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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.
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 proliferate,
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 patients with PCa 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 radiologic progression (detected by rising prostate-specific antigen [PSA] levels or imaging, respectively) with serum testosterone (T) at or below historical castrate level (50 ng/dL).
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.
Prostate Cancer Clinical Trials Working Group Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
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 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.
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.
This biological event defines the emergence of CRPC. This mechanism is consistent with what is seen in many other cancers such as those in colon, kidney, pancreas, and liver, where drug-resistant clones proliferate under the influence of selective therapeutic pressures.
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 50 ng/dL. Improvements in laboratory assays for T, such as liquid chromatography tandem mass spectrometry (lower limit of detection = 0.280 ng/dL) have enabled detection of much lower concentrations,
Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum.
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.
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 6 years in patients with low nadir T levels (≤ 22 ng/dL).
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.
Southwest Oncology Group Trial 9346 (INT-0162) Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162).
These new findings have prompted some professional groups and regulatory bodies to update their guidelines. In 2014, the European Association of Urology lowered its recommended target level for T during ADT to < 20 ng/dL.
In July 2019, the United States Food and Drug Administration published a guideline stating that the percentage of patients achieving and maintaining T < 20 ng/dL should represent a secondary endpoint in clinical trials investigating new therapies for medical castration and that these data be included in labels.
Advanced prostate cancer: developing gonadotropin-releasing hormone analogues guidance for industry. U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research,
Bethesda, MD2019
In light of these data, it appears important that CRPC clinical treatment guidelines should reflect this lower T target (< 20 ng/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/radiologic progression only when T is < 20 ng/dL.
Castrate serum testosterone < 50 ng/dL or 1.7 nmol/L plus either;
a. Biochemical progression: 3 consecutive rises in PSA 1 week apart resulting in 2 50% increases over the nadir, and a PSA > 2 ng/mL or,
b. Radiologic progression: the appearance of new lesions: either 2 or more new bone lesions on bone scan or a soft tissue lesion using response evaluation criteria in solid tumors.
Symptomatic progression alone must be questioned and subject to further investigation. It is not sufficient to diagnose CRPC.
Second-line hormonal therapy for men with chemotherapy-naïve, castration-resistant prostate cancer: American Society of Clinical Oncology Provisional Clinical Opinion.
Disease progression despite castrate levels of testosterone, presenting as either a continuous rise in serum PSA levels, the progression of pre-existing disease, and/or the appearance of new metastases (detectable clinically or by imaging).
Abbreviations: ASCO = American Society of Clinical Oncology; AUA = American Urological Association; CRPC = castration-resistant prostate cancer; CT = computed tomography; EAU = European Association of Urology; CUA-CUOG = Canadian Urological Association-Canadian Uro Oncology Group; ESMO = European Society for Medical Oncology; NCCN = National Comprehensive Cancer Network; PCa = prostate cancer; PSA = prostate-specific antigen; T = testosterone
Implications for Treatment Strategies and Diagnosis
Given the proposed new definition for castration, clinicians should confirm that patients with PCa have reached this lower T target (< 20 ng/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 > 20 ng/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.
Late dosing may result in reduced serum levels of effective drug, inconsistent T suppression, and increases in the frequency of T ‘escapes’ to > 20 ng/dL and even > 50 ng/dL.
The impact of late luteinizing hormone-releasing hormone agonist dosing on testosterone suppression in patients with prostate cancer: an analysis of United States clinical data.
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 > 20 ng/dL and > 50 ng/dL was much higher when injections were late (late injections: 43% T > 20 ng/dL and 27% T > 50 ng/dL; early/on-time injections: 21% T > 20 ng/dL and 4% T > 50 ng/dL), where a late injection was defined as dosing after day 32, 97, 128, and 194 from the previous injection for the 1-month, 3-month, 4-month, and 6-month formulations, respectively.
The impact of late luteinizing hormone-releasing hormone agonist dosing on testosterone suppression in patients with prostate cancer: an analysis of United States clinical data.
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 owing to late dosing or missed doses was common, confirming a scenario where clinicians’ ability to accurately diagnose progression to CRPC may be impacted.
Recent phase III trials in patients with nonmetastatic 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.
Multiple ADT therapy options are available with different active ingredients, mechanisms, and delivery technologies with varying levels of demonstrated T suppression < 20 ng/dL.
The impact of late luteinizing hormone-releasing hormone agonist dosing on testosterone suppression in patients with prostate cancer: an analysis of United States clinical data.
Demonstrated T suppression < 20 ng/dL is an important consideration when selecting ADT therapy. Currently, there is only 1 LHRH agonist formulation with peer-reviewed published clinical data across all dose formulations that confirm maintenance of T suppression to below 20 ng/dL throughout the dosing interval.
