INTERVIEW WITH FERNANDO MALUF
Latin American Oncology Group (LACOG), a Cooperative Group Consensus

INTERVIEW WITH CHARLES RYAN
APCCC 2019 Global vs. Expert Consensus in the Management of Advanced Prostate Cancer Study

INTERVIEW WITH SILKE GILLESSEN & AURELIUS OMLIN
The Side Effects of Advanced Prostate Cancer Consensus Conference 2019 (APCCC)

INTERVIEW WITH JAMES GULLEY
Immunotherapy Across Genitourinary Malignancies

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APCCC 2019: Local Treatment of The Primary (Surgery) in the Metastatic Situation

Basel, Switzerland (UroToday.com) Dr. Thomas Steuber spoke on the role of surgery in the setting of metastatic prostate cancer. Treatment of the primary tumor is considered standard of care in other malignancies (colorectal and ovarian for example). There are certain advantages specifically in surgical removal of the primary tumor. For instance, removing the prostate may prevent local complications, such as urinary obstruction, hematuria, and rectal stenosis. Removal of the primary tumor may also prevent further seeding from an uncontrolled primary tumor and may destroy cells with potential genetic instability.

APCCC 2019: PARP Inhibition for Metastatic Castration-Resistant Prostate Cancer

Basel, Switzerland (UroToday.com) Dr. Kim Chi from Vancouver presented an update on the utilization of PARP inhibitors during the management of castration-resistant prostate cancer (CRPC) session at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC).

APCCC 2019: Which Systemic Therapy for Which Patients with Newly Diagnosed Metastatic Prostate Cancer?

Basel, Switzerland (UroToday.com) Dr. Christopher Sweeny's talk encompassed systemic therapy for prostate cancer. The spectrum of patients starting androgen deprivation therapy (ADT) for metastatic disease is quite vast. There are patients who present with de novo metastatic disease, and some present after previous radical prostatectomy or radiotherapy. Some of the patients are fit and young and some are old and frail. Some have a minimal disease, and some have widespread disease seen on conventional imaging modalities. Lastly, some patients have received ADT with radiotherapy or prostatectomy.

Metastatic hormone-sensitive prostate cancer (mHSPC) patients have a variable response to testosterone suppression, as can be seen in the CHAARTED1 and GETUG 15 trials2 (Table 1).

Table 1- Different patients have variable response to testosterone suppression:

APCCC_CHAARTED_GETUG15.png


From the long-term follow-up of the CHAARTED study after a median follow-up of 53.7 months, for the entire population, we can still see that those who got docetaxel+ADT continued to benefit compared to those who got ADT alone, with a 10-month survival advantage (HR 0.73).3 Specifically in the low volume metastatic disease population, we can see that the indolent patients dilute long term overall survival with docetaxel and we cannot make definitive statements on interim/early results. A few of the low-volume metastatic disease have aggressive disease and benefit from early docetaxel. Currently, it is not possible to identify them, and they do not constitute a large enough proportion to affect the survival of the entire group. In contrast, the high-volume metastatic disease patients benefited even more from docetaxel after long term follow-up.

When assessing the quality of life of these patients – for the ones that received only ADT, the ones with the low-volume disease had no change in the quality of life over 12 months. However, in high volume metastatic disease patients, the quality of life declined, as the disease had progressed. In contrast, for patients who received both ADT and docetaxel: For patients who received ADT only there was a decline in the quality of life for those with low-volume metastatic disease, but for the ones with high-volume metastatic disease there was no decline in quality of life.4

Next, Dr. Sweeney discussed the effect of these treatments on overall survival, as measured by hazard ratio (HR), and can be seen in the summary table 2. Docetaxel has a direct overall survival benefit for high-volume disease and documented improvement in the quality of life. However, for low-volume disease, there appears to be no overall survival benefit for docetaxel. Disease volume appears to be prognostic for the outcome on ADT and predictive for docetaxel benefit. Does this mean that there are different disease biology processes within mHSPC?

Table 2 – Summary of ADT +/- docetaxel treatment effect on overall survival:

APCCC_trials.png


The next medication discussed by Dr. Sweeney was abiraterone. The LATITUDE study showed that patients with high-volume metastatic disease (using CHAARTED criteria) benefit from abiraterone (HR 0.62 95% ci 0.52-0.74, P<0.0001), while for low volume disease there appears to be no statistically significant benefit (HR 0.72, 95% CI 0.47-1.10, p=0.1242).5 Abiraterone in mHSPC patients appeared to slow the time to decline in quality of life.6 When looking at the data from the STAMPEDE-abiraterone data, there was also a clear benefit to abiraterone in high volume disease (overall survival difference of 19.7%, HR 0.54, 95% CI 0.41-0.70, p<0.001), and for low volume disease (overall survival difference of 4.4%, HR 0.66, 95% CI 0.44-0.98, p=0.041). We need longer-term overall survival data to see if the overall survival benefit will be greater with the early use of abiraterone.

The next medication discussed was enzalutamide. The ENZAMET trial’s primary endpoint was overall survival difference between mHSPC patients treated with enzalutamide and ADT compared to those treated with ADT alone.7 This trial demonstrated a clear benefit for the enzalutamide treated patients (Figure 1). In this trial, there is a mixed bag of patients with low- and high- volume disease, de novo vs. metachronous metastases, and many permutations. Table 3 demonstrates the scorecard of other medications which are potent direct androgen receptor inhibitors in mHSPC. These include apalutamide and enzalutamide in the ARCHES trial.8

Figure 1 – Enzamet primary endpoint of overall survival showing the benefit in those treated with enzalutamide:

APCCC_ENZAMET_primary_endpoint.png


Table 3 – Scorecard of other trials of potent direct androgen receptor inhibitors in mHSPC:

APCCC_ADT+placebo.png


Dr. Sweeney ended his talk with a summary table showing direct evidence of some overall survival treatment benefit in mHSPC patients, as of August 2019 (Table 4). Dr. Sweeney concluded his talk stating that it is important to look for patterns in the available data to make decisions for patients. It is important to incorporate disease burden vs. comorbidities vs. treatment benefit vs. treatment risk. Another important issue to revisit at this point in time is treatment breaks, as over 60% of patients are on abiraterone + prednisone, enzalutamide, or apalutamide for more than 3 years. Lastly, we must find usable biomarkers to help us guide therapy in this developing field of treatment.

Table 4 – Overall survival treatment benefit in mHSPC patient as of August 2019:

APCCC_co-morbitity.png



Presented by: Christopher Sweeney, MBBS, Professor of Medicine, Harvard Medical School, Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Sweeney C. et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New England Journal of Medicine. 2015; 373:737-746
    DOI: 10.1056/NEJMoa1503747.
  2. Gravis G. et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncology. 2013 Feb;14(2):149-58. doi: 10.1016/S1470-2045(12)70560-0.
  3. Kyriakopolous et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. Journal of Clinical Oncology. 2018 DOI: 10.1200/JCO.2017.75.3657.
  4. Morgans et al. Quality of Life During Treatment With Chemohormonal Therapy: Analysis of E3805 Chemohormonal Androgen Ablation Randomized Trial in Prostate Cancer. Journal of Clinical Oncology. 2018 Apr 10;36(11):1088-1095. doi: 10.1200/JCO.2017.75.3335.
  5. Fizazi K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. New England Journal of Medicine. 2017; 377:352-360
    DOI: 10.1056/NEJMoa1704174.
  6. Chi K. et al. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncology. Feb;19(2):194-206. doi: 10.1016/S1470-2045(17)30911-7. 2018.
  7. Sweeney C. et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine. 2019; 381:121-131
    DOI: 10.1056/NEJMoa1903835.
  8. Armstrong A. et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology. 2019 DOI: 10.1200/JCO.19.00799.

