Severe Cushing Syndrome From Ectopic Adrenocorticotropin Secretion In Metastatic Prostate Cancer Treated With Osilodrostat

Abstract

Treatment of severe hypercortisolism from Cushing syndrome due to ectopic adrenocorticotropin (ACTH) secretion (EAS) can lead to therapeutic challenges, particularly in the context of high doses of medication needed to normalize cortisol levels and other patient comorbidities. We present a case of a 64-year-old man with known metastatic prostate cancer for several years, whose disease had recently progressed despite androgen deprivation and chemotherapy, who presented with polyuria and generalized weakness. Initial evaluation revealed diabetic ketoacidosis, hypothyroidism, markedly elevated cortisol levels, along with elevated ACTH. He was suspected to have ectopic ACTH-secreting Cushing syndrome with plans to start outpatient treatment with osilodrostat. In the interim, he developed severe hypokalemia and proximal muscle weakness and was readmitted for potassium repletion and initiation of therapy with osilodrostat in combination with prednisone as part of a block-and-replace strategy. His serum cortisol and 24-hour urine cortisol levels progressively decreased with increasing doses of osilodrostat.

Introduction

Ectopic adrenocorticotropin (ACTH) syndrome (EAS) is a rare condition with serious morbidity, representing approximately 10% to 15% of endogenous Cushing syndrome cases [1]. Historically, ACTH-producing tumors have been associated with small cell lung cancer but has been increasingly recognized in other neuroendocrine (NE) tumors (predominantly pulmonary, thymic, and pancreatic carcinoid), and more rarely, medullary thyroid carcinoma and pheochromocytoma [2]. This experience has been corroborated by case series at several centers [3-5]. Early recognition and treatment of this condition is critical to the prevention of life-threatening complications, including hypokalemia, diabetes, severe hypertension, fractures, atypical infections, and thromboembolic effects [1]. Resection of primary tumors may not be possible in cases of occult or metastatic tumors. Various treatment strategies, targeting cortisol synthesis or the glucocorticoid receptor, can be used to improve metabolic parameters in this context, but they require careful consideration of patient comorbidities and drug toxicity. Though initially approved by the US Food and Drug Administration (FDA) only for Cushing disease, osilodrostat has been shown to be an effective and well-tolerated agent in selected cases of EAS with severe hypercortisolism in other countries [6-8]. We report a case in which osilodrostat was used with dramatic improvement in severe hypercortisolism in a case of EAS.

Case Presentation

A 64-year-old man with hypertension, previously diet-controlled type 2 diabetes mellitus, and atrial flutter on apixaban was diagnosed with metastatic prostate adenocarcinoma (Gleason score 4 + 5) in 2022. He initially achieved disease stability but began to show signs of disease progression in January 2024 on a clinical trial with a combined PD-1/CTLA-4 inhibitor. He was ultimately referred to our endocrinology clinic for management of new-onset severe hypercortisolism thought secondary to EAS from metastatic prostate cancer, following admission for diabetic ketoacidosis (DKA).

The patient was diagnosed with metastatic prostate cancer in 2022, after referral for elevated prostate-specific antigen (PSA) to a maximum level of 82 ng/mL (82 μg/L) (reference range <4 ng/mL[<4 μ/L]). He subsequently underwent prostate biopsy demonstrating Gleason 4 + 5 prostate cancer. Synaptophysin immunostains were negative for NE disease. Prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging identified avid disease in the pelvic and retroperitoneal lymph nodes and bones. He was initiated on androgen-deprivation therapy with darolutamide and degarelix/leuprolide, as well as 6 cycles of docetaxel. By early 2023, his PSA declined to less than 0.1 ng/mL(<0.1 μg/L) and persisted at these levels through the end of 2023. In January 2024, he presented with new-onset back pain, and his spine magnetic resonance imaging (MRI) demonstrated extensive osseous metastatic involvement of the T12, L1 to L2, and L4 to L5 vertebral bodies and sacrum. In March 2024, he enrolled in a clinical trial and began treatment with carboplatin, cabazitaxel, and vudalimab, a novel bispecific combined PD-1/CTLA-4 monoclonal antibody. By August 2024, PSMA-PET imaging demonstrated new hepatic and osseous metastases consistent with disease progression and rising PSA (0.79 ng/mL[0.79 μg/L]). He was then initiated on lutetium Lu-177 vipivotide tetraxetan (Pluvicto) therapy.

