Resetting the Bar of Castration Resistance - Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in PCa

[pjoshea13]

New paper below [1].

I have watched plenty of videos where Neal Shore, Alicia Morgans & Charles Ryan get together at a conference to discuss the presentations that interested them. Here they are in a paper - can a video be far behind?

I think that the paper addresses some issues that have often been raised here. It might clarify things for some.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/331...

Review Clin Genitourin Cancer

. 2020 Aug 29;S1558-7673(20)30198-1. doi: 10.1016/j.clgc.2020.08.008. Online ahead of print.

Resetting the Bar of Castration Resistance - Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in Prostate Cancer

Neal D Shore 1 , Alicia K Morgans 2 , Charles J Ryan 3

Affiliations collapse

Affiliations

1 Atlantic Urology Clinics, Myrtle Beach, SC. Electronic address: [e-mail].

2 Feinberg School of Medicine, Northwestern University, Chicago, IL.

3 Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN.

PMID: 33129718 DOI: 10.1016/j.clgc.2020.08.008

Abstract

This review discusses impact of advancements in biologic understanding of prostate cancer (PCa) on definition and diagnosis of castration-resistant PCa (CRPC), predictive factors for progression to CRPC and treatment strategies. More sensitive assays confirm that bilateral orchiectomy reduces serum testosterone (T) closer to < 20 ng/dL than < 50 ng/dL, and evidence suggests that achieving T < 20 ng/dL improves outcomes and delays CRPC emergence. Regular T assessments will evaluate whether T is adequately suppressed in the setting of potential progression to CRPC, given that late dosing may result in T escape. More advanced imaging modalities and biomarker assays allow earlier detection of disease progression. Predictive factors for progression to CRPC include Gleason grade, extent of metastatic spread, germline hereditary factors such as gene mutations affecting androgen receptor amplification or DNA repair deficiency mutations, prostate-specific antigen kinetics, and biomarker analyses. Treatment options for CRPC have expanded beyond androgen deprivation therapy to include therapies that suppress T or inhibit its activity through varying mechanisms. Future directions include therapies with novel biological targets, drug combinations and personalized treatments. Advanced PCa management aims to delay progression to CRPC and prolong survival. With redefinition of castration and advancements in understanding of the biology of disease progression, diagnosis and treatment strategies should be re-evaluated. Definition of CRPC could be updated to reflect the T < 20 ng/dL requirement as this is a 'true' castrate level and may improve outcomes. It is important that androgen deprivation therapy as foundational therapy is continued even as new CRPC therapies are introduced.

Keywords: Androgen deprivation therapy; Castration-resistant; Prostate-specific antigen; Testosterone; Treatment adherence.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

*********************

full:

Resetting the Bar of Castration Resistance – Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in Prostate Cancer

Authors: Neal D. Shorea, Alicia K. Morgansb, Charles J. Ryanc

aAtlantic Urology Clinics, 823 82nd Pkwy, Myrtle Beach, SC, 29572, USA; [e-mail] bFeinberg School of Medicine, Northwestern University, Robert H Lurie Medical Research Center Room 5-121, 303 E Superior, Chicago IL 60611; [e-mail] cMasonic Cancer Center, University of Minnesota Medical School, 420 Delaware Street SE MMC 480, Minneapolis, MN 55455; [e-mail]

Corresponding Author: Neal D. Shore

Keywords: castration-resistant, prostate cancer, testosterone, androgen deprivation therapy, prostate-specific antigen, treatment adherence

Target journal: Clinical Genitourinary Cancer Word count: 4240/4000

Tables and Figures: 4/8

References: 110/120

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Conflict of Interest

Dr. Neal Shore is a consultant for AbbVie, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Clovis Oncology, Dendreon, Ferring, Foundation Medicine, Janssen, Merck, Myovant, Nymox, Pfizer, Sanofi-Genzyme, and Tolmar pharmaceuticals. Dr. Alicia Morgans is a consultant for Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Myovant, and Sanofi-Genzyme, and has research collaborations with Bayer, Seattle Genetics and Genentech. Dr. Charles Ryan is a consultant for Advanced Accelerator Applications, Astellas, Bayer, BMS, Clovis Oncology (Payment to Institution), Dendreon, Janssen (Payment to Institution) Myovant, Roivant and has research collaborations with Sanofi Genzyme and an equity interest in Xcell Biosciences.