A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer.
An eight-month clinical study of LA-2575 30.0 mg: a new 4-month, subcutaneous delivery system for leuprolide acetate in the treatment of prostate cancer.
It is also important to monitor T levels during therapy to confirm suppression of T < 20 ng/dL and consider a change to an alternative ADT therapy if this is not achieved.
Additionally, if high T is owing 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 (eg, 6-month) formulation of ADT could minimize the risk of T ‘escape’ for cases where late dosing may occur, as these formulations require only 2 injections a year.
The impact of late luteinizing hormone-releasing hormone agonist dosing on testosterone suppression in patients with prostate cancer: an analysis of United States clinical data.
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.
Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer.
Although this bipolar androgen therapy strategy seems paradoxical, favorable results have been seen in patients with both androgen-sensitive and castration-resistant PCa. In a phase II trial,
Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study.
29 patients with mCRPC previously treated with enzalutamide received 400 mg 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 the efficacy of bipolar androgen therapy in patients with mCRPC who had previously received enzalutamide versus those who had previously received abiraterone. Thirty percent (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).
A multicohort open-label phase II trial of bipolar androgen therapy in men with metastatic castration-resistant prostate cancer (RESTORE): a comparison of post-abiraterone versus post-enzalutamide cohorts.
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 computed tomography (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.
PSMA PET mapping detects biochemically recurrent PCa with greater sensitivity than conventional imaging techniques and is effective even with very low levels of PSA.
Bridging the imaging gap: PSMA PET/CT has a high impact on treatment planning in prostate cancer patients with biochemical recurrence – a narrative review of literature.
Gallium-68 (68Ga)-PSMA PET/CT is a novel molecular imaging modality that can identify metastases at presentation and help inform treatment recommendations.
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.
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.
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 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 studied,
Egevad et al suggested that Gleason scores be grouped into 4 prognostic categories (4-5, 6, 7, and 8-10) based on analytic break points in the study population.
GETUG Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial.
Burden of metastatic castrate naive prostate cancer patients, to identify men more likely to benefit from early docetaxel: further analyses of CHAARTED and GETUG-AFU15 studies.
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.
Other genetic factors, including certain gene mutations that regulate cell survival, proliferation, or apoptosis, affect development of CRPC/mCRPC and response to treatment.
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.
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.
Advancements in DNA sequencing analysis, expansion of DNA libraries and variants and their predictive and prognostic implications, random amplified polymorphic DNA 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-based cancer biomarkers,
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 American Society of Clinical Oncology 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.
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 nonmetastatic 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.
Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer.
Another study found that low baseline T, defined as T < 11.5 ng/dL, is prognostic for the survival of patients with mCRPC and thus should be considered in the treatment selection process.
Prognostic and predictive value of plasma testosterone levels in patients receiving first-line chemotherapy for metastatic castrate-resistant prostate cancer.
Readily available biomarkers such as neutrophil-to-lymphocyte ratio, lactate dehydrogenase, albumin, alkaline phosphatase, DNA AR, and bone scan index are useful prognostic tools in CRPC progression. In patients with mCRPC receiving first-line chemotherapy, neutrophil-to-lymphocyte ratio was correlated with survival and may serve as a prognostic or risk stratification tool for randomized clinical trials.
Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials.
A prognostic index model using 6 risk factors (lactate dehydrogenase greater than the upper limit of normal, Eastern Cooperative Oncology Group performance status of 2, presence of liver metastases, albumin ≤ 4 g/dL, alkaline phosphatase greater than the upper limit of normal, and time from start of initial ADT to start of abiraterone treatment ≤ 36 months) were predictive for overall survival (OS) in patients with mCRPC treated with abiraterone after docetaxel.
A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel.
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 ≤ .001).
Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients.
Phase 3 assessment of the automated bone scan index as a prognostic imaging biomarker of overall survival in men with metastatic castration-resistant prostate cancer: a secondary analysis of a randomized clinical trial.
Use of new technologies or biomarker assays can allow improved evaluation of disease stage and better treatment decisions.
Advancements in CRPC Therapies
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.
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.
Prostate Cancer Clinical Trials Working Group 3 Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3.
It is of note that these approval studies only required a baseline T value of < 50 ng/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.
through continuation of ADT and confirmation that it remains effective in maintaining T below 20 ng/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.
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 in men treated with darolutamide and ADT was 40.4 months versus 18.4 for men receiving ADT alone.
Additional phase III trials in men with non-metastatic CRPC demonstrated similar metastasis-free survival benefits from combination therapy of ADT with or without apalutamide (40.5 vs. 16.2 months)
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 patients with CRPC undergoing treatment with abiraterone/enzalutamide had morphologically discernable small-cell neuroendocrine tumors, as evaluated by biopsy.