In September 2024, the patient presented to the oncology clinic with complaints of polyuria, dry mouth, generalized weakness, and unsteady gait. Aside from marked proximal muscle weakness, his physical examination was unremarkable. There was no facial fullness, supraclavicular fat pad, striae, or lower extremity edema; the patient's body mass index was 25.3. He was referred to the emergency department for further evaluation.

Diagnostic Assessment

Our patient's laboratory results demonstrated an elevated blood glucose with high anion gap and elevated β-hydroxybutyrate, along with a superimposed metabolic acidosis and hypokalemia (Table 1). His hemoglobin A_1c had risen from a baseline of 6.6% to 8.7% (normal, <5.7%) 2 weeks prior to this visit. Laboratory results were overall concerning for DKA, with hypokalemia initially attributed to this condition. Type 1 diabetes autoantibodies were notable for a mildly positive glutamic acid decarboxylase-(GAD)-65 Antibody (see Table 1). Thyroid function tests revealed low levels of thyrotropin and free thyroxine (Table 2). Given the concern for possible hypophysitis in the setting of PD-1/CTLA-4 therapy, the patient’s cortisol was checked and surprisingly resulted at 111 μg/dL (3062 nmol/L) (morning reference range: 4.8-19.5 μg/dL [132-538 nmol/L]). This was markedly increased from 4.0 μg/dL (110 nmol/L) only 2 months prior. A pituitary MRI was obtained without typical findings of hypophysitis or evidence of an adenoma (Fig. 1). ACTH and chromogranin A levels were elevated at 301 pg/mL (66 pmol/L) (reference range: 7.2-63.3 pg/mL [1.6-13.9 pmol/L]) and 646 ng/mL (646 μg/L) (reference range: 0-187 ng/mL [0-187 μg/L]), respectively. A diagnosis of ectopic ACTH secretion was made.

Table 1.

Relevant laboratory values at initial admission for diabetic ketoacidosis

Laboratory value	September 2024 (admission)	Reference range
Glucose	371 mg/dL (20.6 mmol/L)	70-180 mg/dL (3.89-9.99 mmol/L)
Sodium	140 mEq/L (140 mmol/L)	137-145 mEq/L (137-145 mmol/L)
Potassium	2.9 mEq/L (2.9 mmol/L)	3.5-5.1 mEq/L (3.5-5.1 mmol/L)
Bicarbonate	33 mEq/L (33 mmol/L)	19-27 mEq/L (19-27 mmol/L)
Anion gap	18 mEq/L (18 mmol/L)	5-17 mEq/L (5-17 mmol/L)
β-Hydroxybutyrate	3.85 mmol/L (40.1 mg/dL)	<0.27 mmol/L (<2.8 mg/dL)
pH, venous blood	7.57	7.35-7.45
pCO2, venous blood	39 mm Hg (5.2 kPA)	40-45 mm Hg (5.3-6.0 kPA)
Hemoglobin A1c	8.7%	<6.5%
C-peptide	0.9 ng/mL (0.3 nmol/L)	0.5-3.3 ng/mL (0.2-1.1 nmol/L)
GAD-65 antibody	0.06 nmol/L (<6 U/mL)	<0.02 nmol/L (<2 U/mL)
ZnT-8 antibody	Negative	Negative
Insulin antibody	Negative	Negative
IA-2 antibody	Negative	Negative
Islet cell antibody	Negative	Negative

Abbreviations: GAD, glutamic acid decarboxylase; IA, islet antigen; NA, not available; pCO₂, partial pressure of carbon dioxide; PSA, prostate-specific antigen; ZnT, zinc transporter.

Table 2.