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Abstract: (245/300 words)

Introduction: This review discusses impact of advancements in biologic understanding of prostate cancer (PCa) on definition and diagnosis of castration-resistant PCa (CRPC), predictive factors for progression to CRPC and treatment strategies.

Results: More sensitive assays confirm that bilateral orchiectomy reduces serum testosterone (T) closer to <20ng/dL than <50ng/dL, and evidence suggests that achieving T <20ng/dL improves outcomes and delays CRPC emergence. Regular T assessments will evaluate whether T is adequately suppressed in the setting of potential progression to CRPC, given that late dosing may result in T escape. More advanced imaging modalities and biomarker assays allow earlier detection of disease progression. Predictive factors for progression to CRPC include Gleason grade, extent of metastatic spread, germline hereditary factors such as gene mutations affecting AR amplification or DNA repair deficiency mutations, prostate specific antigen (PSA) kinetics and biomarker analyses. Treatment options for CRPC have expanded beyond ADT to include therapies that suppress T or inhibit its activity through varying mechanisms. Future directions include therapies with novel biological targets, drug combinations and personalized treatments.

Conclusion: Advanced PCa management aims to delay progression to CRPC and prolong survival. With redefinition of castration and advancements in understanding of the biology of disease progression, diagnosis and treatment strategies should be re-evaluated. Definition of CRPC could be updated to reflect the T <20ng/dL requirement as this is a ‘true’ castrate level and may improve outcomes. It is important that ADT as foundational therapy is continued even as new CRPC therapies are introduced.

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Introduction

The onset of castration-resistance in response to androgen deprivation therapy (ADT) for prostate cancer (PCa) is an important biologic inflection point of disease progression, signaling increased risk for disease morbidity and lethality. Prior to development of this pathophysiologic change, the vast majority of malignant cells are androgen-sensitive, and ADT is initially effective through tumor cell growth suppression. However, during prolonged ADT, androgen-insensitive cells selectively proliferate1 and the overall tumor cell population progresses towards an androgen-independent state. Both newly diagnosed patients with metastatic PCa treated with ADT and biochemically recurrent PCa patients previously treated with potentially curative intervention, such as radical prostatectomy or radiotherapy, may develop castration-resistant PCa (CRPC). Onset of CRPC is established in the current scientific environment by confirmation of biochemical and/or radiological progression (detected by rising prostate specific antigen (PSA) levels or imaging, respectively) with serum testosterone (T) at or below historical castrate level (50ng/dL).2

New terminology to describe the stages of advanced disease has become necessary as understanding of PCa biology has evolved. The Prostate Cancer Working Group 2 (PCWG2) introduced the term ‘castration-resistant’ in place of ‘hormone refractory’ to classify tumors that were progressing despite castrate levels of T but remained potentially sensitive to further inhibition of the androgen receptor (AR) axis.3, 4 However, variation between current diagnostic definitions of CRPC used by regulatory bodies and professional organizations may impair physicians’ ability to standardize patient management. This may lead to the misinterpretation that ADT is no longer effective following onset of CRPC, resulting in inappropriate treatment change or ADT termination in some patients.

Recent advancements that aid in management of men with PCa include more accurate androgen assays, new imaging technologies, identification of genetic factors/mutational events that may influence treatment decisions and family counseling, and the approval of several advanced new therapies. This review evaluates the impact of these advancements on the definition and diagnosis of CRPC, predictive factors for progression to CRPC and treatment strategies.

The Pathophysiology of Progression to CRPC

Prostate cancer typically develops as a population of relatively homogenous hormone-sensitive cells. As the majority of cells are androgen-sensitive, and androgen-independent cells are

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scarce, ADT leads to disease regression and a decline in PSA. Progression to CRPC occurs when tumor cell proliferation burgeons concomitantly with castrate levels of androgens and rising PSA, thereby thwarting the initially effective ADT option.5 Androgen-insensitive tumor cells that were originally present in small numbers, or arose through gene mutation, selectively multiply in this environment until the overall neoplastic cell population shifts becomes predominantly hormone-insensitive. When high proportions of androgen-independent cells are present, there is some loss of effectiveness of ADT in disease activity suppression, resulting in increased tumor growth and rise in PSA.6 This biological event defines the emergence of CRPC. This mechanism is consistent with what is seen in many other cancers such as colon, kidney, pancreas and liver, where drug-resistant clones proliferate under the influence of selective therapeutic pressures.7, 8