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).
U.S. Food and Drug Administration approval summary: enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer.
U.S. Food and Drug Administration approval summary: enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer.
Recent evidence from the CARD trial suggests that sequential use of AR targeting agents is less effective than using chemotherapy as a distinct mechanism of action.
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.
ERA 223: a phase 3 trial of radium-223 dichloride in combination with abiraterone acetate and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients with bone-predominant metastatic castration-resistant prostate cancer.
Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis.
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.
Integrating novel targets and precision medicine into prostate cancer care-part 1: the non-androgen-targetable pathways in castration-resistant prostate cancer.
A phase I/II study of the investigational drug alisertib in combination with abiraterone and prednisone for patients with metastatic castration-resistant prostate cancer progressing on abiraterone.
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,
Enzalutamide versus abiraterone as a first-line endocrine therapy for castration-resistant prostate cancer (ENABLE study for PCa): a study protocol for a multicenter randomized phase III trial.
Abiraterone acetate plus LHRH therapy versus abiraterone acetate while sparing LHRH therapy in patients with progressive, metastatic and chemotherapy-naive, castration-resistant prostate cancer (SPARE): study protocol for a randomized controlled trial.
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 patients with mCRPC with homologous recombination repair alterations after results from a phase III trial indicating improved radiographic PFS in the olaparib treatment group compared with the enzalutamide/abiraterone control group.
Many novel treatments are also under development. Investigational agents for treating non-metastatic or metastatic CRPC include an aldo-keto reductase 1C3 inhibitor and immunotherapy with individualized human leukocyte antigens 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.
In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17beta-hydroxysteroid dehydrogenase type 5 (17betaHSD5; AKR1C3).
Several phase III trials are evaluating programmed cell death 1/programmed cell death-ligand 1 inhibitors for treatment of mCRPC, both as monotherapy and in combination with other therapies.
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 with abiraterone and prednisone/prednisolone.
Roche’s IPATential150 study evaluating ipatasertib in combination with abiraterone and prednisone/prednisolone met one of its co-primary endpoints: Roche. 2020
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 PSA decline of 50% or more in 38% of patients.
The treatment was well-tolerated and is undergoing further investigation and development in an international multi-center phase III trial (NCT03511664).
Studies are also underway to determine appropriate treatments using various imaging modalities to identify CRPC stages. Identification of additional genomic or molecular biomarkers that correlate with time to emergence of CRPC/mCRPC can also improve personalization of disease management. Two tests, BRACAnalysis CDx (a liquid germline test using whole blood to identify BRCA1 and BRCA2 mutations) and FoundationOne CDx (a genomic profiling test on solid tumors to identify microsatellite instability and tumor mutational burden), are approved as companion diagnostic assays for olaparib.
Given the importance of low T levels in optimal management of advanced PCa, simply prescribing ADT is not adequate–ADT should be administered with best practices to maintain very low T levels and improve patient outcomes. It is important to regularly assess T levels in patients receiving ADT. Further examination of strategies to ensure on-time dosing, such as clinical practice improvement and patient education, should be considered. Ongoing trials continue to assess differences in clinical effectiveness between treatments in maintaining low T suppression, and additional studies evaluating potential differences between LHRH agonist formulations and LHRH agonists versus antagonists (eg, the HERO trial
) may enhance our understanding of how to achieve optimal outcomes.
Conclusions
The ultimate goal of therapy for advanced PCa is to delay disease progression and prolong survival. ADT, the foundation of treatment in these patients, aims to achieve and maintain the lowest possible levels of T. Given the updated target T level to confirm castration, the definition of CRPC should also be updated to reflect a level of T < 20 ng/dL, as attainment of this lower level may lead to improved outcomes (Table 3). Regular T monitoring will enable physicians to identify settings in which T is inadequately suppressed and adjust therapy if necessary. Considering the significant advancements in understanding PCa progression, optimal management strategies for CRPC diagnosis and treatment continue to be investigated. Key advances in CRPC include improvements in androgen assay and imaging modalities, prognostic predictors for CRPC development, identification of genetic contributors to and treatment-related factors associated with CRPC progression, and the introduction of novel therapies.
