Prostate cancer is the 3rd most common cancer diagnosed in males in Singapore and accounts for 12% of all male cancers diagnosed from 2008 to 2018.¹ According to the Singapore Cancer Registry report from 2015, the incidence has been increasing from 9.7 per 100,000 previously to 28.5 per 100,000 in 2008-2012.¹

Males in Singapore have a higher rate of prostate cancer than their counterparts in Asia, for example, China, Japan and India, but the rates are still much lower than those in the US, UK and Australia.¹ Locally, Malay and Indian men appear to have a lower risk of prostate cancer as compared to Chinese men at about 15.9-17.9 per 100,000 as compared to 25.6 per 100,000.¹

The current MOH guidelines² published in 2010 suggest that men who are between 50-75 years of age with an expected life expectancy of more than 10 years may be offered screening for prostate cancer after a discussion of both the potential benefits and harm associated with cancer screening. In the absence of a strong family history, routine screening for men should not be offered for men under 50 years of age. High risk men such as African–American men or men with a strong family history of prostate cancer (one or more first-degree relatives (father/brothers)) diagnosed before 65 years old, may be offered screening at a younger age.

NOMENCLATURE OF METASTATIC PROSTATE CANCER

Metastatic Prostate cancer can occur in several scenarios; initial localised disease that had curative treatment but recurred either biochemically and/or with radiographic evidence; de novo metastatic disease.³

The mainstay of treatment for metastatic prostate cancer involves suppression of the male hormone testosterone either surgically or chemically.³ Bilateral Orchiectomy or Androgen Deprivation Therapy (ADT) in the form of gonadotropin-releasing hormone antagonist or agonist have been shown to be equally as good in achieving castration levels of testosterone. ⁴

As patients are often sensitive to hormonal manipulation, this phase of treatment is often known as hormone-sensitive prostate cancer.

HORMONE-SENSITIVE PROSTATE CANCER (HSPC)

In addition to ADT or surgical castration, there have been several new developments in the treatment of hormone-sensitive prostate cancer.

High Volume/High Risk Patients
In patients who have high volume/high risk disease defined by the number of bony metastasis and/or presence of visceral disease and/or a pre-existing Gleason score, a novel anti-androgen like Abiraterone, a CYP17 antagonist, has shown improvement in Overall Survival (OS) in the LATITUDE5 study, with a Hazard Ratio of 0.62 and a 3-year survival rate of 66% compared to 49% with ADT alone.

Docetaxel, a taxane chemotherapy that binds to tubulin and stabilises microtubules, thereby inhibiting mitosis, has also been shown to have an OS benefit.

A recent meta-analysis6 comparing Docetaxel and ADT with ADT alone in the HSPC state showed a significant survival benefit favouring the combination. The earliest study to show this, the CHAARTED7 study, showed most of the benefit of Docetaxel was obtained in the high volume HSPC cohort.

Docetaxel vs Abiraterone/Prednisolone
Although the effectiveness of Docetaxel and Abiraterone/ Prednisolone appears to be similar based on the STAMPEDE⁸ trial, there are clear differences between the 2 treatment regimens.

Docetaxel Treatment Regimen
The Docetaxel regimen is a 3-weekly intravenous treatment regimen for a total of 18 weeks, while Abiraterone/Prednisolone regimen is taken orally at 1000mg/10mg every day until disease progression which may result in a prolong period of drug exposure. In the local context, the cost of treatment of Abiraterone/Prednisolone is much higher compared to the cost of chemotherapy (which is generic).

Differing Side Effects
Apart from duration of treatment, the side effects of Docetaxel differ from Abiraterone/Prednisolone with chemotherapy associated with myelosuppression, febrile neutropenia, alopecia and neuropathy. Abiraterone/Prednisolone can cause an elevated liver function test and mineralocorticoid-associated side effects of hypertension, hypokalaemia and oedema.

Low Volume/Low Risk
Patients In patients with low volume/low disease burden HSPC, the evidence for Docetaxel is conflicting with the meta-analysis⁶ and STAMPEDE9 showing a benefit from chemotherapy in all metastatic HSPC patients, while CHAARTED⁶ clearly showed no benefit in the low volume burden HSPC patients.

Locally, most physicians would tend to offer chemotherapy to the high disease burden patients as defined by CHAARTED.

CASTRATE-RESISTANT PROSTATE CANCER (CRPC)

CRPC state occurs once the patient has progressed either biochemically or with radiographic evidence, following initial treatment in HSPC setting.

In patients with castrate-resistant prostate cancer, it is still important to continue on the existing ADT. Often, treatment options of CRPC are heavily dependent on the previous treatments that had been offered.