Impact of Improved Androgen Assays on Definition and Diagnosis of CRPC

Findings from Androgen Assays with Increased Sensitivity

The therapeutic goal of ADT is to reduce circulating T to castrate levels. Assay technology established over 40 years ago determined that bilateral orchiectomy resulted in serum T levels of 50ng/dL. Improvements in laboratory assays for T, such as liquid chromatography tandem mass spectrometry (LC-MS/MS, lower limit of detection=0.280 ng/dL) have enabled detection of much lower concentrations,9, 10 and these more sensitive assays confirm that castrate levels of T are less than 20ng/dL.11 Several studies suggest that T levels <20ng/dL improve outcomes to a greater extent than levels between 20 and 50ng/dL, and levels >50ng/dL.12-17 Achieving lower T levels likely inhibits repopulation of hormone-sensitive PCa cells and delays the associated risk of mutation or shift towards hormone-insensitivity. A recent systematic review described the mechanism of tumor cell populations transitioning from hormone-sensitive to insensitive, and reported that emergence of CRPC was delayed by up to six years in patients with low nadir T levels (≤22ng/dL).17 This suggests that less profound or suboptimal T suppression may promote earlier emergence of a hormone-insensitive tumor microenvironment leading to cell proliferation. Consistent with this hypothesis, intermittent ADT has not been shown to benefit patients with metastatic PCa despite a non-inferior result to continuous ADT in non-metastatic PCa.18, 19

These new findings have prompted some professional groups and regulatory bodies to update their guidelines. In 2014, the European Association of Urology (EAU) lowered its recommended target level for T during ADT to <20ng/dL.20 In July 2019, the US Food and Drug Administration (FDA) published a guideline stating that the percentage of patients achieving and maintaining T

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<20ng/dL should represent a secondary endpoint in clinical trials investigating new therapies for medical castration and that these data be included in labels.21

Implications for Definition of CRPC

In light of these data, it appears important that CRPC clinical treatment guidelines should reflect this lower T target (<20ng/dL). As understanding of the biological complexities of PCa deepens, there is an opportunity to update and standardize the definition of CRPC (Table 1). A new definition could recommend that castration-resistance be confirmed with rising PSA or clinical/radiological progression only when T is <20ng/dL.

Implications for Treatment Strategies and Diagnosis

Given the proposed new definition for castration, clinicians should confirm that PCa patients have reached this lower T target (<20ng/dL) before diagnosing them with CRPC. This can be aided by regular T assessments to monitor levels during therapy and appropriate modification of treatment strategies. Clinicians should avoid routinely testing PSA in isolation as this can lead to an erroneous diagnosis of CRPC if there is an assumption that the patient’s T has been appropriately suppressed, when this may not be the case.

What remains unclear, however, is the action required in settings where T is >20ng/dL despite ongoing ADT. One of the more common causes of increases in T is late dosing of luteinizing hormone-releasing hormone (LHRH) agonists, the most frequently used drugs for ADT delivery.22, 23 Late dosing may result in reduced serum levels of effective drug, inconsistent T suppression and increases in the frequency of T ‘escapes’ to >20ng/dL and even >50ng/dL.24 Data from more than 22,000 patients revealed frequent occurrence of late LHRH injections and resultant ineffective castration. The proportion of patients in this analysis with T >20ng/dL and >50ng/dL was much higher when injections were late (late injections: 43% T >20ng/dL and 27% T >50ng/dL; early/on-time injections: 21% T >20ng/dL and 4% T >50ng/dL), where a late injection was defined as dosing after day 32, 97, 128, 194 from the previous injection for the 1- month, 3-month, 4-month, and 6-month formulations, respectively.24 Each ‘month’ in this analysis was approximately 32 days, and this definition was developed based on independent clinical advice by adding approximately 4 days per month to the 28-day month used in pivotal approval trials. Ineffective suppression of T during ADT due to late dosing or missed doses was common, confirming a scenario where clinicians’ ability to accurately diagnose progression to CRPC may be impacted.