Тablе 3Implications of T Levels on CRPC Diagnosis: Original Versus Proposed Castration Definition
Castration Definition
T ≤ 20 ng/dL
20 < T ≤ 0 ng/dL
T > 50 ng/dL
Original: ≤ 50 ng/dL
Effective T suppression Continue LHRH monotherapy If PSA is high, diagnose as CRPC
Proposed: ≤ 20 ng/dL
Ineffective T suppression Consider approaches to suppress T before diagnosing as CRPC
As new CRPC therapies are developed, it is important to recognize the continued importance of ADT as foundational therapy; clinical studies of abiraterone, enzalutamide, apalutamide, darolutamide, docetaxel, cabazitaxel, radium-223, and sipuleucel-T were all performed with ongoing ADT. Where T is higher than target, owing to reduced response to a particular treatment or dosing nonadherence, physicians should ensure adherence to ADT dosing schedules or consider prescribing an alternative ADT formulation with published data supporting its ability to achieve and maintain T < 20 ng/dL. A formulation change with a longer dosing schedule (ie, 6-month) may be beneficial if adherence to dosing schedules appears difficult (Figure 1). Regardless of dosing timeliness, a change in ADT monotherapy is important when T remains high to restore effective T suppression.
Figure 1Flowchart of Recommended Approaches to Resolve Ineffective T Suppression
Future directions for treatment include biomarker-driven options such as targeted therapies and immuno-oncologic agents. In addition to the clinical benefits delivered by these new therapies, further research should evaluate optimization of ADT to delay time to CRPC progression and improve OS or PFS. All clinical studies should capture key data such as T levels at baseline and during treatment to continually monitor effective T suppression. Significant advancements in understanding PCa progression and updates to the definition of castration offer potential to improve clinical outcomes for patients with advanced PCa. Further understanding of the biology of progression of PCa, identification of therapeutic resistance, definition of castration, and development of novel therapies for CRPC hold promise for improving the lives of many patients.
Disclosure
Dr 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 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 Ryan is a consultant for Advanced Accelerator Applications, Astellas, Bayer, BMS, Clovis Oncology (payment to institution), Dendreon, Janssen (payment to institution) Myovant, and Roivant and has research collaborations with Sanofi Genzyme and an equity interest in Xcell Biosciences.
Acknowledgments
Medical writing and editing support were provided by consultants at Xelay Acumen Group, Inc, funded by Tolmar Pharmaceuticals, Inc .
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Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell’s fault.
Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum.
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.
Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162).
Advanced prostate cancer: developing gonadotropin-releasing hormone analogues guidance for industry. U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research,
Bethesda, MD2019
Second-line hormonal therapy for men with chemotherapy-naïve, castration-resistant prostate cancer: American Society of Clinical Oncology Provisional Clinical Opinion.
The impact of late luteinizing hormone-releasing hormone agonist dosing on testosterone suppression in patients with prostate cancer: an analysis of United States clinical data.
A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer.
An eight-month clinical study of LA-2575 30.0 mg: a new 4-month, subcutaneous delivery system for leuprolide acetate in the treatment of prostate cancer.
Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer.
Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study.
A multicohort open-label phase II trial of bipolar androgen therapy in men with metastatic castration-resistant prostate cancer (RESTORE): a comparison of post-abiraterone versus post-enzalutamide cohorts.
Bridging the imaging gap: PSMA PET/CT has a high impact on treatment planning in prostate cancer patients with biochemical recurrence – a narrative review of literature.
Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial.
Burden of metastatic castrate naive prostate cancer patients, to identify men more likely to benefit from early docetaxel: further analyses of CHAARTED and GETUG-AFU15 studies.
Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer.
Prognostic and predictive value of plasma testosterone levels in patients receiving first-line chemotherapy for metastatic castrate-resistant prostate cancer.
Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials.
A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel.
Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients.
Phase 3 assessment of the automated bone scan index as a prognostic imaging biomarker of overall survival in men with metastatic castration-resistant prostate cancer: a secondary analysis of a randomized clinical trial.
Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3.
U.S. Food and Drug Administration approval summary: enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer.
ERA 223: a phase 3 trial of radium-223 dichloride in combination with abiraterone acetate and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients with bone-predominant metastatic castration-resistant prostate cancer.
Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis.
Integrating novel targets and precision medicine into prostate cancer care-part 1: the non-androgen-targetable pathways in castration-resistant prostate cancer.
A phase I/II study of the investigational drug alisertib in combination with abiraterone and prednisone for patients with metastatic castration-resistant prostate cancer progressing on abiraterone.
Enzalutamide versus abiraterone as a first-line endocrine therapy for castration-resistant prostate cancer (ENABLE study for PCa): a study protocol for a multicenter randomized phase III trial.
Abiraterone acetate plus LHRH therapy versus abiraterone acetate while sparing LHRH therapy in patients with progressive, metastatic and chemotherapy-naive, castration-resistant prostate cancer (SPARE): study protocol for a randomized controlled trial.
In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17beta-hydroxysteroid dehydrogenase type 5 (17betaHSD5; AKR1C3).
Roche’s IPATential150 study evaluating ipatasertib in combination with abiraterone and prednisone/prednisolone met one of its co-primary endpoints: Roche. 2020 (Available at:)
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