Intermittent Androgen Deprivation Therapy Research Articles

Editorial Comment

No AccessJournal of UrologyAdult Urology1 Oct 2021Editorial CommentThis article comments on the following:Real-World Practice Patterns and Predictors of Continuous versus Intermittent Androgen Deprivation Therapy Use for Prostate Cancer in Older Men Brock O’Neil Brock O’NeilBrock O’Neil Department of Surgery-Urology,Huntsman Cancer Hospital, Salt Lake City, Utah More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001876.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 206(4), p. 941 Reference 1. : Implementing continuous quality improvement in an integrated community urology practice: lessons learned. Urology 2021; doi: 10.1016/j.urology.2020.11.068. Crossref, Google Scholar © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of UrologyMay 25, 2021, 12:00:00 AMReal-World Practice Patterns and Predictors of Continuous versus Intermittent Androgen Deprivation Therapy Use for Prostate Cancer in Older Men Volume 206Issue 4October 2021Page: 941-941 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Brock O’Neil Department of Surgery-Urology,Huntsman Cancer Hospital, Salt Lake City, Utah More articles by this author Expand All Advertisement PDF DownloadLoading ...

Interpreting Testosterone and Concomitant Prostate Specific Antigen Values during Androgen Deprivation Therapy for Recurrent Prostate Cancer

Measurement of testosterone levels during androgen deprivation therapy (ADT) is broadly recommended, but how therapy should be altered in response to testosterone values during ADT remains controversial. Our objective was therefore to evaluate the relation between testosterone and concomitant prostate specific antigen (PSA) levels during ADT on clinical outcomes. Patients from the continuous androgen deprivation arm of the PR.7 trial of intermittent ADT for biochemically recurrent prostate cancer following radiotherapy were included. Statistical analyses evaluated the prognostic importance of testosterone levels during ADT relative to concomitant PSA levels. We similarly evaluated whether the number of testosterone breakthroughs >1.7 nmol/l predicted the time to castrate-resistant prostate cancer (CRPC), cancer specific survival (CSS) or overall survival (OS) with Kaplan-Meier and Cox regression analyses. Overall, the prognostic importance of testosterone on outcomes was eclipsed by the prognostic value of concomitant PSA values. The occurrence of testosterone values >0.7 nmol/l in the first year of therapy was associated with subsequent rises >1.7 nmol/l, but the number of testosterone breakthroughs per patient had no relationship to the risk of CRPC, CSS or OS. A time-dependent adjusted analysis indicated as expected that PSA values were prognostic, but there was no association of relative cumulative testosterone exposure with outcomes. In this large-scale trial with long followup, breakthrough testosterone was unrelated to time to CRPC, CSS or OS. Castrate testosterone values during ADT for recurrent prostate cancer provides prognostic information that must be considered alongside the time since ADT initiation and concomitant PSA values.

Patient‐reported outcomes following neoadjuvant endocrine therapy, external beam radiation, and adjuvant continuous/intermittent endocrine therapy for locally advanced prostate cancer: A randomized phase III trial

BackgroundWe evaluated patient‐reported outcomes (PRO) during neoadjuvant androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) followed by either adjuvant continuous ADT (CADT) or intermittent ADT (IADT) for patients with locally advanced prostate cancer (Pca).MethodsA multicenter, randomized phase III trial enrolled 303 patients with locally advanced Pca. The patients were treated with 6 months (M) of ADT followed by 72 Gy of EBRT, and were randomly assigned to CADT or IADT after 14 M. The PROs were evaluated at sic points: baseline, 6 M, 8 M, 14 M, 20 M, and 38 M using FACT‐P questionnaires and EPIC urinary, bowel, and sexual bother subscales.ResultsThe FACT‐P total scores were significantly better (p < 0.05) in IADT versus CADT at 20 M (121.6 vs.115.4) and at 38 M (119.9 vs. 115.2). The physical well‐being scores (PWB) were significantly better (p < 0.05) in IADT versus CADT at 38 M (25.4 vs. 24.0). The functional scores were significantly better in IADT than those in CADT at 14 M (20.2 vs18.7, p < 0.05) and at 20 M (21.0 vs.18.9, p < 0.05).ConclusionThe PRO was significantly favorable in IADT on FACT‐P total score at 20 M and 38 M, PWB and functional scores at 38 M.