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Recent phase III trials in patients with non-metastatic CRPC have concluded that delaying progression to metastatic CRPC (mCRPC) may improve overall clinical outcomes, increase survival and postpone the need for additional CRPC treatments.25, 26 Multiple ADT therapy options are available with different active ingredients, mechanisms and delivery technologies with varying levels of demonstrated T suppression <20ng/dL.24, 27 Demonstrated T suppression <20ng/dL is an important consideration when selecting ADT therapy. Currently, there is only one LHRH agonist formulation with peer-reviewed published clinical data across all dose formulations that confirm maintenance of T suppression to below 20ng/dL throughout the dosing interval.28-31 It is also important to monitor T levels during therapy to confirm suppression of T <20ng/dL and consider a change to an alternative ADT therapy if this is not achieved.

Additionally, if high T is due to late dosing or other factors such as sub-optimal administration, clinicians should consider process improvements in practice logistics or patient education regarding the importance of dosing adherence. For example, prescribing a longer- lasting, e.g. 6-month, formulation of ADT could minimize the risk of T ‘escape’ for cases where late dosing may occur, as these formulations require only two injections a year.24 Consideration of alternative molecules or delivery systems is also appropriate, as ADT therapies are not necessarily interchangeable.

It should be noted, however, that although T suppression is generally considered important in treating PCa, some studies have shown benefit of androgen supplementation as therapy.32, 33 Although this bipolar androgen therapy (BAT) strategy seems paradoxical, favorable results have been seen in both androgen-sensitive and castration-resistant PCa patients. In a phase II trial,34 29 mCRPC patients previously treated with enzalutamide received 400mg T cypionate intramuscularly, with 9 demonstrating 50% decline in PSA from baseline. Patients were then re-treated with enzalutamide and 15 of them demonstrated 50% PSA reduction, suggesting re-sensitization to enzalutamide. Another recent phase II trial evaluated efficacy of BAT in mCRPC patients who had previously received enzalutamide vs. those who had previously received abiraterone. 30% (9/30) of post-enzalutamide patients and 17.2% (5/29) of post-abiraterone patients achieved 50% PSA decline and progression-free survival (PFS) was significantly longer in post-enzalutamide patients (median PFS: 12.8 vs. 8.1 months).35

Emerging Technologies: Improved Imaging Modalities and Biomarker Assays

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Advanced imaging modalities and tumor specific tracers have potential as predictors of CRPC risk and outcomes36 and may prompt changes in the PCa/CRPC management landscape. These advanced techniques help physicians detect disease progression earlier and allow for selection of appropriate treatment options.

The Radiographic Assessments for Detection of Advanced Recurrence (RADAR) III group recommends use of Next Generation Imaging (NGI) techniques in clinically appropriate settings to detect previously unidentified metastases. Positron emission tomography (PET) with novel prostate-specific tracers has greater sensitivity for detecting PCa recurrence or progression than conventional imaging with CT or technetium bone scan. Several novel radiotracers have been developed for use in PCa, including anti-1-amino-3-18F- fluorocyclobutane-1-carboxylic acid (F-FACBC), C-choline and agents targeting prostate- specific membrane antigen (PSMA). F-FACBC PET is widely used in the United States as it allows a reasonable balance between availability, specificity and sensitivity.36 Whole-body MRI and PSMA PET imaging are rapidly gaining traction in many other countries.37, 38 PSMA PET mapping detects biochemically recurrent PCa with greater sensitivity than conventional imaging techniques and is effective even with very low levels of PSA.37, 39 Gallium-68 (68Ga)-PSMA PET/CT is a novel molecular imaging modality that can identify metastases at presentation and help inform treatment recommendations.40

Traditional staging using CT, MRI or m-technetium labeled whole-body bone scintigraphy is most effective in patients with low-risk, localized disease with a low probability of progression.41 Conventional strategy does not appear to be as accurate in the diagnosis and staging of patients with localized intermediate- and high-risk disease or micro-metastatic disease; a long-term treatment study found that traditional imaging technologies did not detect metastases in over 25% of patients with metastatic disease and biochemical recurrence.42 Therefore, imaging that can detect metastases early and selectively diagnose patients whose disease is more likely to cause harm is required.43 Multi-parametric MRI and PSMA-PET are promising and have already been incorporated into some clinical trials. Physicians managing patients with hormone-sensitive biochemical recurrence, with locally recurrent disease identified by NGI techniques after prostatectomy, may also feel more confident that pelvic radiation of the identified affected area may eradicate recurrent disease. It should be noted that NGI are still under investigation; clinical decisions for patients diagnosed with non-metastatic CRPC based on conventional scans, yet with evidence of metastatic disease with NGI techniques, should continue to be based on robust data from phase III trials that utilized conventional imaging. However, as there appears to be no biological reason why patients with metastases only

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identified by NGI would obtain less benefit than those identified using conventional methodology, studies to confirm clinical benefit in patients with metastases only identified with NGI will be useful when recommending changes in management of advanced disease.