In non-metastatic CRPC patients who have biochemical recurrence with no evidence of metastatic disease based on the CT (Computed Tomography) scan and bone scan, novel agents like Enzalutamide and Apalutamide has been shown to delay metastasis-free interval as compared to placebo in PROSPER¹⁰ and SPARTAN¹¹ respectively. Both treatments have received FDA approval for this indication.

In patients who have had Abiraterone/Prednisolone in the HSPC setting, Docetaxel is a suitable option based on the TAX 327 trial which showed an improvement in OS for patients treated with the 75mg/m2 of Docetaxel.¹² Local retrospective data in this setting shows that an attenuated dose of 60mg/m2 3-weekly has similar efficacy to the standard of 75mg/m2 with acceptable toxicity profile, and that weekly Docetaxel at 20mg/m2 to 35mg/m2 has significant palliative benefits in patients who are symptomatic from the cancer, despite a lower OS.¹³

Likewise, in patients who had Docetaxel in the HSPC setting, novel anti-androgens such as Abiraterone/Prednisolone and Enzalutamide are both suitable agents in the CRPC setting. COU-AA trials^14,15and AFFIRM/PREVAIL^16,17 trials have showed similar efficacy with the absolute improvement in median OS by 4 months in respective trials. Both novel anti-androgens are oral agents with different side effect profiles. Patients on Enzalutamide experience more fatigue and seizures were reported in a small proportion of patients on it (<1%).

Our local data on Abiraterone/Prednisolone in the CRPC setting is comparable with other clinical data overseas reflecting a lower OS in patients, likely due to patients selection factors i.e. poorer performance status, shorter response to ADT of less than 12 months, high burden of disease and prior use of older anti-androgens.¹⁸

In patients who have disease that have progressed post Docetaxel, Cabazitaxel at the dose of 20mg/m2 can be considered as 2nd line chemotherapy.

Cabazitaxel is a taxane designed specifically for anti-tumour activity in the Docetaxel-resistant patients. The TROPIC19 study evaluated Cabazitaxel at 25mg/m2 given every 3 weeks against the control Mitoxantrone, showing an OS favouring Cabazitaxel. PROSELICA20 subsequently showed that Cabazitaxel at 20mg/m2 was non-inferior to 25mg/m2 with respect to OS with decreased toxicity compared to 25mg/m2.

Side effects are similar to Docetaxel including chemotherapy- related cytopenias, febrile neutropenia and GI toxicities.

Radium-223, an alpha particle emitting radionuclide that binds to the hydroxyapatite in osteoblastic bone metastatic has been shown to improve overall survival in CRPC patients who have bone-only metastasis and without nodal metastasis of more than 3 cm as noted in the ALSYMPCA study.²¹ The OS was prolonged in the radium 223 group median OS 14.9 versus 11.3 months in the control group.

Side effects include diarrhoea and thrombocytopenia.

Lastly, bone modifying agents in the form of Bisphosphonates²² and Rank Ligand antibody Denosumab²³, have been shown to reduce the risk of skeletal-related adverse events such as pathological fractures, spinal cord compression and symptomatic bony pain requiring palliative radiation or surgery.

The potential side effects are hypocalcaemia or a small risk of osteonecrosis of the jaw in patients.

THE FUTURE

The future management of advanced prostate cancer remains bright with several upcoming trials that are on the horizon. We look forward to the studies on PARP (Poly (Adp-Ribose) Polymerase) inhibitors and its role in patients with germline or somatic alterations in homologous recombination repair genes.

The ENZAMET study which investigates the role of Enzalutamide and chemotherapy in the high risk HSPC setting could answer the question on a combination of novel anti-androgens and chemotherapy.

In addition, we eagerly await results from PSMA Lu177 therapy, a very promising approach known as theranostics, in the treatment of advanced prostate cancer. There are also a number of genomic-related treatment strategies that are being investigated now that will pave the way for what will be truly personalised medicine.

Dr Ravindran Kanesvaran is a Senior Consultant at the Division of Medical Oncology at the National Cancer Centre Singapore. He is also an Assistant Professor at the Duke- NUS Medical School. He is actively involved in graduate medical education and is the Programme Director of the Medical Oncology Senior Residency Programme. His research interests include genitourinary oncology and geriatric oncology.

Dr Johan Chan is currently a Medical Oncology fellow at the National Cancer Centre Singapore, who works with Dr Ravindran Kanesvaran. His main interest is in genitourinary oncology.

GPs can call for appointments through the GP Appointment Hotline at 6436 8288 for more information.

REFERENCES:

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