Threshold dynamics of a stochastic model of intermittent androgen deprivation therapy for prostate cancer

Intermittent androgen deprivation therapy is often used to treat prostate cancer, but there are few mathematical modelling studies of it. To explore the mechanisms of such therapy, we describe intermittent therapy with impulsive differential equations, then we propose a novel mathematical model of intermittent androgen deprivation therapy with white noise. We first studied the model’s basic properties including the existence and uniqueness of the solution. By using the theory of stochastic differential equations, we investigated the thresholds for the extinction and persistence of prostate cancer cells, which are markedly affected by the antigenicity of tumours and noise parameters. Moreover, sufficient conditions for the stationary distribution and ergodicity of the system are provided. The results show that reducing the period of pulsed interventions or increasing the dosages (or frequencies) of the therapy will be helpful for curing prostate cancer.

Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer

BackgroundThe standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in...

Turnover Modulates the Need for a Cost of Resistance in Adaptive Therapy.

Adaptive therapy seeks to exploit intratumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer that determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this article, we study a general, but simple, mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka-Volterra model. For tumors close to their environmental carrying capacity, a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost-turnover interplay in data from 67 patients with prostate cancer undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision-making process. SIGNIFICANCE: Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy.See related commentary by Strobl et al., p. 811.

Rationale for Involved Field Stereotactic Body Radiation Therapy-Enhanced Intermittent Androgen Deprivation Therapy in Hormone-Sensitive Nodal Oligo-Recurrent Prostate Cancer Following Prostate Stereotactic Body Radiation Therapy.

Lymph node recurrent prostate cancer is a common clinical scenario that is likely to increase significantly with the widespread adoption of novel positron emission tomography (PET) agents. Despite increasing evidence that localized therapy is disease modifying, most men with lymph node recurrent prostate cancer receive only systemic therapy with androgen deprivation therapy (ADT). For men who receive localized therapy the intent is often to delay receipt of systemic therapy. Little evidence exists on the optimal combination of local and systemic therapy in this patient population. In this hypothesis generating review, we will outline the rationale and propose a framework for combining involved field SBRT with risk adapted intermittent ADT for hormone sensitive nodal recurrent prostate cancer. In patients with a limited number of nodal metastases, involved field stereotactic body radiation therapy (SBRT) may have a role in eliminating castrate-resistant clones and possibly prolonging the response to intermittent ADT. We hypothesize that in a small percentage of patients, such a treatment approach may lead to long term remission or cure.

A Time Scales Approach for Modeling Intermittent Hormone Therapy for Prostate Cancer.

Prostate cancer is a common cancer among males in the USA and is often treated by intermittent androgen deprivation therapy. This therapy requires a patient to alternate between periods of androgen suppression treatment and no treatment. Prostate-specific antigen levels are used to track relative changes in tumor volume of prostate cancer patients undergoing intermittent androgen deprivation therapy. During this therapy, there is a pause between treatment cycles. Traditionally, continuous ordinary differential equations are used to estimate prostate-specific antigen levels. In this paper, we use dynamic equations to estimate prostate-specific antigen levels and construct a novel time scale model to account for both continuous and discrete time simultaneously. This allows us to account for breaks between treatment cycles. Using empirical data sets of prostate-specific antigen levels, a known bio-marker of prostate cancer, across multiple patients, we fit our model and use least squares to estimate two parameter values. We then compare our model to the data and find a resemblance on treatment intervals similar to our time scale.