APCCC 2019: Wishes in Locally Advanced Prostate Cancer

Basel, Switzerland (UroToday.com) Dr. Alberto Briganti presented his wishes for the future treatment of locally advanced prostate cancer. Dr. Briganti mentioned 4 major points where he would like to see progress. The first issue was the intensification of tailored multi-modal approaches. In the past, neoadjuvant androgen deprivation therapy (ADT) prior to surgery had proved to be non-beneficial. However, with the novel androgen receptors antagonists, Dr. Briganti believes we could retry this strategy. In fact, there have been several phase II trials assessing the role of enzalutamide, abiraterone, docetaxel, and LHRH agonists before surgery. Unfortunately, these were only phase II trials with a limited number of patients and the pathological/imaging endpoints that were used in these studies still need to be correlated with clinical outcomes. In any case, there are currently many ongoing trials assessing novel molecules in the neoadjuvant setting (Table 1). These include the assessment of the role of novel immunotherapy medications such as the anti-PD-L1 pembrolizumab.

Table 1 – Ongoing trials assessing novel molecules in the neoadjuvant setting:

APCCC_novel_molecules.png

Another option to pursue is the use of various genomic tests such as the DECIPHER test to select ideal candidates for postoperative radiotherapy. The DECIPHER test is an independent predictor of metastases after adjusting for other variables.1 Aside from pathological stage T3b/T4, Gleason scores above 8, and lymph node invasion, a Decipher score of above 0.6 has been shown to predict recurrence.2 There are also several ongoing trials assessing genomic-driven adjuvant therapies, such as the PRO-IMPACT trial evaluating the clinical utility of Decipher for the administration of postoperative therapies (NCT02080689).

There is also an ADT response signature (ADT-RS). It has been created from gene expression patterns that may serve as an early marker of androgen resistance. Patients with a low ADT-RS had similar 10-year metastasis rate in those treated with ADT compared to those not treated with ADT. In contrast, those with a high ADT-RS, treatment with ADT conferred significantly lower 10-year metastasis rate than those not treated with ADT (9.4% vs. 29.2%, p=0.02).3

The second issue discussed was image-guided surgery. Despite its increasing use and enhanced accuracy, the PET-PSMA has a sensitivity of 24.4% per node, and 38.2% per patient, which is quite low.4 Therefore, PET-PSMA will not be able to replace an anatomically defined extended pelvic lymph node dissection. Incorporation of the PET-PSMA imaging during surgery, creating a radio-guided surgery, will enhance our accuracy and allow us to remove all involved lymph nodes (Figure 1).

Figure 1- Radio-guided surgery:

APCCC_radio-guided.png

The third issue discussed by Dr. Briganti was the use of novel tools to improve local control. These include three-dimensional elastic augmented-reality robotic radical prostatectomy using hyper-accuracy three-dimensional reconstruction technology. This is a novel system used to identify capsular involvement when performing nerve-sparing surgery. This allows incorporating the MRI images into the robotic console during surgery and enhancing accuracy during surgery (Figure 2).

Figure 2- Three-dimensional elastic augmented-reality robotic radical prostatectomy using hyper-accuracy three-dimensional reconstruction technology.

APCCC_three-dimesional.png

The fourth and last point was centralization of care. A large population-based study has shown that the overall survival of radical prostatectomy surgeries improved in direct correlation to the facility volume.5 Therefore, surgeries of high-risk patients should be performed strictly in high-volume centers.

Dr. Briganti concluded his talk mentioning the currently ongoing SPCG-15 trial which will randomize patients with high-risk prostate cancer to surgery + extended pelvic lymph node dissection + adjuvant radiotherapy with 2 years of bicalutamide, and to radiotherapy + ADT for 18 months (Figure 3).

Figure 3 – SPCG-15 trial:

APCCC_SPCG-15.png


Presented by: Alberto Briganti, MD, Professor of Urology, Università Vita-Salute San Raffaele, Deputy Director, Urological Research Institute (URI) of IRCCS Ospedale Università Vita-Salute San Raffaele, Milan, Italy

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Spratt DE, Yousefi K, Deheshi S, et al. Individual Patient-Level Meta-Analysis of the Performance of the Decipher Genomic Classifier in High-Risk Men After Prostatectomy to Predict Development of Metastatic Disease. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jun 20 2017;35(18):1991-1998.
  2. Dalela D, Santiago-Jimenez M, Yousefi K, et al. Genomic Classifier Augments the Role of Pathological Features in Identifying Optimal Candidates for Adjuvant Radiation Therapy in Patients With Prostate Cancer: Development and Internal Validation of a Multivariable Prognostic Model. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jun 20 2017;35(18):1982-1990.
  3. Karnes RJ, Sharma V, Choeurng V, et al. Development and Validation of a Prostate Cancer Genomic Signature that Predicts Early ADT Treatment Response Following Radical Prostatectomy. Clinical cancer research : an official journal of the American Association for Cancer Research. Aug 15 2018;24(16):3908-3916.
  4. Yaxley JW, Raveenthiran S, Nouhaud FX, et al. Outcomes of Primary Lymph Node Staging of Intermediate and High Risk Prostate Cancer with (68)Ga-PSMA Positron Emission Tomography/Computerized Tomography Compared to Histological Correlation of Pelvic Lymph Node Pathology. The Journal of urology. Apr 2019;201(4):815-820.
  5. Joshi SS, Handorf ER, Sienko D, et al. Treatment Facility Volume and Survival in Patients with Advanced Prostate Cancer. European Urology Oncology.
 

APCCC 2019: PSMA Targeted Therapies

Basel, Switzerland (UroToday.com) Dr. Michael Hofman discussed PSMA targeted therapies at the management of CRPC session at APCCC 2019, presenting data from both of his groups in Australia. Dr. Hofman notes that theranostics combines targeted therapeutics with a diagnostic companion, for example, a radioactive small molecule targets prostate-specific membrane antigen (PSMA), which is highly overexpressed in prostate cancer.

Lutetium-177 (177-Lu) is a short path beta emitter with a mean length of 1mm, average penetration of 0.3 mm, and a 6.7-day half-life. Starting in 2015, there was retrospective data to suggest a high activity of 177-Lu, with the first published case report of 177-Lu-PSMA-617 showing complete treatment response after two cycles of 177-Lu-PSMA-617. Dr. Hofman notes that 2015 was also the first time they performed their first 177-Lu-PSMA treatment at Peter Mac. In 2015, his group also started enrolling to the first prospective phase 2, single-arm study1. During enrollment, 43 men were screened to identify 30 patients eligible for treatment, which included a mean administered radioactivity dose of 7.5 GBq per cycle. There were 17 (57%) of 30 patients that achieved a PSA decline of 50% or more, and there were no treatment-related deaths. Objective response in nodal or visceral disease was reported in 14 (82%) of 17 patients with measurable disease. Clinically meaningful improvements in pain severity and interference scores were recorded at all time points, and 11 (37%) patients experienced a ten point or more improvement in global health score by the second cycle of treatment. The most common toxic effects related to [177Lu]-PSMA-617 were grade 1 dry mouth recorded in 26 (87%) patients, grade 1 and 2 transient nausea in 15 (50%), and grade 1 and 2 fatigue in 15 (50%). Grade 3 or 4 thrombocytopenia possibly attributed to [177Lu]-PSMA-617 occurred in four (13%) patients.

Updated date from Dr. Hofman shows they have now screened 75 patients and enrolled 50 patients for analysis. Although not as yet published, Dr. Hofman notes that 15 of 50 patients had re-treatment with LuPSMA with a PSA >50% response rate of 73%. In an assessment of the 16 patients they didn’t treat, these patients were excluded for low PSMA-expression (50%) and discordant FDG+ disease (50%). Median OS in for these patients was only 2.5 months (95% CI 1.7-5.0 months)2.