Predictive Factors for Progression to CRPC

Established Prognostic Factors

There are established tumor specific factors that play a role in progression or are associated with a shorter time to CRPC onset. The value of Gleason score as a predictor of recurrence after curative treatment has been studied44, 45 and a recent review found it to be a good predictor of long-term prognosis on deferred treatment.46 Egevad, et al. suggested that Gleason scores be grouped into four prognostic categories (4-5, 6, 7, 8-10) based on analytic break points in the study population.46 High metastatic burden and de novo presentation are also known to be associated with a poor prognosis for patients receiving ADT,47, 48 with time of metastatic occurrence (prior local therapy vs. de novo) and volume of disease (low volume vs. high volume) as proven independent prognostic factors for survival and time to onset of CRPC.49

Hereditary Genetic Factors/Mutations

Genes that affect activation or amplification of androgen receptors (AR) are known to contribute to CRPC progression.50 Other genetic factors, including certain gene mutations that regulate cell survival, proliferation or apoptosis, affect development of CRPC/mCRPC and response to treatment.51 Studies have demonstrated that several key genetic factors may correlate with risk and timing of progression to CRPC. For example, pathogenic germline variants in cancer- susceptibility genes, including ATM, ATR, BRCA2, FANCL, MSR1, MUTYH, RB1, TSHR, and WRN, have been observed in patients with mCRPC.52 Gene rearrangements between the AR- regulated gene TMPRSS2 (21q22.3) and ERG (21q22.2) are common genetic mutations in PCa, and there may be prognostic value in combining ERG status and AR overexpression to predict the risk of progression, given the binary nature of PCa.53 Circulating microRNAs have also shown to correlate with PSA response during ADT.54

Advancements in DNA sequencing analysis, expansion of DNA libraries and variants and their predictive and prognostic implications, random amplified polymorphic DNA (RAPD) identification, enhanced polymerase chain reaction and transactivation assays can also assist in the discovery of genetic mutations that may contribute to CRPC progression and possibly aid in earlier identification of, or quantification of risk of developing, CRPC. Prognostic tools such as the Prolaris cell cycle progression test, which generates individual risk models using tissue-

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based cancer biomarkers,55, 56 and Decipher, a biopsy-based multigene expression classifier that aids in risk stratification for men considering active surveillance,57 are now commercially available. However, such tools are not yet widely validated and it is unclear whether their use will improve long-term outcomes. A recent ASCO guideline on the use of molecular biomarkers in localized PCa recommended these assays only be used in situations when their results, considered together with routine clinical factors, are likely to affect clinical decisions.58

Hormonal Kinetics

Interestingly, the kinetics of both T (reflecting therapeutic effect) and PSA (reflecting underlying disease biology) may correlate with time to CRPC progression. An analysis of hormonal kinetics in men with non-metastatic PCa receiving intermittent ADT found that a longer time to PSA rise during the first off-treatment interval of intermittent ADT was associated with a lower risk of CRPC.59, 60 Another study found that low baseline T, defined as T <11.5ng/dL, is prognostic for the survival of mCRPC patients and thus should be considered in the treatment selection process.61

Novel Prognostic Approaches

Readily available biomarkers such as neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), albumin, alkaline phosphatase, DNA AR and bone scan index (BSI) are useful prognostic tools in CRPC progression. In mCRPC patients receiving first-line chemotherapy, NLR was correlated with survival and may serve as a prognostic or risk stratification tool for randomized clinical trials.62 A prognostic index model using six risk factors (LDH greater than upper limit of normal (ULN), Eastern Cooperative Oncology Group performance status of 2, presence of liver metastases, albumin ≤4g/dL, alkaline phosphatase >ULN and time from start of initial ADT to start of abiraterone treatment ≤36 months) were predictive for overall survival (OS) in mCRPC patients treated with abiraterone after docetaxel.63 Kohli et al. described a prognostic correlation between plasma cell-free DNA AR amplification (ARamp) and survival, demonstrating that ARamp was associated with poor outcomes (2-year OS of 35% in ARamp vs 71% in non-ARamp patients; log-rank p-value ≤0.001).64 Bone scan index, a quantitative assessment of bone scan data that represents the total tumor burden as a fraction of total skeletal weight,65 has also been identified as an independent predictor of time from initiation of ADT to CRPC.66 Use of new technologies or biomarker assays can allow improved evaluation of disease stage and better treatment decisions.