PSA Levels after IMRT for Prostate Cancer: Discriminating Second Plateau from PSA Failure

After IMRT combined with androgen deprivation therapy (ADT) for prostate cancer, PSA levels generally decrease to the nadir; by withdrawing ADT, the PSA level gradually rises and reaches a plateau after a while. Following IMRT alone, the PSA level gradually decreases and reaches a plateau. In the present study, this plateau is named as “first plateau (P1)”. In some cases, however, PSA rises after the first plateau and reaches a second plateau (P2) without cancer recurrence. We assume this phenomenon reflects the recovery of normal prostate cells. The objective of this study is to investigate clinical features of the second plateau and to compare patients who experienced PSA failure to those who settled at the second plateau phase. Of 348 patients with T1-3N0M0 prostate cancer treated by IMRT with or without neoadjuvant/adjuvant ADT, 35 patients receiving ADT for > 3 years or intermittent ADT were excluded, and 313 patients followed for 79-129 (median 106) months were analyzed. The total dose was 72.6-78 Gy with daily fractions of 2.0, 2.1, or 2.2 Gy. PSA failure was defined as PSA rise of > 2.0 ng/mL above the nadir. “Plateau” was defined algorithmically as an interval where PSA value at any measurement point falls into a range of the preceding three values and “elevation” as a consequent PSA rise without satisfying the criteria of “plateau”. Cox proportional-hazard models were used to find predictors for P2. The slope of elevation after P1 (E1) was calculated as a regression coefficient in a linear regression. Mean PSA nadir, P1 and P2 levels were compared between the PSA-failure and non-failure groups. Of 313 patients, P1 was observed in 177 patients (56.5%). In 67 (21.4%), PSA levels did not elevate above nadir and in 69 (22.0%) PSA levels increased after nadir without satisfying the criteria of plateau. Eventually, PSA failure was observed in 50 patients (16.0%). P2 was observed in 52 (16.6%) and elevation after P2 (E2) was observed in 24 (7.7%). T3 and neoadjuvant ADT were associated with lower likelihood of the occurrence of P2 on multivariate analysis. In fully-analyzable cases (n = 93), mean PSA nadir, P1 and P2 levels, and E1 slope for the non-PSA-failure group (n = 74) were 0.11, 0.31, and 0.41 ng/mL, and 0.11 ng/mL/year, respectively. Those for the PSA-failure group (n = 19) were 0.26, 0.54, and 0.82 ng/mL, and 0.48 ng/mL/year, respectively. All these factors except the mean P2 level were significantly higher in the PSA-failure group. The ROC curve identified the E1 slope of 0.28 ng/mL/year as an optimal cut-off value predicting risks of PSA failure with the highest accuracy (AUC:0.88, 95% CI: 0.79-0.96). By applying the criteria of “plateau” proposed in this study, 52 of 313 patients (16.6%) treated by IMRT experienced the second plateau. A comparison of the E1 slope indicated PSA rise of >0.28 ng/mL/year after P1 could be a predictor discriminating PSA failure from second plateau.

Impact of Late Dosing on Testosterone Suppression with 2 Different Leuprolide Acetate Formulations: In Situ Gel and Microsphere. An Analysis of United States Clinical Data.