Dr. Hofman concluded by highlighting several trials with 177Lu-PSMA that are ongoing:

TheraP Trial: 177Lu-PSMA-617 versus cabazitaxel

TheraP Trial


VISION Trial: 177Lu-PSMA versus best supportive care

VISION Trial


PRINCE Trial: PSMA-lutetium Radionuclide therapy and immuNotherapy in prostate cancer

PRINCE Trial


LuPARP Trial: Phase 1 trial of 177Lu-PSMA-617 therapy and olaparib  

LuPARP


#UpFrontPSMA: high-volume metastatic hormone naïve prostate cancer 

UpFrontPSMA


#LuTectomy: 177Lu-PSMA prior to surgery

LuTectomy


Presented by: Michael S. Hofman, MBBS (Hons), FRACP, FAANMS, Peter MacCallum Cancer Centre, Melbourne, Australia 

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
1. Hofman MS, Violet J, Hicks RJ, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): A single-center, single-arm phase 2 study. Lancet Oncol 2018 Jun;19(6):825-833.

2. Thang SP, Violet J, Sandhu S, et al. Poor Outcomes for Patients with Metastatic Castration-resistant Prostate Cancer with Low Prostate-specific Membrane Antigen (PSMA) Expression Deemed Ineligible for 177Lu-labelled PSMA Radioligand Therapy. Eur Urol Oncol 2018 Dec 13 [Epub ahead of print].

APCCC 2019: Wishes in Biomarkers

Basel, Switzerland (UroToday.com) Dr. Mark Rubin briefly shared his thoughts on the future of metastatic prostate cancer in regards to biomarkers. He began his talk with some definitions of prognostic and predictive biomarkers.

APCCC 2019: Wishes in Polymetastatic Prostate Cancer

Basel, Switzerland (UroToday.com) In the past, androgen deprivation therapy (ADT) was the only available option for metastatic prostate cancer. When looking at data published 15 years ago, approximately 4.4-7% of metastatic patients lived for more than 10 years.1,2 The independent predictors of survival were lower PSA, low volume disease, lack of pain, and lower Gleason score.1 However, in the last 10 years, there has been tremendous progress in the available treatment options for metastatic prostate cancer patients (Figure 1). Serial systemic therapy with combinations of ADT with chemotherapy, abiraterone, or enzalutamide, and other therapies are now standard of care. Local and metastases directed therapy are still considered investigational at present, but earlier interventions in certain circumstances have shown to improve outcomes.

When assessing and comparing older and newer cohorts of metastatic prostate cancer patients’ outcomes have improved significantly in the last 10 years, with 5-year overall survival rates increasing from 10% between 2004 and 2007 to 26% between 2010-2013.3

Figure 1- Significant progress in the treatment option for metastatic prostate cancer in the last 10 year: 

APCCC_oligom.png

It is difficult to predict what the future holds in this field, but we can certainly imagine. Dr. Oh predicts that immunotherapy will gain a substantial role in the treatment of these patients and that we might even be able to think of the word “cure,” although we are still a long way away. For example, the number of search results for the combination of “cancer” and “cure” in PubMed has risen substantially in the past years (Figure 2).

Figure 2 – PubMed citations of the words “cancer” and “cure”:

APCCC_PM_citations.png


The standard approach currently used for the treatment of metastatic prostate cancer incorporates monotherapy of one single advanced drug until resistance develops, and then treatment is switched. Some of the analyzed combinations have shown excess toxicity. However, by designing a rapidly-cycling, non-cross-reactive treatment regimen we might be able to:

  1. Treat intrinsic heterogeneity
  2. Prevent drug resistance
  3. Increase long term disease control
  4. Minimize toxicity
This management strategy is called Prostate Cancer Intensive, Non-Cross-Reactive Therapy (PRINT) for metastatic castrate-resistant prostate cancer (mCRPC). Dr. Oh described an ongoing study at Mount Sinai using this principle in mCRPC patients (Figure 3).

Dr. Oh concluded his talk summarizing some of his personal predictions for the future of metastatic prostate cancer. First, the molecular characterization of tumors will be increasingly relevant as newer targeted drugs are developed. Second, Immunotherapy in metastatic prostate cancer will be more effective. Third, more combination therapies (local and systemic) will be used. Lastly, Functional “cures” of metastatic prostate cancer will become more common. Dr. Oh believes that a cure is possible in metastatic prostate cancer if our definition is flexible.

Figure 3: PRINT ongoing study for mCRPC patients:

Print for mCRPC 2



Presented by: William Oh, MD, Professor, Medicine, Hematology, Urology and Medical Oncology, Mount Sinai Hospital, New York, USA

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Tangen CM, Faulkner JR, Crawford ED, et al. Ten-Year Survival in Patients with Metastatic Prostate Cancer. Clinical Prostate Cancer. 2003;2(1):41-45.
  2. Klaff R, Berglund A, Varenhorst E, Hedlund PO, Jonler M, Sandblom G. Clinical characteristics and quality-of-life in patients surviving a decade of prostate cancer with bone metastases. BJU international. Jun 2016;117(6):904-913.
  3. Francini E, Gray KP, Shaw G, et al. Impact of new systemic therapies on overall survival (OS) of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) in a hospital-based registry. Journal of Clinical Oncology. 2018;36(6_suppl):203-203.

APCCC 2019: Wishes in Oligometastatic Prostate Cancer

Basel, Switzerland (UroToday.com) Dr. Himisha Beltran gave an overview looking into the future of oligometastatic disease, and where she predicts we will be in two years’ time.

The current definition of oligometastatic disease is based on the number of metastases (1-5). Importantly, novel imaging modalities such as PET-PSMA have resulted in defining a worse disease state. For example, if conventional imaging (CT and bone scans) are negative but the PET-PSMA recognizes 3 lesions, patients are upstaged to metastatic setting. Furthermore, when 3 lesions e identified in standard imaging, but if many more are seen in PET PSMA imaging, the patient is upstaged from low-volume to high volume metastatic disease.

The goals of care should be determined by biology and stratified by:

  • Low metastatic potential.
  • Intermediate or heterogeneous disease.
  • Systemic disease.
For low metastatic potential - the goals should be delaying ADT, coming off systemic therapy, and perhaps even cure. Not all metastatic lesions come from the same clone of the primary tumor.1 It is not clear if molecular alterations in the primary tumor predict patterns of spread and the relative indolence of certain metastatic lesions. The primary tumor can continue to seed metastases, which provides us the reason why we should probably treat the primary tumor even in metastatic disease. The STAMPEDE2 and HORRAD3 trials point to greater benefit of removing the primary tumor in patients with low-volume disease. This potentially might be due to the greater contribution of the primary tumor clones.4

For intermediate or heterogeneous disease – An example of this is when one lesion progresses, and the others are stable (Figure 1). This could be explained by the fact that there is different biology across metastases. Could this mean that the different metastases came from different primary tumors? Or maybe the reason is the acquisition of resistance mutations during progression (Figure 2)? The way to combat heterogeneity in the same patient is with multimodal therapy. The goal should be to stay on the same systemic therapy and slow down progression.

For systemic disease – local/focal therapy may have no impact and the systemic therapy may need to be intensified. There are many methods to capture the underlying systemic disease. These include using molecular imaging, ctDNA, circulating tumor cells, exosomes, and other means. It is still not clear what exactly we are looking for – tumor burden, micrometastases, alteration in oncogenes/tumor suppressor genes, or metastases markers.

One method to capture tumor burden noninvasively is by using novel imaging modalities such as the PSMA PET, which is highly sensitive. However, it is not clear if we can use these advanced imaging tools to predict metastatic patterns before “detecting” them. For instance, in bone metastases – what we might see, might not be what is truly underneath (which is more aggressive biology). In contrast, for pulmonary metastases, what we see may not be what is underneath (which is a more indolent disease).

Figure 1 – Stable and progressing metastatic lesions:

Lesion Progression

Figure 2 -Acquisition of resistance mutations during progression:

Lesion Progression 2


The concept of metastases to metastases seeding leads to further intra-patient heterogeneity. It is difficult to capture by single-site biopsy. The therapeutic implications of this concept are that multimodal therapy needs to be used. Today it is possible to use liquid biopsies to detect intra-patient clonal heterogeneity, with whole-exome sequencing of matched plasma ctDNA and metastatic tumor burden. Using circulating tumor cells, we can capture the evolving heterogeneity, with serial testing identifying evolution/emergence of clones/subclones and evolution patterns.