Pituitary-related laboratory values prior to initiating osilodrostat treatment

Laboratory value	March 2024	May 2024	July 2024	August 2024	September 2024 (admission)	Reference range
Thyrotropin	4.08 μg/mL (4.08 mIU/L)	1.66 μg/mL (1.66 mIU/L)	1.68 μg/mL (1.68 mIU/L)	1.08 μg/mL (1.08 mIU/L)	0.13 μg/mL (0.13 mIU/L)	0.41-4.81 μg/mL (0.41-4.81 mIU/L)
Free T4	1.20 ng/dL (15.4 pmol/L)	1.39 ng/dL (17.9 pmol/L)	1.32 ng/dL (17.0 pmol/L)	1.22 ng/dL (15.7 pmol/L)	0.64 ng/dL (8.2 pmol/L)	0.83-1.90 ng/dL (10.7-24.5 pmol/L)
Total T4	—	—	—	—	4.07 μg/dL (52.4 nmol/L)	5.00-10.69 μg/dL (64.4-137.6 nmol/L)
Total T3	88.6 ng/dL (1.36 nmol/L)	68.9 ng/dL (1.06 nmol/L)	77.0 ng/dL (1.18 nmol/L)	59.2 ng/dL (0.91 nmol/L)	42.9 ng/dL (0.66 nmol/L)	78-158 ng/dL (1.20-2.43 nmol/L)
Cortisol	16.1 μg/dL (444 nmol/L)	2.8 μg/dL (77 nmol/L)	4.2 μg/dL (116 nmol/L)	16.3 μg/dL (450 nmol/L)	111 μg/dL (3062 nmol/L)	4.8-19.5 μg/dL (132-538 nmol/L) (6-10 Am)
ACTH	41.2 pg/mL (9.1 pmol/L)	12.7 pg/mL (2.8 pmol/L)	17.1 pg/mL (3.8 pmol/L)	143 pg/mL (31.5 pmol/L)	301 pg/mL (66.3 pmol/L)	7.2-63.3 pg/mL (1.6-13.9 pmol/L)
Prolactin	—	—	—	—	12.8 ng/mL (12.8 μg/L)	3.5-16.9 ng/mL (3.5-16.9 μg/L)
PSA	0.19 ng/mL (0.19 μ/L)	0.14 ng/mL (0.14 μ/L)	0.29 ng/mL (0.29 μ/L)	0.73 ng/mL (0.73 μ/L)	3.01 ng/mL (3.01 μ/L)	<4.0 ng/mL (<4.0 μ/L)
Chromogranin A	166 ng/mL (166 μg/L)	—	—	271 ng/mL (271 μg/L)	646 ng/mL (646 μg/L)	0-187 ng/mL (0-187 μg/L)

Abbreviations: ACTH, adrenocorticotropin; PSA, prostate-specific antigen; T3, triiodothyronine; T4, thyroxine.

Figure 1.

Magnetic resonance imaging (MRI) of the pituitary + sella with and without contrast. A, Sagittal precontrast T1-weighted MRI scan demonstrates a T1-hyperintense signal measuring 6 × 5 mm (blue arrow) within the mid-posterior left pituitary that appears greater than expected for the normal pituitary bright spot. This was thought to be consistent with a proteinaceous Rathke cleft cyst. B, Coronal postcontrast T1-weighted MRI scan: There was no evidence of hypophysitis or an adenoma.

Following correction of hypokalemia, treatment of DKA, and initiation of levothyroxine, the patient was discharged with plans to initiate therapy to lower cortisol levels as an outpatient. However, before therapy could be started, he developed lower extremity edema, irregular pulse, and severe weakness; he was unable to ambulate without assistance. He was referred back to the emergency department for treatment of suspected hypokalemia and initiation of treatment for EAS.

The patient was readmitted to the general medical service, where his potassium level was 2.0 mEq/L (2.0 mmol/L), and an electrocardiogram (EKG) revealed sinus tachycardia with ventricular bigeminy. Blood pressure was 123/78 mm Hg. Serum cortisol was 207 μg/dL (5710 nmol/L) and ACTH was 551 pg/mL (121 pmol/L). The patient’s 24-hour urine cortisol was 6460 μg/d (17 830 nmol/d) (reference range <60 μg/d [<165 nmol/d]). He also had elevated liver function tests (Table 3).

Table 3.