Nonadherence to dosing schedules for androgen deprivation therapy increases the risk of testosterone escape for patients with prostate cancer. Two approved formulations of leuprolide acetate, the most commonly prescribed androgen deprivation therapy in the United States, use different extended release delivery technologies: an in situ gel and microspheres. We evaluated the prevalence and impact of late dosing on testosterone suppression for gel and microsphere formulations of leuprolide acetate. We retrospectively analyzed records of patients with prostate cancer treated with gel or microsphere delivery of leuprolide acetate. Analyses used 2 definitions of "month," "28-day" (late dosing after day 28, 84, 112 or 168) and "extended" (late dosing after day 32, 97, 128 and 194). Frequencies of late dosing and associated testosterone values were calculated. A total of 2,038 patients received gel and 8,360 received microsphere formulations of leuprolide acetate. More than 80% and 27% of injections were late for 28-day and extended month, respectively. For 28-day month late injections 10% (gel delivery) and 14% (microsphere delivery) of testosterone values were above 50 ng/dl, and 25% (gel) vs 33% (microsphere) were above 20 ng/dl. For extended month 18% (gel) vs 25% (microsphere) were above 50 ng/dl, and 34% (gel) vs 44% (microsphere) were above 20 ng/dl. Microsphere leuprolide acetate was 1.5 times more likely to have testosterone above 50/20 ng/dl vs gel. Least square mean testosterone was 34 ng/dl (gel) vs 46 ng/dl (microsphere) for 28-day month, and 48 ng/dl (gel) vs 76 ng/dl (microsphere) for extended month. Leuprolide acetate therapies were frequently administered late. Gel formulation demonstrated higher rates of testosterone 50 ng/dl or less and 20 ng/dl or less than microsphere formulation. Optimal testosterone suppression can impact prostate cancer progression and patient survival, and differences in extended release technology for androgen deprivation therapy appear relevant.

The management of hot flushes for men treated with androgen deprivation therapy for prostate cancer: a survey of UK practice

Androgen deprivation therapy (ADT) is one of the main treatments for prostate cancer. Short-term ADT of between 6 months and 3 years is often used in combination with radiotherapy to treat localised and locally advanced prostate cancer. Permanent or intermittent ADT is used to treat metastatic disease. Hot flushes affect 44-80% of men undergoing ADT for prostate cancer, with around 27% saying they are the most distressing side effect.1 A recent UK survey found 30.7% of men treated with ADT reported moderate or major problems with hot flushes.2 Low testosterone levels are thought to cause dysfunction in thermoregulation in the hypothalamus, resulting in peripheral vasodilatation.3 Symptoms include a feeling of warmth, flushing of the skin, perspiration, chills, anxiety and palpitations. A variety of treatments have been evaluated and there is evidence of efficacy for several of them, however they all have additional side effect profiles. The National Institute for Health and Care Excellence (NICE) and European Association of Urology recommend offering medroxyprogesterone or cyproterone acetate.4-5 NICE has said there is currently a lack of evidence to support the use of complementary therapies. Addressing the side-effects of cancer treatment is one of the top ten Living with and Beyond Cancer research priorities established by the National Cancer Research Institute. However, there is little evidence on the standard of care that UK clinicians offer to men suffering with hot flushes.

S1628 Metastatic Prostate Adenocarcinoma With a Unique GI Presentation

INTRODUCTION: Prostate adenocarcinoma is one of the most common forms of cancer in men. Common areas of metastasis include bone and lymph nodes. However, several less common sites of invasion exist which require histological confirmation, especially in patients with a history of prostate cancer. Misdiagnosis can lead to inappropriate treatment and complications. We present a rare case of metastatic prostate adenocarcinoma in the rectum discovered during colonoscopy. CASE DESCRIPTION/METHODS: An 85-year-old patient with a history of prostate adenocarcinoma (Gleason 3 + 3 = 6) status post brachytherapy, cryosurgery, and intermittent androgen deprivation therapy (ADT) presented with a one year history of altered bowel habits, intermittent rectal pain, and bleeding. CT colonogram showed a low rectal mass with lobulated margins extending into perirectal fat. Colonoscopy revealed a rectal infiltrating mass 4-5 cm from the anal verge. Biopsy and immunohistochemistry confirmed poorly differentiated AE-1/AE-3 and NKX3.1 positive adenocarcinoma of prostatic origin. Axumin PET Scan demonstrated abnormal uptake in the left perirectal and left pelvic lymph nodes. Due to lack of obstructive symptoms, the patient was started on systemic therapy with Enzalutamide 160 mg PO daily with follow up PSA every 2-3 months to monitor progress. DISCUSSION: Rectal metastasis of prostate adenocarcinoma is a rare finding with few cases reported in the literature. This is likely because Denovilliers’ fascia serves as an anatomic barrier between the rectum and the prostate. Literature review suggests several potential routes of dissemination to the rectum including direct invasion of Denovilliers’ fascia, lymphatic dissemination, and seeding of the tissue during needle biopsy. Patients may present with symptoms of bowel obstruction, rectal pain or bleeding, and changes in bowel habits typical of rectal tumors without urological symptoms of prostate tumors. Immunohistochemical examination is imperative in making a definitive diagnosis. Treatment methods in prior case reports include chemotherapy, radiation, hormone therapy, and surgical intervention with neoadjuvant ADT. It is not clear if rectal metastasis in prostate adenocarcinoma portends a poor prognosis. Collation of data from these rare cases, including our own, may help define the prognosis and appropriate management of such a metastatic tumor.