According to Dr. Beltran, in two years, when the Advanced Prostate Cancer Consensus Conference (APCCC) 2021 occurs, we will have more data regarding how we have altered the natural history of oligometastatic prostate cancer. Hopefully, we will be able to answer some or perhaps all the following questions:

  1. What happens to patients who progress after local therapy for oligometastatic prostate cancer?
  2. If more oligometastases develop, do we just give more local therapy? Is there a need for systemic therapy at some threshold? And what is that threshold?
  3. When a widespread disease has developed, is the timing of this important? Was this delayed by local therapy? Is this important and does it have any significance?
Dr. Beltran summarized her talk and predicted that in two years from now we will have refined clinical definitions for disease stratification. We will have also nominated molecular biomarkers to capture biologic disease states, and we will have defined goals of care and improved patient selection.


Presented by: Himisha Beltran, MD, Medical Oncologist, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Kneppers J, Krijgsman O, Melis M, et al. Frequent clonal relations between metastases and non-index prostate cancer lesions. JCI Insight. 2019;4(2):e124756.
  2. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet (London, England). Dec 1 2018;392(10162):2353-2366.
  3. Boeve LMS, Hulshof M, 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. European urology. Mar 2019;75(3):410-418.
  4. Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. Apr 16 2015;520(7547):353-357.
 


APCCC 2019: Wishes in Prostate Cancer Imaging

Basel, Switzerland (UroToday.com) Dr. Stefano Fanti, a radiologist from Bologna, Italy, gave his point of view on how he sees the future in terms of prostate cancer imaging.

He began stating that the use of conventional imaging such as CT and bone scan should be regarded as obsolete starting from now. Novel imaging such as PET PSMA and MRI should be incorporated into practice immediately, as they are available and can give us enhanced and more accurate information when compared to the conventional and standard imaging modalities.

Conventional imaging (CT and bone scans) has limited sensitivity to depict nodal and bone disease in prostate cancer. Next-generation imaging, includes whole-body diffusion-weighted

MRI with novel radiopharmaceuticals for combined PET and CT, and combined PET and MRI is substantially more accurate in defining the extent of disease.1 Next-generation imaging enables:

  • Earlier initiation of treatment in patients whose disease cannot be diagnosed by conventional imaging.
  • Optimal change in treatment through earlier detection of disease progression.
  • Detection of the oligometastatic state, which may be treated more aggressively.
  • Guidance of tissue biopsies for molecular tumor characterization.
  • Development of novel predictive and prognostic biomarkers to guide therapies.
According to the EAU guidelines, it could be very tempting to conclude that bone scan and abdominopelvic CT must be replaced by more sensitive tests in all patients undergoing initial prostate cancer staging. But, the clinical benefit of detecting metastases at an earlier time-point still remains unclear.2 The guidelines state that the prognosis and ideal management of patients diagnosed with metastatic disease by these more sensitive imaging modalities is still unknown. It is unclear whether these patients should be contraindicated to local treatments and managed using systemic therapies, or whether they should be submitted to aggressive local and metastases-directed therapies.

Furthermore, according to the EAU guidelines to date, oligometastatic prostate cancer remains a systemic disease, which cannot be detected due to the insensitivity of the current diagnostic tests.3 The guidelines support well-designed controlled trials evaluating the management and outcome of patients with (and without) metastases detected by choline PET/CT, MRI, and PSMA PET/CT before any decision can be made regarding treatment.

It is clear that in the future of prostate cancer imaging will be deeply incorporated in all stages of the disease, from diagnosis to treatment, and to follow-up. This will include the initial diagnosis, staging, once biochemical recurrence occurs, at therapy planning and at therapy monitoring. Currently, there are 27 and 11 ongoing clinical trials assessing the role of PSMA in disease staging, and therapy planning, respectively. Hopefully, in the next few years, we will have plenty of data regarding the use of novel imaging modalities in disease staging and therapy planning.

Dr. Fanti concluded his talk with two interesting points:

  1. In the very near future use of the combined modality of MRI and PET PSMA will be routine, giving us tremendous amounts of anatomical and functional information regarding prostate disease (Figure 1).
  2. The ideal imaging tool should be small, portable, accurate and not expensive. Unfortunately, the currently used machines are the exact opposite – large, cumbersome, not-portable, and very expensive. Hopefully, with time these attributes will improve as well.
Figure 1 – mpMRI incorporated with PET-PSMA in prostate cancer:


APCCC_future_of_PCa_imaging.png


Dr. Fanti ended his talk with a nice slide showing his ABC's of prostate cancer imaging:

ABCs_of_PCa.png

*NGI = Next-generation imaging


Presented by: Stefano Fanti, MD, Professor, Department of Experimental, Diagnostic and Specialty Medicine - DIMES, Director of Nuclear Medicine Division of the PET Unit, Director of Speciality School of Nuclear Medicine, University of Bologna, Bologna, Italy

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Perez-Lopez R, Tunariu N, Padhani AR, et al. Imaging Diagnosis and Follow-up of Advanced Prostate Cancer: Clinical Perspectives and State of the Art. Radiology. 2019;292(2):273-286.
  2. Eiber M, Herrmann K, Fendler WP, Maurer T. (68)Ga-labeled Prostate-specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Imaging: The New Kid on the Block-Early or Too Early to Draw Conclusions? European urology. Dec 2016;70(6):938-940.
  3. Hicks RJ, Murphy DG, Williams SG. Seduction by Sensitivity: Reality, Illusion, or Delusion? The Challenge of Assessing Outcomes after PSMA Imaging Selection of Patients for Treatment. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. Dec 2017;58(12):1969-1971.

APCCC 2019: Wishes in Global Access to Treatments

Basel, Switzerland (UroToday.com) Dr. Karim Fizazi gave a brief talk on what can be approved in global access to treatment of advanced prostate cancer. His talk began with data on current access to radiotherapy on a worldwide level (Figure 1). This data showed that there is still a long way to go for us to reach the required numbers in a large percentage of countries in the world.

Figure 1 – Access to radiotherapy worldwide - Difference between demand and supply of radiotherapy machines:

APCCC_access_to_radiotherapy.png


The next topic discussed was the use of generic drugs, which will significantly lower the price needed to pay for the treatment of each patient. Lowering the price significantly will enable to make the medication available to a much larger proportion of the population. An example of an already commonly used generic drug is docetaxel. Before the loss of exclusivity, the cost of docetaxel per one cycle of use was approximately 1500 Euro. When the drug became generic, the cost came down to 20 Euro per cycle! However, according to a recently published paper, the cost of other generic drugs might not be sufficiently low to sustain publicly funded health care systems.1

For abiraterone, the expected access to generic medication is in 2019. In the US the cost is expected to decrease from 9000 USD to 2500 USD for uninsured patients, and no major change is expected for insured patients. In Brazil, the price is expected to go down from 3000 USD to approximately 1300-2300 USD, and in Europe, abiraterone is patent protected until September 2022. However, specifically for abiraterone, there may be an alternative that irrespective of the generic medication issue. A recently published study demonstrated that low-dose abiraterone with food was just as effective as standard dose abiraterone.2 In this study, low dose abiraterone with low-fat breakfast was shown to be non-inferior to standard dosing abiraterone with respect to PSA metrics. Reducing the dose of abiraterone by ¾ is could tremendously reduce the associated cost, and this requires further research.

The next drug discussed was cabazitaxel, with its generic form expected to start in 2021. CARD – is a randomized phase 4 trial comparing cabazitaxel and an androgen receptor (AR)-targeted agent in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and an alternative AR-targeted agent. The results of this trial are expected to be shown at the ESMO meeting in 2019, in Barcelona. This trial will show us if cabazitaxel has the same efficacy as abiraterone for example or better.

