Castrate resistant prostate cancer

EAU definition:

Castrate serum testosterone < 1.7 nmol/L plus either of:

3 consecutive PSA rises, at least one week apart, resulting in two 50 % increases over the nadir, and a PSA > 2 ng/mL or
Appearance of 2 or more new bone lesions on bone scan or a soft tissue lesion based on RECIST

Management principles

Continue ADT
Balance on toxicity of treatments vs benefit and quality of life
Multidisciplinary approach – including nursing, palliative care, GP, medical oncology, rad onc
Treat symptomatic bone metastases
Keep an eye on the ureters
Think about genetics

Treatment options are dependent on:

Previous treatments already used
Patient co-morbidities and functional performance
Locally available treatments and expenses
Genetic variants or histological variants
Trial availability

Mechanisms of castrate resistance

Ability of cancer cells to utilise intracellular androgens (via de novo synthesis, or exogenously from adrenals or tumour microenvironment)
Increased AR expression
AR mutations, allowing it to be activated by alternate ligands like glucocorticoids
Alterations in AR signalling promoting tumour growth
Synthesis of AR variants which are active even in the absence of ligands

Non metastatic castrate resistant prostate cancer (M0)

Increasingly seen entity with earlier administration of ADT in recurrent disease.

Traditionally based on conventional imaging.

Multiple RCTs have shown metastasis free progression and overall survival benefits for darolutamide (ARAMIS), enzalutamide (PROSPER) and apalutamide (SPARTAN) in M0 CRPC when added to ADT.

Treatment options for CRPC:

Complete androgen blockade – addition of non steroidal anti-androgen (bicalutamide)
Docetaxel
2^nd generation non steroidal anti-androgens (enzalutamide, darolutamide)
Abiraterone (CYP17a / 17a hydroxylase inhibitor) + prednisone
Cabazitaxel
Radium
Sipileucel T
Theranostics
Immunotherapy
PARP inhibitors

Complete androgen blockade

Addition of bicalutamide to men with a rising PSA aims to reduce the effect of adrenally produced androgens.
20 – 30 % of men will respond with a fall in PSA, with associated risk of side effects of anti-androgens (notably gynaecomastia).
There is limited evidence that it produces any tangible survival benefit.
There is also the anti-androgen withdrawal phenomenon – in men with rising PSA on complete androgen blockade, who initially responded, some will have a fall in PSA on withdrawal of the anti-androgen, although this is usually short lived.

Docetaxel

Mechanism:

Semi-synthetic taxane chemotherapy – inhibits microtubules to induce cytotoxic and apoptotic cell death

75 mg / m²given IV every 3 weeks, for 6 – 10 cycles, combined with prednisone.

PBS approved and indicated up front de novo metastatic prostate cancer, but also castrate resistant metastatic prostate cancer.

Contra-indicated in those with poor performance status.

Side effects:

Nausea/vomiting
Alterations in taste and smell
Hypersensitivity / anaphylaxis
Neutropenia and febrile neutropenia
Thrombocytopenia
Oral mucositis
Peripheral neuropathy
Hand-foot syndrome
Cardiac toxicity – reduced ejection fraction
Visual changes
Hair loss
Death up to 1 %

Efficacy – median survival 18.9 months in head to head trial vs mitozantrone for CRPC

2^nd generation non steroidal anti-androgen – enzalutamide

Enzalutamide mechanism:

Inhibits binding of DHT and testosterone to the androgen receptor
Stops AR translocation to the nucleus
Stops AR binding to DNA
Higher affinity for AR cf. bicalutamide

Given orally, 160 mg daily (4 x 40 mg tablets)

PBS listed for metastatic CRPC and nmCRPC – not in conjunction with chemotherapy and must have WHO performance status of 2 or less.

PREVAIL study showed improvement in OS versus placebo (HR 0.71) in chemo-naïve population – enough to stop study and recommend placebo group take enzalutamide.