Population-based Assessment of Intermittent Androgen Deprivation Therapy Utilization for Relapsed, Nonmetastatic, Hormone-sensitive Adenocarcinoma of the Prostate.

Androgen deprivation therapy (ADT) is the standard of care for men with nonmetastatic hormone-sensitive prostate cancer (nmHSPC) after treatment failure. Although intermittent ADT (iADT) is noninferior to continuous ADT for prostate cancer outcomes, with superior quality of life and cost-to-benefit ratio, little is known regarding its real-world utilization. The authors aimed to determine the utilization of iADT in a Canadian Provincial Cancer Program for relapsed nmHSPC and identified risk factors associated with the nonreceipt of iADT. This retrospective population-based cohort study used linked administrative databases to identify all patients with relapsed nmHSPC from 2012 to 2016 and quantified ADT prescription history. Patients were defined as iADT eligible if prostate-specific antigen (PSA) was <4 ng/mL and trending downwards on ≥2 sequential PSAs after ≥6 months of ADT. Univariable and multivariable logistic regression analyses were performed to determine factors associated with nonreceipt of iADT. A total of 601 men with relapsed, nmHSPC were included with a median age at relapse of 73 (range, 46 to 96), pre-ADT PSA of 12.2 ng/mL, and a median pre-ADT PSA doubling time of 7.8 months. 80.9% of the cohort were eligible to receive iADT and 74.4% were treated with iADT. On multivariable analysis, patients originally treated with surgery (odds ratio [OR], 0.19; 95% confidence interval [CI], 0.08-0.46) or having a Gleason Score ≥8 (OR, 0.30; 95% CI, 0.12-0.78) had decreased odds of receipt of iADT. Patients with longer PSA doubling times were more likely to receive iADT (OR, 2.71; 95% CI, 1.17-6.31). The utilization of iADT was relatively common for men in Manitoba during the study period, however, the uptake of iADT can be improved among identified subgroups.

Androgen driven evolutionary population dynamics in prostate cancer growth

&lt;p style='text-indent:20px;'&gt;Prostate cancer worldwide is regarded the second most frequent diagnosed cancer in men with (899,000 new cases) while in common cancer it is the fifth. Regarding the treatment of progressive prostate cancer the most common and effective is the intermittent androgen deprivation therapy. Usually this treatment is effective initially at regressing tumorigenesis, mostly a resistance to treatment can been seen from patients and is known as the castration-resistant prostate cancer (CRPC), so there is no any treatment and becomes fatal. Therefore, we proposed a new mathematical model for the prostate cancer growth with fractional derivative. Initially, we present the model formulation in detail and then apply the fractional operator Atangana-Baleanu to the model. The fractional model will be studied further to analyze and show its existence of solution. Then, we provide a new iterative scheme for the numerical solution of the prostate cancer growth model. The analytical results are validated by considering various values assigned to the fractional order parameter &lt;inline-formula&gt;&lt;tex-math id="M1"&gt;\begin{document}$ \alpha. $\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;&lt;/p&gt;

30: Is Intermittent Androgen Deprivation Therapy An Underutilized Strategy for Management of Relapsed, Non-Metastatic, Castration Sensitive Prostate Cancer? - A Population-Based Assessment of a Provincial Cancer Program

30: Is Intermittent Androgen Deprivation Therapy An Underutilized Strategy for Management of Relapsed, Non-Metastatic, Castration Sensitive Prostate Cancer? - A Population-Based Assessment of a Provincial Cancer Program

Maintenance of sexual activity following androgen deprivation in males.