For the other drugs used in prostate cancer, the expected loss of patent is as follows:

Denosumab – 2025, enzalutamide – 2027, apalutamide – 2032, with no known estimated dates for Radium-223 and darolutamide.

Another important issue that is sometimes overlooked is the use of surgical castration vs. the use of LHRH agonists and antagonists. Surgical castration is effective as medical castration but is significantly cheaper. In a recently published study, 10,000 prostate cancer metastatic patients were assessed, and predictors of surgical castration were searched for.3 The study showed that the likelihood to receive surgical castration is greatly associated with the following factors:

  • Hispanic race (OR 1.3)
  • Low socioeconomic status (OR 2)
  • Rural area (OR 1.5)
  • Medicaid/public insurance (OR 2.2)
In contrast, patients with military/Veterans Affairs insurance were significantly less likely to receive surgical castration compared with patients with private insurance (OR, 0.34; 95% CI, 0.13-0.88). It would seem that low socioeconomic status is generally associated with a greater probability of undergoing surgery.

Dr. Fizazi concluded his talk at the Advanced Prostate Cancer Consensus Conference (APCCC) 2019 hoping that in 2 years’ time, at the APCCC 2021 meeting, the global access to various prostate cancer treatments will be greatly improved.


Presented by: Karim Fizazi, MD, Ph.D. Professor of Medicine of Institut Gustave Roussy, (IGR) in Villejuif, France

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Cheung WY, Kornelsen EA, Mittmann N, et al. The economic impact of the transition from branded to generic oncology drugs. Current oncology (Toronto, Ont.). Apr 2019;26(2):89-93.
  2. Szmulewitz RZ, Peer CJ, Ibraheem A, et al. Prospective International Randomized Phase II Study of Low-Dose Abiraterone With Food Versus Standard Dose Abiraterone In Castration-Resistant Prostate Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. May 10 2018;36(14):1389-1395.
  3. Borno HT, Lichtensztajn DY, Gomez SL, Palmer NR, Ryan CJ. Differential use of medical versus surgical androgen deprivation therapy for patients with metastatic prostate cancer. Cancer. Feb 1 2019;125(3):453-462.

APCCC 2019: Synthesis -- Optimal Treatment of Men with Newly Diagnosed Prostate Cancer

Basel, Switzerland (UroToday.com) Dr. Clarke gave a summary talk on the topic of optimization of the treatment of newly diagnosed metastatic prostate cancer.

APCCC 2019: Immunotherapy for Metastatic Castrate Resistant Prostate Cancer

Basel, Switzerland (UroToday.com) Immunotherapy expert Dr. Charles Drake delivered the immunotherapy for mCRPC at the management of CRPC session at the Advanced Prostate Cancer Consensus Conference (APCCC) 2019.

The first major successful trial in immunotherapy for prostate cancer was the IMPACT trial in 2010.1 Sipuleucel-T was FDA approved based on results of the phase III IMPACT clinical trial. This trial enrolled 512 patients with mCRPC who had an asymptomatic disease/minimally symptomatic with no visceral metastases, randomizing men to three infusions of sipuleucel-T (n=341) or placebo (n=171). The IMPACT trial noted a 4.1-month improvement in OS for those taking sipuleucel-T compared to placebo and a 22% reduction in risk of death. There was no difference between the groups with regards to objective disease progression or PSA response (secondary endpoints). An assessment of safety profile for patients in this study found that the treatment was overall well tolerated with minimal concern for severe adverse events.13 Furthermore, the immunologic assessment showed that patients with high antibody titers against PA2024 benefited the most from treatment, noting longer survival.

Pembrolizumab recently gained FDA approval for mCRPC patients with MSI + tumors. In a case series of 1,551 tumors from 1,346 patients, 1,033 patients who had adequate tumor quality for MSI analysis.2 Twenty-three of these 1,033 patients (2.2%) had tumors with high MSI scores, and an additional nine had indeterminate scores with evidence of dMMR. Eleven patients with MSI-H/dMMR CRPC received anti-PD-1/PD-L1 therapy, of which six (54.5%) had a greater than 50% decline in PSA levels, and four of whom had radiographic responses.

The STARVE-PC phase 2 trial was a biomarker-driven study of ipilimumab plus nivolumab for AR-V7 expression mCRPC patients.3 There were 15 patients enrolled with AR-V7-expressing circulating tumor cells that received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks. Six of 15 men (40%) had DNA-repair deficiency mutations (three in BRCA2, two in ATM, one in ERCC4; none had microsatellite instability), and the PSA response rate was 13%, ORR was 25% in those with measurable disease, median PSA-PFS was 3.0 months, median PFS was 3.7 months, and median OS was 8.2 months.

There are several exciting immunotherapy trials ongoing/planned:

IMbassador250: Atezolizumab + enzalutamide versus enzalutamide alone

APCCC_IMbassador_250.png


Neo-RED-P: Neoadjuvant trial of regulatory T Cell Depletion

APCCC_Neo-RED-P.png


MAGIC-8: MAximizing ADT ImmunoGenIcity with Anti-IL-8

APCCC_MAGIC-8.png


Dr. Drake concluded that the ongoing immunotherapy combination phase III trials are exciting, but that data will take time to mature and will not be available anytime soon.


Presented by: Charles G. Drake, MD, PhD, Department of Medicine, Division of Hematology/Oncology, Co-Director, Cancer Immunotherapy Programs, Columbia University Medical Center, New York, NY

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363(5):411-422.
  2. Abida W, Cheng ML, Armenia J, et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol 2019 Apr 1;5(4):471-478.
  3. Boudadi K, Suzman DL, Anagnostou V, et al. Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. Oncotarget 2018 Jun 19;9(47):28561-28571.

APCCC 2019: Radium-223 and Bone Health Agents: Lessons Learned

Basel, Switzerland (UroToday.com) Professor Oliver Sartor from Tulane University discussed the impact and utility of radium-223 at today’s bone and bone metastases session at APCCC 2019.

APCCC 2019: Optimal Steroid use with Abiraterone

Basel, Switzerland (UroToday.com) During this discussion, Dr. Gert Attard explained how to maximize therapy of steroids with abiraterone acetate. Abiraterone acetate is currently given for two indications:

  1. Newly diagnosed high-risk metastatic hormone-sensitive prostate cancer (mHSPC), with prednisone 5 mg daily.
  2. For metastatic castration-resistant prostate cancer (mCRPC) with prednisone 10 mg daily.
Abiraterone can cause mineralocorticoid access derived adverse effects, including hypokalemia, which has been reported in 11%, 2% and 3% in the abiraterone arm in the LATITUDE,1 COU-302,and COU-3013 trials, respectively.

The half-life of prednisone is less than 16 hours, while the half-life of dexamethasone is much longer (36-54 hours). Dexamethasone has a higher ratio of glucocorticoid to mineralocorticoid activity than prednisone. It also has greater activity as a single agent in mCRPC disease compared to prednisone.4 Approximately 25% of patients progressing on abiraterone with prednisone have a PSA decline after they are switched to dexamethasone.5,6

In a recently published study,7 various regimens of prednisone in combination with abiraterone were compared, including one arm with dexamethasone. The primary endpoint was no mineralocorticoid excess (grade ≥1 hypokalemia or grade ≥2 hypertension) through 24 weeks (6 cycles) from treatment. The study design is shown in figure 1. The results are shown in figure 2, including the rates of demonstrated hypokalemia. Of the 164 randomized men to prednisone 5 mg, twice daily, once daily, or 2.5 mg twice daily, or dexamethasone, 0.5 mg, once daily, 24/34 patients (70.6%, 95% CI, 53.8%-83.2%), 14/38 patients (36.8%, 95% CI, 23.4%-52.7%), 21/35 patients (60.0%, 95% CI, 43.6%-74.4%), and 26/37 patients (70.3%, 95% CI, 54.2%-82.5%), respectively, had no mineralocorticoid excess.