Laboratory parameters during osilodrostat dose titration

Time since osilodrostat initiation, d	Baseline	D 8	D 19	D 28	D 35	D 38	Reference range
Serum cortisol, immunoassay	207 μg/dL (5710 nmol/L)	144 μg/dL (3972 nmol/L)	37.4 μg/dL (1032 nmol/L)	18.2 μg/dL (502 nmol/L)	24.8 μg/dL (684 nmol/L)	15.7 μg/dL (433 nmol/L)	4.8-19.5 μg/dL (132-538 nmol/L) (6-10 Am)
24-h urine cortisol, LC/MS	6460 μg/d (17 830 nmol/d)	—	428 μg/d (1182 nmol/d)	134 μg/d (370.1 nmol/d)	—	—	≤60.0 μg/d (<165 nmol/d)
ACTH	551 pg/mL (121 pmol/L)	—	—	—	656 pg/mL (144 pmol/L)	—	7.2-63.3 pg/mL (1.6-13.9 pmol/L)
Hemoglobin A1c	10.1%	—	—	—	5.6%	—	<5.7%
Alkaline phosphatase	343 U/L (6050 nkat/L)	392 U/L (6530 nkat/L)	421 U/L (7020 nkat/L)	403 U/L (6720 nkat/L)	565 U/L (9420 nkat/L)	583 U/L (9720 nkat/L)	40-129 U/L (667-2150 nkat/L)
AST	77 U/L (1280 nkat/L)	96 U/L (1600 nkat/L)	86 U/L (1430 nkat/L)	98 U/L (1630 nkat/L)	152 U/L (1530 nkat/L)	350 U/L (5830 nkat/L)	10-37 U/L (167-617 nkat/L)
ALT	80 U/L (1330 nkat/L)	117 U/L (1950 nkat/L)	100 U/L (1670 nkat/L)	111 U/L (1850 nkat/L)	89 U/L (1480 nkat/L)	126 U/L (2100 nkat/L)	9-50 U/L (150-833 nkat/L)
Potassium	4.4 mEq/L (4.4 mmol/L)	3.6 mEq/L (3.6 mmol/L)	4.6 mEq/L (4.6 mmol/L)	4.7 mEq/L (4.6 mmol/L)	4.1 mEq/L (4.1 mmol/L)	4.6 mEq/L (4.6 mmol/L)	3.5-5.1 mEq/L (3.5-5.1 mmol/L)
Osilodrostat dose	None	5 mg twice daily	10 mg twice daily	10 mg twice daily	10 mg twice daily	10 mg each morning/15 mg nightly

Abbreviations: ACTH, adrenocorticotropin; ALT, alanine transaminase; AST, aspartate transaminase; LC/MS, liquid chromatography–mass spectrometry.

Treatment

We considered the severity of the patient's hypercortisolemia, hepatic dysfunction, and tolerability of various treatment options. We elected to treat the patient with osilodrostat for EAS. He was initiated on aggressive potassium repletion, spironolactone 50 mg twice per day, and osilodrostat 5 mg nightly, along with prednisone 5 mg daily as part of a block-and-replace strategy [8-10]. Potassium levels and EKG were closely monitored. He was also initiated on prophylaxis for Pneumocystis jirovecii pneumonia (PJP) with trimethoprim-sulfamethoxazole (TMP-SMX). He continued anticoagulation with apixaban for atrial fibrillation.

Outcome and Follow-up

While the osilodrostat dose was undergoing titration, the patient was again readmitted for severe weakness and hypokalemia. MRI of the lumbar spine did not demonstrate spinal cord compression. Eight days after osilodrostat initiation, noncontrast computed tomography (CT) chest images revealed multifocal bronchopneumonia in the bilateral upper lung zones. Infectious work-up revealed an elevated β-D-glucan level of 453 pg/mL (453 ng/L) (reference range <80 pg/mL [<80 ng/L]). A bronchoscopy with bronchoalveolar lavage (BAL) was performed, and BAL PJP PCR returned positive at 62 200 copies/mL. As a result, prophylactic TMP-SMX was escalated to a PJP treatment dose. Serum cortisol and 24-hour urine cortisol levels improved significantly with osilodrostat (see Table 3, Fig. 2), which was progressively increased over the course of his prolonged hospitalization. His insulin requirements also declined. The last collected 24-hour urine cortisol was 134 μg/d (370 nmol/d), obtained just before the final dose increase to 15 mg each morning and 10 mg nightly. His final serum cortisol level on this dose was 15.7 μg/dL (433 nmol/L). Unfortunately, the patient ultimately developed pneumoperitoneum from invasion of his prostate cancer into the bladder, leading to septic and hemorrhagic shock. He was transitioned to comfort measures shortly thereafter and eventually died 53 days from osilodrostat initiation.

Figure 2.

Serum cortisol in response to osilodrostat. Serum cortisol levels in μg/dL by hospital days, with dose increases indicated with blue solid arrows. Results of 24-hour urine cortisol levels are indicated with purple dashed arrows. bid, twice per day; ICU, intensive care unit; qAM, every morning; qhs, every night at bedtime; qPM, every evening.