Androgen deprivation therapy (ADT) is a common treatment for men with systemic prostate cancer. However, ADT leads to sexual dysfunction, causing >80 % of couples to cease sexual activity completely. Here, we use a biopsychosocial framework to review factors that may influence the ability of patients on ADT to remain sexually active. We address sexual factors prior to ADT, neurobiological factors, intermittent ADT, sex aids, exercise, sleep, partner factors, masculinity, non-penetrative intimacy, depressive symptoms, and access to counselling or patient education programs. We make suggestions for future research in order to extend our understanding in this field with the goal of improving evidence-based treatment protocols and practice. Importantly, we suggest that clinicians should discuss options for sexual intimacy after ADT with both patients and their partners, as sexual inactivity is not inevitable for most, and strategies are available for helping maintain sexual intimacy.

Reverse intermittent androgen deprivation therapy: Prostate cancer and hypopituitarism

Testosterone replacement in the context of untreated prostate cancer is a controversial topic, where the symptomatic benefits of testosterone therapy contrast with the risk of disease progression. We report the case of a 76-year-old gentleman, under watchful waiting for known prostate cancer, who underwent a transsphenoidal resection of a pituitary macroadenoma. The adenoma and subsequent surgical treatment resulted in secondary testosterone deficiency, effectively ‘self-commencing’ endogenous androgen deprivation therapy. After discussion with the endocrine team, careful intermittent testosterone supplementation was undertaken to address his symptoms, with the patient undergoing prostate-specific antigen surveillance. This was felt to be similar to intermittent androgen deprivation therapy in reverse. Here, we review current evidence regarding testosterone therapy in the context of prostate cancer. Level of Evidence: 5

Clinical Outcomes of Stereotactic Body Radiotherapy With Immediate Versus Delayed Hormone Therapy in Men With Oligometastatic Recurrence of Prostate Cancer

AimsStereotactic body radiotherapy (SBRT) with the delayed option of androgen deprivation therapy (ADT) is the current treatment paradigm in men relapsed with oligometastatic prostate cancer based on the outcome of a phase II randomised controlled study. The immediate (concomitant) use of ADT in this clinical setting potentially augments the efficacy of SBRT by improving systemic disease control. The aim of this study was to compare the clinical outcomes of these two treatment strategies. Materials and methodsEighty-eight patients with up to three oligometastases and controlled primary disease who had been treated using SBRT with immediate or delayed ADT were included in this retrospective analysis. Progression-free survival (PFS), widespread failure-free survival (WFFS) and freedom from further interventions (FFFI) were assessed using Kaplan–Meier and Cox proportional hazard regression methods. Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. ResultsThirty-nine patients (44.3%) were treated with SBRT and immediate ADT (continuous ADT, n = 7; intermittent ADT, n = 32) and 49 (55.7%) with SBRT and delayed ADT. The median follow-up was 24 months (interquartile range 13.5–37.0 months). PFS in the immediate and delayed ADT groups were 26 months and 16 months, respectively (P < 0.007). The median WFFS in the immediate ADT group was not reached compared with 21 months in the delayed ADT group (P = 0.025). The 1- and 2-year FFFI in the immediate ADT group were 88% and 64.1%, respectively, significantly higher than those in the delayed ADT group (63.8% and 30.2%, respectively, P < 0.002). Acute toxicities of grade 1–2 occurred in 17.9% of the immediate ADT group and 18.4% of the delayed ADT group (P = 0.96). Only one case of grade 3 late toxicity (pelvic insufficiency) was identified in this study. ConclusionsSBRT with concomitant ADT improves PFS, WFFS and FFFI as compared with SBRT with delayed ADT; this finding needs validation in a prospective, randomised study.