Interestingly, plasma adrenocorticotrophic hormone and urinary mineralocorticoid metabolites after 8 weeks of treatment were higher with prednisone, 2.5 mg, twice daily and 5 mg once daily than with 5 mg twice daily or dexamethasone, 0.5 mg, once daily. The level of urinary glucocorticoid metabolites appeared higher in patients who did not meet the primary endpoint, regardless of glucocorticoid regimen. It is important to note that the total lean body mass decreased in the prednisone groups and total body fat increased in the prednisone, 5 mg, twice daily and dexamethasone groups. In the dexamethasone group, there was an increase in serum insulin and insulin resistance, while total bone mineral density decreased.

The authors concluded that abiraterone acetate with prednisone, 5 mg, twice daily or dexamethasone, 0.5 mg, once daily met the prespecified threshold for the primary endpoint (95% CI excluded 50% mineralocorticoid excess). In contrast, abiraterone acetate with prednisone, 5 mg, once daily or 2.5 mg twice daily did not meet the threshold. Abiraterone acetate in combination with dexamethasone appeared to be especially active but may be associated with adverse metabolic consequences.

Figure 1 – Study design comparing various regimens of prednisone in combination with abiraterone:

Clinical Trial Design


Figure 2 – Final results of the study:


Primary End Point Syndrome of Secondary Mineralocorticoid Excess


Dr. Attard concluded his talk stating that prednisone 5 mg BID and dexamethasone 0.5 mg once a day can minimize mineralocorticoid excess. However, this came at the cost of increased body fat for prednisone, and an increase in serum insulin and insulin resistance for dexamethasone. Prednisone 5 mg once daily minimizes the long-term physiological side effects but with a greater risk of mineralocorticoid excess. Dr. Attard emphasized that lower steroid doses require careful monitoring and ensuring that patients are medically optimized prior to beginning abiraterone.


Presented by: Gert Attard, MD, PhD, FRCP, John Black Charitable Foundation Endowed Chair in Urological Cancer Research, University College London Cancer Institute, London, UK

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Fizazi K1, Tran N1, Fein L1, Matsubara N1, Rodriguez-Antolin A1, Alekseev BY1, Özgüroğlu M1, Ye D1, Feyerabend S1, Protheroe A1, De Porre P1, Kheoh T1, Park YC1, Todd MB1, Chi KN1; LATITUDE Investigators. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. doi: 10.1056/NEJMoa1704174. Epub 2017 Jun 4.
  2. Ryan CJ1, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. doi: 10.1056/NEJMoa1209096. Epub 2012 Dec 10.
  3. de Bono JS1, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. doi: 10.1056/NEJMoa1014618.
  4. Venkitaraman R1, Lorente D2, Murthy V3, Thomas K4, Parker L2, Ahiabor R2, Dearnaley D2, Huddart R2, De Bono J2, Parker C5. A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol. 2015 Apr;67(4):673-9. doi: 10.1016/j.eururo.2014.10.004. Epub 2014 Oct 16.
  5. Romero-Laorden N1,2, Lozano R1,3,4, Jayaram A5,6, López-Campos F1,7, Saez MI4,8, Montesa A4,8, Gutierrez-Pecharoman A2,9, Villatoro R4,10, Herrera B4,11, Correa R4,12, Rosero A1,13, Pacheco MI1,4, Garcés T1,4, Cendón Y1,14, Nombela MP1, Van de Poll F1, Grau G1,4, Rivera L1,4, López PP1, Cruz JJ3, Lorente D15, Attard G5,6, Castro E16,17, Olmos D1,4,8. Phase II pilot study of the prednisone to dexamethasone switch in metastatic castration-resistant prostate cancer (mCRPC) patients with limited progression on abiraterone plus prednisone (SWITCH study). Br J Cancer. 2018 Oct;119(9):1052-1059. doi: 10.1038/s41416-018-0123-9. Epub 2018 Aug 21.
  6. Lorente D1, Omlin A2, Ferraldeschi R1, Pezaro C1, Perez R1, Mateo J1, Altavilla A1, Zafeirou Z1, Tunariu N1, Parker C3, Dearnaley D3, Gillessen S4, de Bono J1, Attard G1. Tumour responses following a steroid switch from prednisone to dexamethasone in castration-resistant prostate cancer patients progressing on abiraterone. Br J Cancer. 2014 Dec 9;111(12):2248-53. doi: 10.1038/bjc.2014.531. Epub 2014 Oct 14
  7. Gerhardt Attard, MD, PhD,corresponding author1 Axel S Merseburger, MD,2 Wiebke Arlt, MD, DSc,3 Cora N Sternberg, MD,4 Susan Feyerabend, MD,5 Alfredo Berruti, MD,6 Steven Joniau, MD, PhD,7 Lajos Géczi, MD,8 Florence Lefresne, MD,9 Marjolein Lahaye, MSc,9 Florence Nave Shelby, PhD,9 Geneviève Pissart, MSc,9 Sue Chua, MBBS,10 Robert J Jones, MBChB, PhD,11 and Bertrand Tombal, MD, PhD12 Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer A Randomized, Open-label Phase 2 Study. JAMA Oncol. 2019 Aug; 5(8): 1159–1167.

APCCC 2019: Management of Fatigue, Cognition, Dementia

Basel, Switzerland (UroToday.com) Dr. Charles Ryan discussed the management of fatigue and cognitive changes induced by androgen deprivation therapy (ADT). Fatigue in patients treated with ADT is common, occurring in more than 40% of them. The addition of potent androgen receptor (AR) targeting agents may worsen this. Long term ADT may be associated with cognitive changes and dementia development. Fatigue might represent something more extensive than just fatigue and maybe a sign of cognitive decline and depression.

Fatigue and cognition appear to be a key driver when physicians choose therapy for metastatic castrate-resistant prostate cancer (mCRPC) patients.1 Fatigue is usually reported at the top of the list of the adverse effects, as can be seen in the ENZAMET (31% of enzalutamide treated patients)2 and ARAMIS (12.5% of darolutamide treated patients)3 trials in metastatic hormone-sensitive prostate cancer (mHSPC) patients. Fatigue is both a disease by itself and a treatment factor. The combination of abiraterone + prednisone + ADT significantly improved fatigue in the LATITUDE trial,4 as can be seen in figure 1.

Figure 1 – The combination of abiraterone + prednisone + ADT significantly improved fatigue:


APCCC_combination.png


A randomized trial published in 2017 demonstrated that exercise interventions in prostate cancer patients treated with ADT improve fatigue/vitality in those who need it the most. Those with the highest baseline levels of fatigue and the lowest baseline levels of vitality improved the most with exercise.5 Moreover, it has been shown that resistance exercise is more beneficial than aerobic only exercise.5 In a recent meta-analysis, cancer-related fatigue was shown to be best managed by exercise and support, and not drugs.6

The next topic discussed by Dr. Ryan was the effect of ADT on cognition. Apparently, the normal brain is filled with androgen receptors, and androgens are known to be neuroprotective. With age, testosterone and dihydrotestosterone decline rapidly, and low testosterone levels are associated with Beta Amyloid and cognitive deterioration.7 Two studies using different methods have shown that after one year of ADT there is a modest cognitive decline.8,9

Before concluding his talk, Dr. Ryan spoke about the association between ADT and dementia. Dementia is a chronic or persistent disorder of the mental processes caused by brain disease or injury; and marked by memory disorders, personality changes, and impaired reasoning. In a population-based study published in 2016 and using claims-based data, an association between ADT and dementia development was described.10 This study had many limitations consisting of the fact that the data was claims-based and did not consist of clinically validated diagnoses. Moreover, it did not capture the spectrum of cognitive impairment experienced by patients. There is a hypothesis that dementia in ADT treated patients arises after ADT in an at-risk population and is not caused directly by ADT.