Discussion

EAS from prostate cancer is exceedingly rare, with fewer than 50 cases reported in the literature to date [11-15]. Though no repeat biopsy data were available, we believe that this may have occurred through NE transdifferentiation of prostate tumor cells, leading to ectopic production of ACTH. In normal prostate tissue, NE-like cells are present in less than 1% of prostate epithelial cells [16]; their physiological function remains unclear. NE-like cells lack the expression of androgen receptors and PSA and do not typically proliferate [16]. In prostate cancer, it has been suggested that NE transdifferentiation is associated with long-term androgen deprivation therapy (ADT), chemotherapy, and radiation [17]. Given the lack of androgen receptors present in NE-like cells, NE transdifferentiation is thought to represent treatment escape from long-term ADT [13]. Additionally, radiation-induced alterations to the transcription of chromogranin A have also been posited as a potential mechanism [18]. Unfortunately, NE prostate cancer is associated with disease progression and poor prognosis [11, 16], which occurred in our patient.

The management of EAS typically includes resection of the tumor producing ACTH when able, or, in cases of metastatic or occult disease, bilateral adrenalectomy or medical therapy with steroidogenesis inhibitors (eg, ketoconazole, levoketoconazole, metyrapone, osilodrostat), glucocorticoid receptor blockade (eg, mifepristone), or adrenolytic agents (eg, mitotane) [19]. Intravenous etomidate can be used in critically ill patients and in those unable to tolerate oral medications. In this case, neither histologic confirmation of the diagnosis nor DOTATATE (dodecanetetraacetic acid-tyrosine-3-octreotate) PET/CT were pursued, as they were not felt to contribute to any changes in clinical management in the acute setting. At the time of our evaluation, our patient had evidence of hepatic dysfunction, which was taken into consideration when selecting a cortisol-lowering medication. Osilodrostat can cause hypokalemia, edema, and worsening hypertension via steroid precursors that accumulate upstream of the blockade. Correction of hypokalemia is thus recommended prior to osilodrostat initiation. Spironolactone remained necessary throughout the admission, and potassium supplementation requirements declined from more than 120 mEq/d to 0 to 20 mEq/d while on this medication.

Osilodrostat, the newest medical therapy for pituitary Cushing disease, inhibits 11-β-hydroxylase, immediately preceding cortisol synthesis. In the United States, it was not FDA approved for other syndromes of cortisol excess until recently. However, osilodrostat (in doses of 1-60 mg/d) has been described in case reports and case series of severe cortisol excess from EAS with successful control and relatively rapid normalization of hypercortisolism [6-8, 20-23]. In this report, osilodrostat was selected for its known ability to control severe hypercortisolism, favorable side effect profile, and lack of contraindication in patients with hepatic insufficiency. A final dose of 25 mg was used effectively. Given the potential for adrenal insufficiency, a block-and-replace strategy was used [8-10]. Though our patient ultimately had a poor outcome from progression of his prostate cancer, osilodrostat was highly effective in improving his hypercortisolemia and was well tolerated.

Learning Points

• EAS from prostate cancer is exceedingly rare and thought to occur through NE transdifferentiation of prostate cancer cells.

• In EAS, vigilance for the sequelae of severe hypercortisolemia, including hypokalemia, severe hyperglycemia, and atypical infections, is extremely important.

• Though previously FDA approved only for pituitary Cushing disease, osilodrostat is a highly effective and well-tolerated option for the treatment of severe hypercortisolemia in EAS, and FDA approval has recently been expanded to include treatment of all forms of endogenous Cushing syndrome, including EAS.

Contributors

L.K.L., B.J., and S.L.W. were involved in the diagnosis and management of this patient. All were involved in writing, editing, and revising the manuscript.

Abbreviations

ACTH

adrenocorticotropin

ADT

androgen deprivation therapy

BAL

bronchoalveolar lavage

CT

computed tomography

DKA

diabetic ketoacidosis

EAS

ectopic adrenocorticotropin secretion

EKG

electrocardiogram

FDA

US Food and Drug Administration

GAD

glutamic acid decarboxylase

MRI

magnetic resonance imaging

NE

neuroendocrine

PJP

Pneumocystis jirovecii pneumonia

PSA

prostate-specific antigen

PSMA-PET

prostate-specific membrane antigen positron emission tomography

T3

triiodothyronine

T4

thyroxine

TMP-SMX

trimethoprim-sulfamethoxazole

Funding

L.K.L. and B.J. were supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (No. T32 DK007559-31.

Disclosures

B.J., L.K.L., and S.L.W. have no disclosures.

Informed Patient Consent for Publication

Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution.

Data Availability Statement

Original data generated and analyzed for this case report are included in this published article.