-based biomarker to predict benefit of …[28 months vs 4 months] androgen deprivation therapy with radiotherapy in men with localized high-risk prostate cancer … .”

Improving Cancer Detection Based on Prostate MRI

Multiparametric MRI functions to detect prostate cancer and guide MRI-ultrasound fusion biopsies and treatment. Optimally an MRI study leads to a biopsy of only clinically significant cancer, defined as Gleason score of 7 or greater. The PIRADS (Prostate Imaging-Reporting and Data System) offers a numerical estimate for the likelihood of the presence of cancer based on the MRI. This estimate of cancer’s aggressiveness is based on a scale of 1 through 5, with 1 and 2 representing low likelihood, 3 – concerning and 4 and 5 very suspicious for cancer. Unfortunately, even this system has deficiencies.

As reported by Bhattacharya et al, Ther Adv Urol. 2022, compared to the examination of a  subsequent prostatectomy as ground truth, “12% of aggressive cancers, mostly those less than 1 cm, were missed on MRIs. False positive rate was greater than 35%. Additionally, there is high inter-reader variability. As a result, many unnecessary biopsies continue to be performed”.

“Radiomics” refers to the analytic system for extracting features of significance from MRI images that are not perceived by visual examination. There is extensive research on using radiomics to facilitate greater interpretive and predictive information from the MRI and to improve on the stratification of the PI-RAD system.

The underestimation of cancer extent on MRI is addressed by Priester et al, in ”Prediction and Mapping of Intra-prostatic Tumor Extent with Artificial Intelligence”, European Urology June 2023. One of their objectives was to improve the accuracy of tumor delineation of clinically significant cancer on the MRI to facilitate more effective focal radiation therapy, a technique increasingly gaining acceptance for intermediate-risk cancer. To accomplish this an AI model was developed combining MRI imaging, biopsy data, PSA and PSA Density values and prostate volume to produce “three-dimensional cancer estimation maps and margins.” When compared to cancer extent found on companion prostatectomy specimens, the AI estimate model was more accurate than one based on conventional MRI interpretation, ensuring a better outcome for focal radiation therapy.  This AI model is FDA-approved and commercially available: “Avenda Health AI Prostate Cancer Planning Software”.

Predicting Early Recurrence after Prostatectomy

An AI-powered method was developed to predict early recurrence at 36 months after prostatectomy based on digitized pathology slides in conjunction with clinical and outcome data (Huang et al, JCO Clin Cancer Inform, 2022). The AI platform was trained on 243 digitized whole-mount slides of prostatectomy specimens combined with information about Gleason score, staging, margin status and clinical outcome. The method was validated on 92 patients who had recurrence in <3 years and 151 who recurred after 3 years.

The 100,000 x 100,000  pixels surveyed per slide has the advantage (compared to the standard microscopic evaluation) of recording small, but relevant, regions that escape visual notice, and perhaps most important, capture immune features (not included in the Gleason Grade Groupings), of the tumor microenvironment and stroma (supporting cells) that are so influential in driving the cancer’s behavior.

Based on this data the study provided a prediction of biochemical recurrence within 3 years after surgery for men with cancer in all Gleason Grade Groups and performed better than conventional risk stratification systems. The authors felt that this AI method for identifying patients at risk for early recurrence would benefit the selection of personalized treatment.

AI in Association with Cancer Diagnosis and Gleason Grading

AI algorithms have performed well in this task and have been multiply validated. Many are certified for clinical use. The usefulness of AI has not been to replace pathologists in analyzing biopsy specimens, but to augment the heavy workload of pathologists. “Pathologic examination of prostate specimens is laborious and time-consuming due to the large number of slides per case – 50-100 slides per case.” (Tolkach)

In a comprehensive study by Tolkach et al. (Nature NPI Precision Oncology, 2023) 7473 biopsy cores were digitized, assessed for tumor detection and the results were compared with the findings of expert pathologists. “We show high levels of diagnostic accuracy for prostate cancer detection and agreement levels for Gleason grading comparable with experienced genitourinary pathologists.”

BOTTOM LINE

The application of artificial intelligence is becoming widespread in the field of prostate cancer with the promise of improving clinical practice.

Read More

PCa Commentary | Volume 182 – October 2023

Background

With the increased use of PSMA PET/CT scanning both at initial diagnosis of advanced prostate cancer and at disease recurrence, a substantial number of men will be found to have some extent of metastatic disease — either metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC). The second of these states will have arisen in what is termed ‘non-metastatic’ castration-resistant cancer (rising PSA despite castrate level of testosterone), in which, upon PET scanning, metastases are frequently identified. There is no current consensus regarding the appropriate treatment regimens for these disease states. Three options have been studied:

Metastases-directed radiation therapy only, i.e., no androgen deprivation therapy (ADT)
until progression
MDT combined with ADT
The newest option, MDT combined with intermittent hormone therapy (IHT)
Studies to date report that all three options prolong overall survival compared to ADT only.