The ARA-COG study (Androgen Receptor And Cognitive function in darolutamide and enzalutamide treated patients) is a randomized trial aiming to compare the percent change in the maximally changed cognitive domain by 24 weeks of treatment with either enzalutamide or darolutamide in mCRPC patients (Figure 2).

Figure 2 – The ARA-COG trial design:

APCCC_ARA-COG_trial.png


In summary, ADT may be associated with fatigue and cognitive dysfunction, and claims-based data suggest an association between ADT and Alzheimer’s disease. The measurement of cognitive function remains challenging. It is therefore important to include assessments of patients reported outcomes and mediators of cognitive function in future trials. The more potent androgen receptor antagonists may improve disease outcome but may lead to compounded effects and require detailed study.


Presented by: Charles Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology and Director of the Division of Hematology, Oncology, and Transplantation, University of Minnesota, USA

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
  1. Gillessen S. et al. Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. European Urology. Urol 2018 Feb;73(2):178-211. doi: 10.1016/j.eururo.2017.06.002.
  2. Davis IA et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine. 2019; 381:121-131
    DOI: 10.1056/NEJMoa1903835.
  3. Fizazi K. et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2019; 380:1235-1246
    DOI: 10.1056/NEJMoa1815671.
  4. Chi K. et al. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. The Lancet Oncology. 2018 DOI:https://doi.org/10.1016/S1470-2045(17)30911-7.
  5. Taafe et al. Effects of Different Exercise Modalities on Fatigue in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Year-long Randomised Controlled Trial. European Urology. 2017 Aug;72(2):293-299. doi: 10.1016/j.eururo.2017.02.019.
  6. Mustian et al. Comparison of Pharmaceutical, Psychological, and Exercise Treatments for Cancer-Related Fatigue A Meta-analysis. JAMA Oncology. 2017;3(7):961-968. doi:10.1001/jamaoncol.2016.6914.
  7. Rosario et al. Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer’s disease. Neurobiology of Aging 32. 2011 604–613.
  8. Alibhai SH et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. Journal of Clinical Oncology. 2010 Mar 10;28(8):1301-7. doi: 10.1200/JCO.2009.25.8707.
  9. Gonzalez et al. Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. Journal of Clinical Oncology. 2015 Jun 20;33(18):2021-7. doi: 10.1200/JCO.2014.60.1963.
  10. Nead KT et al. Association Between Androgen Deprivation Therapy and Risk of Dementia. JAMA Oncology. 2016;3(1):49-55. doi:10.1001/jamaoncol.2016.3662.

APCCC 2019: Management of Metabolic Changes

Basel, Switzerland (UroToday.com) Dr. Shore gave a talk on the metabolic complications of androgen deprivation therapy (ADT) and how to manage them.

APCCC 2019: Management of Sexuality and Incontinence Issues in Advanced Prostate Cancer

Basel, Switzerland (UroToday.com) Dr. van Oort discussed the important topic of managing sexuality and incontinence issues in patients with advanced prostate cancer.

According to the EAU guidelines cessation of sexual activity is very common among patients treated with androgen deprivation therapy (ADT), affecting up to 93% of patients. ADT reduces both libido and the ability to gain and maintain erections. The management of acquired erectile dysfunction (ED) is mostly non-specific.

The EAU recommendations for treatment to improve the quality of life in men on ADT include:

  1. Supervised physical exercise
  2. Maintaining healthy weight and diet
  3. Quitting smoking
  4. Yearly screening for diabetes and hypercholesterolemia
  5. Supplementation with vitamin D and calcium
  6. Offer patients with T1-T3 disease multidisciplinary rehabilitation addressing incontinence, sexuality, depression and fear of recurrence, social support and positive lifestyle changes after any radical treatment.
Urinary symptoms are very common among prostate cancer patients at any stage of the disease. The most common urinary symptom which significantly bothers patients is frequency, which occurs in 18.6% of patients. Almost 13% of patients report leaking urine at least once per day. In men who underwent radical prostatectomy the reported level of incontinence is higher with 23.4% reporting of leaking urine at least once per day and 31.4% reported using at least one pad per day.

When assessing sexual symptoms, it is important to remember that 50% of prostate cancer patients will receive ADT at some point in the disease trajectory. Castrate levels of testosterone have a dramatic impact on the patient’s quality of life. ADT also significantly affects the intimate partners of patients, who often experience more distress than the patients themselves. A total of 81.5% of patients report problems reaching an erection, 76.6% have issues with reaching an orgasm, and 81% complain about their overall sexual function.

Patients also lose their libido as a result of their treatment, with some remaining troubled by the loss of erection as well, and some being relieved that the loss of erection is accompanied with the loss of libido. Improvements in ED can improve the patient’s sense of masculinity and self-esteem. Reduction in libido leads to withdrawal of emotional and physical intimacy and can lead to significant partner distress. Many times patients do not want to talk on the adverse effects of ADT while their partners do. The coping mechanisms described by patients include denial, which can lead to isolation of either or both partners, loss of hope of satisfying their partner and subsequent loss of intimacy. This can be even more detrimental than the loss of the ability to have intercourse.

It is therefore imperative that partners be included in the treatment decision, consent process, and provide adequate and appropriate support. When complex sexual and relationship issues arise, it is critical to involve a clinical psychologist, relationship counselor or/and sexologist or sexual medicine specialist.

There is very little information on male partners, and most of the literature is based on heterosexual couples. The physiologic changes due to prostate cancer treatment seem to have a greater impact on the sex life of homosexual couples. As a result of prostate cancer treatment, homosexual men appear to have a lower quality of life, reduced male self-image, and more psychological problems.

Dr. Oort also provided data on the percentage of patients that were offered medical aid to improve erections, showing that there is much room for improvement. A total of 58.6%, 77.4% and 85.2% of patients were not offered medication, devices, or specialist services, respectively, to try and improve erections.

To summarize, Dr. Oort stated that we need to pay more attention to sexuality issues in patients with hormonal treatment, as quality of life is critical for them.

Presented by: Inge van Oort, MD, PhD, Radboud Institute for Molecular Life Sciences, Nijmegen, Netherlands  

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA, Twitter: @GoldbergHanan at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

APCCC 2019: Debate: Antiresorptive Therapy to Reduce SRE Risk in Men with Bone-mCRPC -- For Select Men with CRPC and Bone Metastases

Basel, Switzerland (UroToday.com) The bone and bone metastases session at APCCC 2019 featured a debate regarding the use of antiresorptive therapy to reduce SRE risk in men with bone-mCRPC. Dr. Chris Parker from The Royal Marsden Hospital discussed utilization of these therapies only for very select men.

The basis for antiresorptive therapy to reduce SRE risk in men with bone-metastatic CRPC dates back nearly two decades now to Dr. Fred Saad’s seminal work in 2002. The phase III zoledronic acid 039 trial showed that among men with mCRPC a greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2% p =0.021) or those who received zoledronic acid at 8/4 mg (38.5% p = 0.222)1. Furthermore, the median time to the first skeletal-related event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg (p = 0.011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg (p = 0.491 versus placebo). Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. This clinical trial, published nearly 20 years ago, was crucial in bringing bone health and bone-targeted therapy to the forefront of bone metastasis treatment.

Dr. Parker summarized the evidence base in 2002 after the publication of zoledronic acid 039: (i) the median duration of treatment was only 9 months, (ii) skeletal surveys detected every 3 months detected asymptomatic fractures, (iii) the lower dose was better than the higher dose, (iv) there was no overall survival benefit, (v) there was no quality of life benefit.

Moving forward to 2017, Himelstein and colleagues assessed the effect of longer-interval versus standard dosing of zoledronic acid on skeletal-related events among patients with breast, prostate, multiple myeloma bone metastasis2. For this trial, patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) versus every 12 weeks (n = 911) for 2 years. Among these 1,822 patients 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least one skeletal-related event within 2 years of randomization (risk difference of -0.3%; p < .001 for noninferiority). This trial concluded that the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over two years. 