Advancements in CRPC Therapies

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As understanding of the biochemical pathways involved in PCa and CRPC has deepened, treatment options have expanded beyond traditional ADT to include combination-therapies that further eliminate AR signaling via multiple mechanisms.67 However, all phase III studies that resulted in approval of these drugs were conducted with concomitant ADT, so it is imperative that patients continue ADT in combination with additional treatments, even when progression to CRPC/mCRPC has been confirmed. The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) introduced the concept of ‘no longer clinically benefiting’ to underscore the distinction between first evidence of progression and a clinical need to terminate or change treatment.68 It is of note that these approval studies only required a baseline T value of <50ng/dL, with no required assessment of ADT efficacy during the studies and no subsequent collection of T levels. Future clinical trials in this space should collect these data to further evaluate the benefits of profound T suppression.

The main reason for continuing ADT, even where significant populations of androgen- insensitive cells are established, is to prevent repopulation of androgen-sensitive tumor cells that persist through amplification of the AR or development of AR mutations.69 Because highly adapted tumors may be ultra-sensitive to androgen signaling, it is important to maintain low androgen levels 69, 70 through continuation of ADT and confirmation that it remains effective in maintaining T below 20ng/dL. This is critical particularly as practice patterns in real-world settings include some inappropriate discontinuation of ADT in patients with CRPC, contrary to guidelines and product labels.70

Androgen pathway inhibitors such as abiraterone, enzalutamide, apalutamide, and darolutamide have demonstrated clinically significant impact on the androgen axis when given concomitantly with ADT (Table 2) as part of treatment strategies designed to achieve maximal inhibition of AR activation. A recent phase III trial that randomized men with non-metastatic CRPC to ADT with or without darolutamide determined that median metastasis-free survival (MFS) in men treated with darolutamide and ADT was 40.4 months vs. 18.4 for men receiving ADT alone.71 Additional phase III trials in men with non-metastatic CRPC demonstrated similar MFS benefits from combination therapy of ADT with or without apalutamide (40.5 vs 16.2 months)72 or enzalutamide (36.6 vs. 14.7 months).73 Recent approvals of abiraterone, apalutamide, and enzalutamide for the treatment of patients with metastatic, castration-sensitive PCa provide further evidence that earlier use of these androgen pathway inhibitors delays disease progression and improves survival. However, recent data suggest that up to 17% of CRPC patients undergoing treatment with abiraterone/enzalutamide had morphologically

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discernable small-cell neuroendocrine tumors, as evaluated by biopsy.74 Thus, researchers and clinicians should be mindful of the possibility that long-term, rigorous suppression of androgen pathways may induce neuroendocrine differentiation. Additional treatments for metastatic CRPC include taxane-based chemotherapeutic agents (docetaxel, cabazitaxel), cancer immunotherapy (sipuleucel-T) and the radiopharmaceutical radium Ra-223 dichloride (Table 2).

Questions remain regarding the interplay of resistance, tumor biology and optimal sequencing for CRPC therapies.75 Recent evidence from the CARD trial suggests that sequential use of androgen receptor targeting agents is less effective than using chemotherapy as a distinct mechanism of action.76 It is also critical to avoid combining therapies simply because they have different mechanisms of action in the hope that they may be synergistic, as other trials have demonstrated that this can lead to excess adverse events and potential harm.77, 78 Trials are also underway to evaluate whether earlier introduction of these drugs may lead to improved disease control. Given the variety of treatment options, physicians should individualize the approach to therapy for each patient, carefully taking into consideration treatment goals, risk/benefit ratio, drug accessibility and cost.

Future Directions

Ongoing clinical trials are evaluating optimal sequencing of currently available therapies and combination treatments to optimize outcomes in men with PCa, as well as and novel therapies and diagnostic tools.79-81 In all these investigations, it will be important to ensure that the foundation of androgen deprivation is effectively maintained and to assess the outcomes of these therapies based on androgen dynamics at baseline and during treatment.

