Attenuated androgen discontinuation in patients with hereditary angioedema: a commented case series

Background Hereditary angioedema (HAE) is characterized by potentially severe and life-threatening attacks of localized swelling. Prophylactic therapies are available, including attenuated androgens. Efficacy of attenuated androgens has not been assessed in large, randomized, placebo-controlled trials and can be associated with frequent, and sometimes severe, side effects. As better tolerated targeted therapies become available, attenuated androgen withdrawal is increasingly considered by physicians and their patients with HAE. Attenuated androgens withdrawal has not been systematically studied in HAE, although examination of other disorders indicates that attenuated androgen withdrawal may result in mood disturbances and flu-like symptoms. Standardized protocols for attenuated androgen discontinuation that continue to provide control of attacks while limiting potential attenuated androgen withdrawal symptoms are not established as the outcomes of different withdrawal strategies have not been compared. We aim to describe the challenges of attenuated androgen discontinuation in patients with HAE and how these may continue into the post-androgen period. Case presentation We present a retrospective case series of 10 patients with confirmed type I HAE who have discontinued prophylactic treatment with attenuated androgens. The most common reason for attenuated androgen discontinuation was side effects. Attenuated androgens were either immediately withdrawn, tapered and/or overlapped with another treatment. The major challenge of discontinuation was the management of an increased frequency and severity of HAE attacks in some patients. Conclusions Healthcare teams need to undertake careful planning and monitoring after attenuated androgens discontinuation, and modify treatment strategies if HAE control is destabilized with an increased number of attacks. Discontinuation of attenuated androgens is definitively an option in an evolving HAE treatment landscape, and outcomes can be favourable with additional patient support and education.

Celebrating the 80th anniversary of hormone ablation for prostate cancer

In this special issue of Endocrine-Related Cancer, we are celebrating the 80th anniversary of hormone ablation as treatment for metastatic prostate cancer. Our understanding has evolved from the observation that androgen withdrawal, either surgical or pharmacological, resulted in prostatic atrophy in animal models, to its application in patients, to investigation of the mysterious way in which prostate cancer escapes androgen dependence. We are now in an era of novel AR pathway inhibitors, combination of androgen ablation with chemotherapy, PARP inhibitors, immunotherapies, guided radiotherapy, and novel drug application based upon genetic testing of individual tumors. In this Anniversary Issue, we bring together a collection of eight reviews that cover not only the history of 80 years of progress after the initial identification of androgen ablation as an effective treatment of prostate cancer, but subsequent improvements in the understanding of the biology of the disease, development of novel treatment paradigms, resistance to those treatments and disease progression following that resistance.

Nanovectorization of Prostate Cancer Treatment Strategies: A New Approach to Improved Outcomes

Prostate cancer (PC) is the most frequent male cancer in the Western world. Progression to Castration Resistant Prostate Cancer (CRPC) is a known consequence of androgen withdrawal therapy, making CRPC an end-stage disease. Combination of cytotoxic drugs and hormonal therapy/or genotherapy is a recognized modality for the treatment of advanced PC. However, this strategy is limited by poor bio-accessibility of the chemotherapy to tumor sites, resulting in an increased rate of collateral toxicity and incidence of multidrug resistance (MDR). Nanovectorization of these strategies has evolved to an effective approach to efficacious therapeutic outcomes. It offers the possibility to consolidate their antitumor activity through enhanced specific and less toxic active or passive targeting mechanisms, as well as enabling diagnostic imaging through theranostics. While studies on nanomedicine are common in other cancer types, only a few have focused on prostate cancer. This review provides an in-depth knowledge of the principles of nanotherapeutics and nanotheranostics, and how the application of this rapidly evolving technology can clinically impact CRPC treatment. With particular reference to respective nanovectors, we draw clinical and preclinical evidence, demonstrating the potentials and prospects of homing nanovectorization into CRPC treatment strategies.