So, what changed in the last 20 years? According to Dr. Parker, there are several changes, including (i) the mean overall survival of these metastatic patients increasing from 15 months to 32 months, (ii) an increase in the median time to skeletal-related event from 11 months in Dr. Saad’s initial trial in 2002 to 31 months in PREVAIL3, (iii) the type skeletal-related event has changed from a large proportion of fractures in zoledronic acid 039 to primarily radiation therapy to the SRE in PREVAIL, and (iv) an awareness of bone health management.

Dr. Parker notes that a major concern for prolonged treatment for all-comers is osteonecrosis of the jaw for patients on bisphosphonates. As depicted below, the cumulative hazard for this devastating adverse event increases substantially after 3-4 years on the medication:

Cumulative Hazard

Even though men are living longer and are on ADT for longer than they ever have before, new drugs for prostate cancer (ie. abiraterone, enzalutamide, etc.) both reduce the risk of skeletal-related events, but with adverse effects on bone health. So, as Dr. Parker notes, bone health is increasingly important, whereas skeletal-related events are less important.

According to the NICE guidelines for bone health in 2017, oral bisphosphonates are recommended as an option for patients if their 10-year probability of osteoporotic fragility fracture risk is at least 1%. The UK Prostate Clinical Excellence Group guidance in 2019 suggested several lifestyle measures for men on ADT, such as weight-bearing exercises, smoking cessation, ≤ 2 units of alcohol per day, and adequate calcium and vitamin D status. They also recommended that men starting ADT for more than 1 year should be considered for oral bisphosphonates.

Dr. Parker concluded with the following summary table depicting differences in bone health management between 2002 and 2020:

Anti Resorptive Therapy
Presented by: Chris Parker, MD, MRCP, FRCR, The Royal Marsden Hospital, Surrey, UK

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

APCCC 2019: Testosterone Measurement - Which Test and When?

Basel, Switzerland (UroToday.com) Dr. Martin Gleave presented on the topic of testosterone measurement and its various nuances in the context of advanced prostate cancer.

The discovery of how testosterone is synthesized resulted in the receipt of the Nobel prize in 1939 by Adam Butenandt and Leopold Ruzicka. Another Nobel prize was awarded to Charles Huggins in 1966 for discoveries concerning the hormonal treatment of prostate cancer.

Testosterone measurement is important as androgens are the drivers of activity of the androgen receptor (AR). Maintenance of castrate testosterone levels required in metastatic castrate-resistant prostate cancer (mCRPC) is a key factor for intermittent and continuous androgen deprivation therapy (ADT). By consensus, testosterone levels below 50 ng/dl (1.7 nM) is defined as castrate. It is also known that serum testosterone levels (and perhaps other serum androgens) is prognostic for time to CRPC and potentially predictive of AR signaling pathway inhibition.

It is important to note that some patients on ADT will not achieve castrate testosterone levels. At a testosterone level of 1.7 nmol/l approximately 63-87% will achieve castration1-4, while at a testosterone level of 0.7 nmol/l, approximately 88-97% will achieve castration1,2,4,5. The combination of LHRH agonists with abiraterone will usually achieve testosterone levels of less than 0.3 nM. Time to CRPC on LHRH agonists has been linked to serum testosterone levels6.7.

In the COU-301 trial8 serum testosterone levels in mCRPC patients were measured by LC-MS/MS and were shown to be prognostic for overall survival (Figure 1), with longer overall survival rates in patients with serum androgens above the median.

2 Longer Overall Survival in Patients with Serum Androgens

Figure 1. Longer overall survival in patients with serum androgens above the median (p<0.0001) in the Cou-301 trial

The quantification of testosterone at low levels in men on ADT is challenging as it is the limit of quantification. Historically, testosterone was measured with solvent extraction followed by RIA or GC-MS. Automated immunoassays for total testosterone were developed for high-throughput, clinical laboratory environment. The automated immunoassays are unfortunately inaccurate at low testosterone levels due to endogenous and exogenous interferences, and issues with calibration at low analyte concentrations. Approximately 3% of samples with testosterone levels below 0.7 nM by automated immunoassay were actually above 0.7 nM, using the LC-MS method. Therefore, suboptimal testosterone levels in castrated patients should be confirmed by either MS or a validated immunoassay and interpreted with caution before any changes are made to treatment.

The Canadian consensus statement recommends achieving a serum testosterone level of less than 0.7nmol/l as there appears to be an associated clinical benefit9. Additional recommendations include regular monitoring of testosterone and PSA levels throughout the first year of ADT treatment, using validated LC-MS/MS methods for testosterone assays at low testosterone levels (<0.7 nmol/l).

In conclusion, lower testosterone levels correlate with better freedom from CRPC. Breakthrough testosterone levels above 1.7 nmol/l have higher rates of failure. Testosterone levels should be assessed periodically to ensure castrate levels (every 3- months), with confirmation of lab assays at low testosterone levels. Lastly, the role of testosterone and other serum androgens as prognostic and predictive biomarkers in mCRPC requires more study.

Presented by: Martin Gleave, CM, MD, FRCSC, FACS, Executive Director, Vancouver Prostate Centre, Vancouver, Canada 

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA, Twitter: @GoldbergHanan at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
1. Oefelein MG, Cornum R. Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: the case for monitoring serum testosterone and a treatment decision algorithm. The Journal of urology. Sep 2000;164(3 Pt 1):726-729. 

2. Morote J, Esquena S, Abascal JM, et al. Failure to maintain a suppressed level of serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer. Urologia internationalis. 2006;77(2):135-138. 

3. Wechsel HW, Zerbib M, Pagano F, Coptcoat MJ. Randomized open labelled comparative study of the efficacy, safety and tolerability of leuprorelin acetate 1M and 3M depot in patients with advanced prostatic cancer. European urology. 1996;30 Suppl 1:7-14; discussion 19-21. 

4. McLeod, David, Norman Zinner, Kevin Tomera, Donald Gleason, Nick Fotheringham, Marilyn Campion, Marc B. Garnick, and Abarelix Study Group. "A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer." Urology 58, no. 5 (2001): 756-761.

5. Kawakami J, Morales A. Clinical significance of suboptimal hormonal levels in men with prostate cancer treated with LHRH agonists. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. Mar-Apr 2013;7(3-4):E226-230. 

6. lotz L, O'Callaghan C, Ding K, et al. Nadir. Testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Apr 1 2015;33(10):1151-1156.

7. Tombal B, Cornel EB, Persad R, Stari A, Gomez Veiga F, Schulman C. Clinical Outcomes and Testosterone Levels Following Continuous Androgen Deprivation in Patients with Relapsing or Locally Advanced Prostate Cancer: A Post Hoc Analysis of the ICELAND Study. The Journal of urology. Nov 2017;198(5):1054-1060.

8. Ryan CJ, Molina A, Li J, et al. Serum androgens as prognostic biomarkers in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Aug 1 2013;31(22):2791-2798.

9. Klotz L, Shayegan B, Guillemette C, et al. Testosterone suppression in the treatment of recurrent or metastatic prostate cancer - A Canadian consensus statement. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. Feb 2018;12(2):30-37.

APCCC 2019: Local Treatment of the Primary (RT) in the Metastatic Situation

Basel, Switzerland (UroToday.com) Dr. Robert Bristow gave a presentation on the concept of local radiotherapy to the primary tumor in the metastatic prostate cancer setting. He began his talk discussing the concept of oligometastatic disease. This disease concept was originally coined by Hellman and Weichselbaum.1 Oligometastatic disease is limited to specific organs and in limited numbers. Implicit in the concept of oligometastatic disease is the fact that it manifests a potentially less aggressive disease course. A unique subset of patients might benefit (in terms of disease progression and /or overall survival) from aggressive localized therapies. Patients with this type of disease may also have unique biologic characteristics that would differentiate the disease course. They have unique clinical and molecular characteristics allowing for a therapeutic window of treatment with multimodal therapy. 
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