Prostate-specific antigen dynamics predict individual responses to intermittent androgen deprivation

Intermittent androgen deprivation therapy (IADT) is an attractive treatment for biochemically recurrent prostate cancer (PCa), whereby cycling treatment on and off can reduce cumulative dose and limit toxicities. We simulate prostate-specific antigen (PSA) dynamics, with enrichment of PCa stem-like cell (PCaSC) during treatment as a plausible mechanism of resistance evolution. Simulated PCaSC proliferation patterns correlate with longitudinal serum PSA measurements in 70 PCa patients. Learning dynamics from each treatment cycle in a leave-one-out study, model simulations predict patient-specific evolution of resistance with an overall accuracy of 89% (sensitivity = 73%, specificity = 91%). Previous studies have shown a benefit of concurrent therapies with ADT in both low- and high-volume metastatic hormone-sensitive PCa. Model simulations based on response dynamics from the first IADT cycle identify patients who would benefit from concurrent docetaxel, demonstrating the feasibility and potential value of adaptive clinical trials guided by patient-specific mathematical models of intratumoral evolutionary dynamics.

A randomized phase II study of apalutamide (APA), androgen deprivation therapy (ADT), or APA + ADT in patients (pts) with biochemically relapsed (BCR) prostate cancer (PC).

320 Background: While there is no standard therapy for BCR PC following local therapy, intermittent ADT is widely used. We evaluated utility of APA alone, ADT (luteinizing hormone–releasing hormone agonist [LHRHa]) alone, or APA + LHRHa in ADT-naïve BCR PC pts. Methods: Pts with BCR PC after primary definitive local therapy and prostate-specific antigen (PSA) doubling time (PSADT) ≤ 12 mo were randomized 1:1:1 to open-label 240 mg APA daily, LHRHa alone, or APA + LHRHa for 12 mo, followed by a 12-mo observation period off therapy. Pts were stratified by PSADT (&lt; 6 vs 6-12 mo) and age (≤ 70 vs &gt; 70 y). Primary end point: mean change from baseline (BL) in health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy-Prostate total score at 12 mo. Secondary end points included PSA nadir &lt; 0.2 ng/mL by 7 mo, time to PSA progression (TTPpsa), and time to testosterone (T) recovery. Results: 90 pts (APA, n = 29; LHRHa, n = 30; APA + LHRHa, n = 31) were treated for median of 12 mo with similar distribution of BL characteristics across groups: 67% age ≤ 70 y; 67% PSADT &lt; 6 mo. There was no significant difference in HRQoL in APA vs LHRHa at 12 mo, or between LHRHa vs APA + LHRHa groups. At median follow-up of 30-33 mo, TTPpsa in APA, LHRHa, and APA + LHRHa groups was 26 mo, 31 mo, and 36 mo, respectively. Compared to LHRHa alone, APA + LHRHa resulted in a trend toward improved TTPpsa (HR [95% CI] 0.56 [0.23-1.36], p = 0.196), and APA alone resulted in a trend for shorter TTPpsa (HR 1.09 [0.49-2.43], p = 0.824). PSA nadir &lt; 0.2 ng/mL was reached in 89%, 89%, and 97% in APA, LHRHa, and APA + LHRHa pts. Median time to T recovery was similar in LHRHa and APA + LHRHa groups (23 mo vs 24 mo). Grade 3-4 adverse events (AEs) occurred in 17% of APA, 14% of LHRHa, and 29% of APA + LHRHa pts. The only grade 3-4 AE reported in &gt; 1 pt per group was hypertension (APA, 3%; LHRHa, 0; APA + LHRHa, 13%). Conclusions: Addition of APA to LHRHa resulted in a trend for longer TTPpsa and a higher proportion of pts achieving optimal PSA nadir without significant difference in HRQoL or time to T recovery. Observed AEs were consistent with known safety profiles. Results support further evaluation of APA + LHRHa for a specified duration in BCR PC. Clinical trial information: NCT01790126.