Androgen use in hereditary angioedema: A critical appraisal and approaches to transitioning from androgens to other therapies

Background: Hereditary angioedema (HAE) is a rare genetic disorder clinically characterized by recurrent attacks of subcutaneous and mucosal swelling. Attenuated androgens have been a prophylactic treatment option to reduce the frequency of HAE attacks for > 4 decades. However, the advent of effective on-demand treatments and highly effective, more tolerable, long-term prophylactic therapies has led to a decline in the use of attenuated androgens for the management of HAE in regions where newer therapies are available. A consensus about the best approach for discontinuing or tapering off attenuated androgen therapy does not exist. Objective: To develop a consensus on androgen tapering for patients with HAE. Methods: We sent an open-ended survey about androgen tapering to 21 physicians who treat HAE, 12 of whom responded. We reviewed the collective experience of the participating physicians in combination with results from a literature review on the topic. Results: The survey and literature review underscored potential concerns related to rapid androgen withdrawal in patients with HAE, including physician and patient concerns that the frequency and severity of attacks would abruptly worsen. In addition, discontinuation of attenuated androgens may have the potential for transient adverse effects, such as an increase in the rate of attacks or effects related to hormone withdrawal. Our survey showed that physicians often taper androgens to prevent increases in HAE attacks and possible withdrawal complications. Conclusion: Based on both experiences of the physicians who responded to our survey and reports in the endocrine literature, we provided recommendations for androgen tapering. However, we noted that the likelihood of adverse effects due to androgen withdrawal in patients with HAE is poorly understood and requires further study.

CPT1A Supports Castration-Resistant Prostate Cancer in Androgen-Deprived Conditions

Prostate cancer (PCa) is the most common cancer in men, and the global burden of the disease is rising. The majority of PCa deaths are due to metastasis that are highly resistant to current hormonal treatments; this state is called castration-resistant prostate cancer (CRPC). In this study, we focused on the role of the lipid catabolism enzyme CPT1A in supporting CRPC growth in an androgen-dependent manner. We found that androgen withdrawal promoted the growth of CPT1A over-expressing (OE) tumors while it decreased the growth of CPT1A under-expressing (KD) tumors, increasing their sensitivity to enzalutamide. Mechanistically, we found that CPT1A-OE cells burned more lipid and showed increased histone acetylation changes that were partially reversed with a p300 specific inhibitor. Conversely, CPT1A-KD cells showed less histone acetylation when grown in androgen-deprived conditions. Our results suggest that CPT1A supports CRPC by supplying acetyl groups for histone acetylation, promoting growth and antiandrogen resistance.

Trends in prescribing preferences (PPrefs) of U.S.-based oncologists for patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) following docetaxel (DO).

243 Background: PPrefs of 467 US-based medical oncologists (MOs) in post-DO mCRPC pts were studied prospectively. A validated, proprietary, live, case-based market research tool was utilized with a core case scenario and 4 distinct treatment (Rx) outcomes following chemotherapy (CTx). Data were acquired using blinded audience response technology. Research support sources were double blinded. Methods: Core case: 59 y/o status post (s/p) radical prostatectomy with PSA failure after 15 months (mo), s/p salvage pelvic radiation (RT) → presents with rise in PSA and 3.5cm pelvic lymph node 16mo following RT→ progresses through multiple Rx over the next 42mo, including combined androgen blockade, anti-androgen withdrawal, sipuleucel-T and abiraterone (ABI). Now starting DO CTx due to increasing bone metastases and bone pain (BP). PPrefs for 4 variant scenarios of DO CTx were probed: (1) DO 75 mg/m2Q3wk x 6 cycles (cy) →Resolution of BP/PSA response → DO held due to cumulative myelosuppression/fatigue. Pt more active off CTx, ECOG PS 1. 3mo later →asymptomatic 30% rise in PSA. (2) DO x 4 cy → decrease in PSA, BP, node size. Prior to cy 6, has asymptomatic PSA progression. (3) DO x 4 cy→ decrease in PSA, BP, node size. Prior to cy 6, has both PSA and BP progression. (4) DO x 2 cy → progression with increased BP, PSA, and pelvic nodal disease. Results: See Table. Conclusions: PPrefs after DO CTx were outcome-dependent. In the absence of BP, ENZ is the most common PPref, even in this ABI-refractory pt. PPref for R223 over 2nd line CTx in the acquired symptomatic resistance setting is notable. PPref for 2nd line CTx increases with rapid, symptomatic disease progression. [Table: see text]