A head-to-head study comparing enzalutamide and abiraterone as first-line endocrine CRPC therapy is planned,85 and an upcoming trial will compare abiraterone with or without LHRH therapy in mCRPC patients.86 PARP inhibitors are being tested alone or in combination for patients with mutations in genes including BRCA1, BRCA2 and ATM. The PARP inhibitor olaparib was recently approved for mCRPC patients with homologous recombination repair (HRR) alterations after results from a phase III trial indicating improved radiographic PFS in the olaparib treatment group compared to the enzalutamide/abiraterone control group.87-89 Rucaparib was also recently approved for mCRPC patients with BRCA mutations.90 Additional studies are enrolling (NCT02854436, NCT04030559, NCT03480646, NCT04033328, NCT02987543, NCT02705469).

Many novel treatments are also under development. Investigational agents for treating non-metastatic or metastatic CRPC include an aldo-keto reductase 1C3 inhibitor and

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immunotherapy with individualized HLA class-I and/or class-II restricted New York esophageal squamous cell carcinoma 1(NY-ESO-1) peptides, which yield antigen-specific T-cell responses.82, 83 Several phase III trials are evaluating PD-1/PD-L1 inhibitors for treatment of mCRPC, both as monotherapy and in combination with other therapies.84 Top-line results from a recent phase III trial of the AKT inhibitor ipatasertib indicate that the investigational drug, in combination with abiraterone and prednisone/prednisolone, met its endpoint of statistically significant improvement in radiographic PFS in patients with mCRPC compared to abiraterone and prednisone/prednisolone.91 Prostate-specific membrane antigen (PSMA) targeted therapy is another promising treatment for progressive mCRPC: a phase II trial of lutetium-177 (177Lu)- PSMA-617, a radiolabeled small molecule that binds with high affinity to PSMA, demonstrated

[RJ-MN]

Thank you, Patrick!

[j-o-h-n]

Question Patrick.... In your current or past job, did you get paid by the word?

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 11/03/2020 2:48 PM EST

[SPEEDYX in reply to j-o-h-n]

I knew I should have taken that Evelyn Wood course!!

[j-o-h-n in reply to SPEEDYX]

Problem is you took the "speedy" sex course instead.....

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 11/03/2020 5:23 PM EST

[GeorgeGlass]

Patrick, I just met with Neil Shore two days ago and he asked if I wanted to start Orgovyx. I said I guess, whatever it is, lets get moving, my psa is up to 20. I'd like to know whether Orgovyx is as good as Firmagon by these measurements:1) which lowers T more? Is there a difference between the two? I couldn't find this in the info you posted above. It just said effective at reducing T in 96.7% of patients.

2) are they equal or different on heart related events (heart and coronary artery stress)

3) I asked Dr. Shore if Orgovyx effects healthy gut bacteria/immune system, and if taking numerous vitamins and supplements messes up the effectiveness of the T lowering and he didn't know. Do you want to take a guess at these questions? My cancer is in the abdomin so injections there might not be a bad idea. How uncomfortable are those monthly injections?

[pjoshea13 in reply to GeorgeGlass]

Hi George,

For a comparison of Orgovyx (Relugolix) & Firmagon (Degarelix), we have:

europeanurology.com/article...

4. Discussion

In this phase 2 study of intermediate-risk PCa patients, adding neoadjuvant/adjuvant relugolix to EBRT resulted in a 95% rate of sustained castration. While the study was not designed or powered to make formal statistical comparisons between relugolix and degarelix, both drugs rapidly induced and maintained castration during the treatment period. Accordingly, effects on PSA response and prostate volume were consistent between relugolix and degarelix groups, as well as consistent with data previously reported with other GnRH analogues [26, 27, 28]. Both relugolix and degarelix yielded rapid reductions in testosterone not seen with GnRH receptor agonists, which are associated with an early testosterone flare. Furthermore, both LH and FSH are fully suppressed while on treatment with both relugolix and degarelix, whereas GnRH agonists do not fully suppress FSH [19].

The rate of gonadotropin and testosterone recovery after treatment discontinuation was rapid with relugolix. These findings are consistent with its pharmacokinetic profile as a daily oral therapy. Fast testosterone recovery with relugolix was associated with a rapid improvement in a range of castration-related symptoms on QoL measures.

Previous data suggest that recovery from degarelix monthly depot injections can take >100 d; in this study, only 16% of degarelix patients had testosterone recovery 84 d after treatment discontinuation. Similar delayed recovery of testosterone has been reported using GnRH agonists, particularly with the 3-mo depot preparations [29, 30].

