Three drugs have recently been approved for advanced prostate cancer that no longer responds to hormone therapy, a condition known as castration-resistant prostate cancer (CRPC). These drugs are known as second-generation anti-androgens and include enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa). Darolutamide, the last drug to be approved, received approval as recently as July 30, 2019 by the Food & Drug Administration (FDA) of the United States and the other two received approvals in 2018.
All three drugs have been shown in clinical trials to significantly prolong the time it takes to develop metastases (spread of cancer to other locations in the body) as well as improve overall survival in men with CRPC who have not yet developed metastases (non-metastatic CRCP). Standard tests such as a radioisotope bone scan and CT scan of the abdomen/pelvis were used to assess spread. These men with CRPC were all at high risk of developing metastases, as indicated by a prostate-specific antigen (PSA) doubling-time below 10 months.
This is an extremely significant development because CRPC is a terminal phase of prostate cancer in which most of the patients are dead in two to four years. In this phase, the cancer no longer responds to first-line hormonal therapy which includes drugs that stop the testicles’ production of testosterone.
Prostate cancer depends on the male hormone testosterone to continue multiplying and spreading, and when it is deprived of testosterone it withers and involutes no matter where in the body it has metastasised to. After a variable period, the cancer eventually outsmarts the drugs and adapts itself to be able to multiply and grow despite castrate levels of testosterone in the bloodstream. It is at this point that the cancer is termed castration-resistant, and it signifies progression of the cancer towards imminent death of the host.
Men with ‘early’ prostate cancer who may not have been cured by surgery and/or radiotherapy and who are subsequently put on hormone therapy to supress the cancer will eventually develop non-metastatic CRPC. After a variable period, these men will experience progression of the cancer by developing metastases. A harbinger of imminent metastases is the progressively shorter time it takes for the PSA to double in value (less than 10 months in the trials) in these men with non-metastatic CRPC.
Since metastases is the usual precursor to death from cancer, any drug that can delay the occurrence of metastases potentially prolongs survival. All three second-generation antiandrogens have empirically been shown to prolong average (median) metastases-free survival by approximately two years more over standard treatments (e.g., 40.5 months versus 16.2 months). In combination with other drugs used to treat CRPC such as abiraterone, docetaxel, cabazitaxel, and others, survivals of five years or more after the development of CRPC can now be realised in what was once an imminently fatal phase of the disease. Apalutamide and abiraterone are currently available in Jamaica but are inordinately expensive and most Jamaicans cannot afford them. Unless they are put on the NHF list of approved drugs for prostate cancer they will remain out of the reach of most Jamaicans.
… AND WHAT’S ON THE HORIZON
Other recent developments in prostate cancer include the use of either chemotherapy or abiraterone (a drug that blocks the adrenal glands and prostate tumour cells from making testosterone) up-front alongside hormone therapy in men with newly diagnosed metastatic prostate cancer who have never received hormone therapy. This combination of drugs results in longer survival of the patients when compared to men who receive hormone therapy alone. It is the new standard of care. Unfortunately, most Jamaican patients are either unable to afford the drugs or are unwilling to consider chemotherapy due to extremely biased preconceptions of it. This is sad as a lot of men unnecessarily shorten their survival and succumb to the cancer earlier than they would have, had they received chemotherapy or been able to afford the abiraterone.
Another recent development is the use of prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/CT scans in the evaluation of the extent of spread of the disease or for evidence of recurrence after local treatments such as radical prostatectomy or radiotherapy that standard tests such as a bone scan and CT scan would be unable to detect when the PSA is minimally elevated. This development is likely to revolutionise the management of prostate cancer soon. Stay tuned!
3-Tesla multiparametric MRI (mpMRI) is already here and is currently being used in Jamaica to identify aggressive prostate cancers and to facilitate targeted biopsies of specific regions of the prostate that harbour these high-risk cancers. It has been extremely valuable in evaluating men who have had a previous negative prostate biopsy and continue to have a persistently elevated PSA. Up to one-third (33 per cent) of these men may have prostate cancer that was simply missed on the previous ultrasound-guided prostate biopsy. Multiparametric MRI selectively identifies prostate cancers that are likely to threaten the patient’s life and facilitates a targeted biopsy of the abnormal areas detected along with the usual standard systematic biopsy. It is not fool proof, however, and it may miss up to 20 per cent of lethal cancers.
On the horizon are liquid biopsies which use patients’ blood and depends on cutting-edge technologies such as next-generation DNA sequencing and digital polymerase chain reaction (PCR) to rapidly assess the genomic mutations as the cancer progresses of circulating tumour cells and cell-free DNA. This will help determine which agents the cancer will respond to best and which agents simply won’t work. This is an example of personalised medicine and is the era of medicine we are about to enter with respect to prostate cancer treatment.
William D. Aiken, DM (Urol), FRCSEd, FACS, FCCS, is senior lecturer (Urology) and consultant urologist, The UWI/UHWI, president, Association of Surgeons in Jamaica, and a past president, Jamaica Urological Society.