AFFIRM study showed improvement in OS versus placebo in post-chemo population – median OS 18 months vs 13 months

Contra-indications:

Neurological disease and risk of seizures – seizure history, CVA, brain mets
Uncontrolled hypertension
Poor performance status

Side effects:

Fatigue +
Back pain
Hypertension
Fluid retention and oedema
Dizziness
Seizures, up to 1 %

Abiraterone

Mechanism: inhibits CYP17a / 17-alpha hydroxylase which blocks conversion of pregnenolone to 17-hydroxypregnenolone, reducing androgen production by both adrenal and tumour

Also blocks glucocorticoid production, so prednisone must be co-administered.

Also results in upregulation and mineralocorticoid excess.

Given orally 1000 mg daily, with 5 – 10 mg prednisone daily.

PBS listed for mCRPC if performance status 2 or less.

COU-AA studies have shown improved median overall survival in both chemo naïve (34 vs 30 months) and post-chemo (14 vs 10 months) populations.

Contraindicated if:

Significant liver disease
Pre existing hypokalemia or hypertension
Contraindications to corticosteroids

Side effects:

Fluid retention and oedema
Hypokalemia
Hypertension
Hepatotoxicity
Steroid side effects of prednisone
UTI

Need to monitor blood pressure and electrolytes whilst on treatment, and monitor for prednisone side effects.

Cabazitaxel

Taxane chemotherapy agent which causes inhibition of microtubules, leading to cell death.

Given IV 20 mg / m²every 3 weeks, until progression or unacceptable toxicity.

Co-administered with prednisone.

Indicated in mCRPC previously treated with docetaxel.

Contraindicated in:

Poor performance status
Peripheral neuropathy
Prior neutropenia with docetaxel

Side effects similar to docetaxel but higher rates of febrile neutropenia (up to 8%, often given prophylactic filgastrim).

Efficacy – showed superiority OS compared to mitozantrone – 15 months medial survival cf. 12 months.

Radium 223

Alpha emitter which has an affinity for bony metastases and causes double stranded DNA breaks.
Administered IV every 4 weeks for up to 6 cycles.
Indicated in mCRPC with symptomatic bony metastases, without visceral mets.
Contra-indicated if taking concurrent abiraterone – high fracture and death rate in trials.
Relatively mild side effects – some haematological toxicity and diarrhoea cf. placebo.
Slight improvement in OS – 14 mo vs 11 mo placebo (patients failed or unfit for chemo)
Also prolonged time to skeletal event and improvement in pain scores.

Sipileucel T

“Autologous cellular immunotherapy” – autologous dendritic cells are loaded ex vivo with prostatic acid phosphatase (PAP) and granulocyte-macrophage colony stimulating factor, and then returned from lab and infused into patient.
Generally well tolerated, although fevers common.
Not available in Australia.
Median overall survival 25 months vs 21 months for placebo in trial.

Denosumab and zoledronic acid

Both indicated for mCRPC with bony metastases.
Zoledronic acid is an IV bisphosphonate which inhibits osteoclast proliferation.
Denosumab is a fully human monoclonal antibody directed against RANKL, which promotes osteoclastic activity.
Neither has a survival benefit, but do delay time to skeletal events.
Side effects (hypocalcaemia and osteonecrosis of the jaw) must be kept in mind. Serum calcium should be monitored and calcium and vitamin D supplementation should be offered.

Immunotherapy

Pembrolizumab is approved by FDA for all MMR deficient cancers or those with high microsatellite instability (MSI) – a rare finding in prostate cancer.

PARP inhibitors

PBS listed for BRCA positive patients with mCRPC who have progressed on previous treatment including novel antiandrogen.
PROfound trial – Olaparib vs enza or abi (in patients who had progressed on the alternate antiandrogen) in patients with BRCA mutations
Median OS 19 months in olaparib vs 14 months abi/enza

PSMA based theranostics

VISION trial – Lutetium vs SOC (ADT) – improved overall survival (15 months vs 11 months) for those treated with at least one novel antiandrogen and one taxane chemo agent.
TheraP – Lutetium vs cabazitaxel – earlier PSA response with less severe toxicity (33 vs 53 % severe toxicity) – June 2022 update showed no different in OS (19 months)