Dividing mHSPC into High Tumor Burden vs Low Tumor Burden

Two major clinical trials (STAMPEDE and CHAARTED) have defined ‘high burden’ as: the presence of visceral metastases or four or more bone lesions one or more beyond the vertebral bodies and pelvis. These studies were based on standard CT and bone scans. This distinction between high and low burden disease has been developed to guide therapeutic regimens such as systemic treatment with Docetaxel with ADT +/- newer anti-androgen receptor agents i.e., Zytiga  or Xtandi) for high-burden disease. For low burden disease, MDT+/- ADT are options, including ablation of the prostate.

An early trial reported by Palma et al, Lancet 2019, established that MDT alone for men with 1-5
metastases had a superior overall survival than ADT only (SABR-COMET trial). Currently recruiting is NCT03721341 using MDT for treatment of 4-10 oligometastatic lesions combined with a variety of standard of care options as selected by the treating physician vs any chosen treatment option but without MDT.

Currently recent and ongoing studies in low burden disease focus on avoiding ADT until disease progression thus avoiding ADT toxicity.

New Techniques Under Development for Estimating Prognosis

Patient selection for MDT is currently best made with PSMA PET/CT scanning, which offers greater sensitivity than conventional imaging. Research is developing techniques to predict prognosis with greater sensitivity. One promising option is assessing the metabolic aggressiveness of the metastatic lesions under consideration for MDT by measuring the  PET SUV (specific uptake value) of individual lesions. SUV is a measure of cancer aggressiveness. In this assessment the SUVmax is calculated, which totals the combined metabolic activity of all the lesions. This requires special technology.

However, the mHSPC disease state is a heterogeneous collection of members each with different
biological behavior and a different risk of progression. An estimate of prognoses for a man with
mHSPC can be assessed by applying the genomic classifier Decipher on tissue from the primary.
A more technologically advanced assessment of biological behavior would be evaluating
microRNA or circulating tumor DNA in blood.

Initial Studies: The ORIOLE and STOMP trials of MDT 

The above-named studies were two early randomized trials of mHSPC employed MDT (with stereotactic radiation therapy) versus observation only in men with 3 or fewer metastatic sites.

The outcome of both trials (as reviewed by Deek et al., JCO 2022), was a prolongation of progression-free survival (PFS) in both studies. MDT targeted three or fewer lesions based on CT and bone scans in each man in the MDT arm. Progression-free survival was superior in both trials compared to observation only with a pooled median PFS of 11.9 months in the MDT arms and 5.9 months with observation only. Men in the study with high-risk mutations in the genes BRCA 1/2, ATM. RB1 and TP53 who received MDT also benefited, but to a lesser extent with a median PFS of 7.5 months.

In the ORIOLE trial at onset, in addition to CT and bone scans, men also had PSMA PET scans. The PET scans detected a total of 36 lesions of which 16 had not been seen on the CT and bone scans, emphasizing the importance of basing MDT on imaging with PSMA PET/CT.

The EXTEND Trial (NCT03599765)

The question addressed in “Addition of Metastases-Directed Therapy to Intermittent
Hormone Therapy for Oligometastatic Prostate Cancer,” Tang et al., JAMA Oncol. 2023, was “Does the addition of metastasis-directed therapy to intermittent hormone therapy improve progression-free survival for men with oligometastatic prostate cancer?” The study anticipated that the known “synergy” between hormone therapy and radiation therapy, would benefit the MDT treated group. MDT was delivered with the CyberKnife to 5 or fewer lesions. The study was randomized 1:1 between those receiving MDT therapy plus IHT and those receiving IHT only. The participants were stratified by the number of metastatic lesions (1-2 vs 3-5). All men received radiation to the prostate. Although some had received varying periods of HT pre-study, at trial onset androgen suppression was delivered for 6 months, after which hormone therapy was withheld until progression. Progression was defined as clinical or a PSA rise of greater than 25% or greater than 2 ng/mL above the nadir.

Both the ORIOLE and EXTEND trials found evidence that the immune system was sensitized to
attack metastatic sites that were too small to be imaged. The presumed explanation: In
destroying the targeted lesions intracellular proteins were released that sensitized T-cells to
attack additional metastatic site too small to be imaged.

Results  

At the time of the report’s analysis the median PFS had not been reached in the MDT /IHT arm but was 15.8 months in the IHT-only group.

A secondary goal of the trial was to prolong the duration during which the testosterone level was near normal. After stopping  ADT at 6 months the men in IHT group experienced testosterone levels greater than 150 ng/dL (low normal) for only 6 months before disease progression. In the MDT/IHT arm the median duration of having a testosterone level about 150 ng/dL had not been determined at the time of data analysis.

The trial reached its goal: By adding MDT to intermittent androgen suppression PFS was prolonged and the duration of normal testosterone level before progression was extended compared to intermittent hormone therapy only.

BOTTOM LINE

The increased use of PSMA scanning at the time of diagnosis is associated with an increased prevalence of metastatic hormone sensitive prostate cancer. A variety of treatment regimens using metastasis directed therapy (MDT) are under active study.

Read More

Join the GRU Community

- Why Join? -