The ability to personalise dosing strategies with a once-daily oral medication with reliable rapid return of testosterone and fast relief from symptoms related to ADT may be advantageous for patients who do not want injections, those receiving a specific duration of therapy, those with disease eligible for intermittent therapy, and elderly patients with comorbidities or acute intercurrent illnesses where fatigue and muscle wasting are problematic.

Both relugolix and degarelix were well tolerated in this study. Although the frequency and type of AEs were not compared between the treatment arms with formal statistical analyses, similar patterns of AEs were reported by patients in both groups, with hot flush and fatigue being the most common. No hepatic-related AEs occurred in either group that resulted in dose modification or treatment discontinuation. Several patients receiving degarelix had injection-site reactions, consistent with past observations with injectable GnRH analogues. With the exception of those local reactions, the incidence and pattern of AEs with relugolix were as expected for a GnRH receptor antagonist [31]. Overall, there were no unexpected safety findings, no evidence of any bone safety or ophthalmological findings, no evidence of drug-induced phospholipidosis, and no safety concerns identified that would limit treatment in most patients.

The lack of blinding in this study is a potential limitation. Although knowledge of treatment assignments is unlikely to have had a meaningful impact on testosterone levels or other pharmacodynamic endpoints, it could have influenced investigators’ assessments of safety and patients’ responses on QoL questionnaires.

Despite the high compliance reported for relugolix administration in this study (>98%), another potential limitation of the trial is that it may not reflect compliance and adherence in a real-world setting. Inconsistent dosing carries the danger of ineffective therapeutic delivery and suboptimal treatment outcomes. Although compliance is more difficult to monitor with self-administered oral medications compared with injections administered by healthcare professionals, compliance can be monitored indirectly with testosterone or PSA levels. Novel strategies are being developed to improve adherence to oral oncology drugs [32]. Studies with longer-term follow-up are needed to further evaluate the clinical impact of more rapid testosterone recovery with relugolix, as well as long-term suppression of both FSH and LH. The phase 3 HERO trial investigating relugolix versus leuprolide over 48 wk is on-going in patients with advanced PCa (NCT03085095) and will evaluate whether relugolix can suppress testosterone through 48 wk in men with advanced PCa. This study will also evaluate whether relugolix can prolong the time to the castration-resistant PCa as compared with leuprolide acetate.

Recently released guidelines on the management of patients with localised intermediate-risk PCa recommend ADT with radiotherapy as a standard treatment option [33]. Considering the limitations of injectable GnRH agonists and GnRH receptor antagonists, there is an unmet need for a novel ADT in this treatment landscape. While other oral GnRH receptor antagonists are currently in development for women’s health indications [34], to our knowledge, relugolix is the only such antagonist in clinical development for PCa."

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See also:

pubmed.ncbi.nlm.nih.gov/334...

"We conducted a systematic review to identify all randomised, controlled trials in which a GnRH antagonist was compared with a GnRH agonist in men with prostate cancer. We identified ten eligible studies including two different GnRH antagonists, degarelix (n = 1681) and relugolix (n = 734), which were compared with the GnRH agonists, leuprolide (n = 714) and goserelin (n = 600)."

"There is consistent but methodologically limited data to suggest that GnRH antagonists - a relatively new class of androgen deprivation therapy for prostate cancer - cause significantly less cardiovascular adverse effects than the more frequently used GnRH agonists."

The full text might give some insight as to Relugolix) versus Degarelix.

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I can't answer [3].

Best, -Patrick

[GeorgeGlass in reply to pjoshea13]

Thanks Patrick, I read through it. Not a whole lot of long term data on relugolix but it sounds like it works on the T. Do you think it's good to use it now or wait for more studies on it?

Regarding your post here (Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in PCa), what is your key takeaway from all the info you provided?

George

[pjoshea13 in reply to GeorgeGlass]

George,

Relugolix seems like a winner. & many will be attracted by it being an oral drug (although some will forget to take it daily). With covid still with us & aggressive mutations gaining ground, who needs those periodic visits for injections?

Glancing through the post, it occurred to me that with "T < 20 ng/dL ... is a 'true' castrate level", we need to remember that free-T is more relevant than total T, & that the true purpose of castration is to deny PCa access to DHT.

-Patrick