Targeted therapies in metastatic prostate cancer and the implications of the Triton3 trial
Prostate cancer is the second most common cancer in Ireland, after non-melanoma skin cancer and is notably more common than breast or colon cancer. Around 3,900 men are diagnosed with prostate cancer in Ireland every year.1 Although only a small percentage of these men will eventually die of prostate cancer, significantly more will develop metastatic disease, where it will spread to areas, such as the lymph nodes, bones, lungs, and liver.
Some cancers, like lymphomas and testicular cancer, are still curable in advanced stages, but most other cancers including prostate are generally not curable once they have spread to other organs. The treatment goal in these patients is to control progression of cancer while minimising side-effects for as many years as possible. Despite advances in systemic therapies and targeted therapies in prostate cancer, not every patient achieves this goal.
There are some issues in the current landscape of treatment. Firstly, many patients are diagnosed at an older age when their performance status, physical condition, and organ function is not at its best. This limits the choice of systemic therapies as some come with high toxicity profiles. Secondly, after initial response, a proportion of prostate cancers stop responding to common treatment techniques like androgen deprivation therapy and androgen receptor pathway inhibitors. Thirdly, systemic chemotherapy can be difficult for patients to tolerate, which limits its use in this setting.
Before looking at new prostate cancer treatment options and trials including TRITON3, let’s examine the options currently available in Ireland.
Androgen deprivation has been the mainstay of prostate cancer treatment since the 1940s when Charles Huggins first demonstrated shrinkage of the prostate gland after surgical castration in dogs and subsequently older men.2 Though surgical castration is still widely practiced, chemical castration is the most common technique utilised in Ireland. LHRH agonists and antagonists both are used in form of monthly, three-monthly or six-monthly injections to supress the levels of testosterone. Compared to surgical removal of the testicles, these injections have better acceptance among patients and castration can be reversed once injections are stopped.
Chemical castration comes with a number of side-effects of testosterone deprivation like hot flushes, mood changes, night sweats, and osteoporosis.
Androgen deprivation therapy has a very high response rate (around 90 per cent), but unfortunately this response lasts only 12-to-18 months at best. At this point the cancer starts to regrow and spread even though there is very little testosterone in the body.3 Therefore, at this stage prostate cancer is termed castrate-resistant prostate cancer (CRPC) and becomes more challenging to control.
Flutamide was the first non-steroidal anti-androgen approved by the US FDA in 1989 for treatment of prostate cancer. Many advances have been made since then to block testosterone receptors and pathways. The ones most commonly used in Ireland are abiraterone, enzalutamide, apalutamide, and darolutamide. Around 70 per cent of prostate cancers respond to these agents and patients usually tolerate them well. As mentioned above, most metastatic prostate cancer patients have other medical conditions at the time of diagnosis, which can limit their use. For example, enzalutamide, which is highly effective in controlling prostate cancer, must be used with caution in patients with an underlying heart condition or certain neurological conditions due to the potential for cardiotoxicity and/or neurotoxicity.
As with androgen deprivation therapy, these agents often stop working after 12-to-18 months when the cancer starts to grow again.
Since the advent of chemotherapy in the 1940s, it has been used in different forms for prostate cancer. At present docetaxel is seen to be the most effective chemotherapy for the treatment of metastatic prostate cancer.4 With a 50 per cent response rate, docetaxel comes with familiar side-effects of taxane-based chemotherapies including neutropaenia, sepsis, peripheral neuropathy, and colitis. This cytotoxic profile limits its use in a significant proportion of patients who would never be able to tolerate the side-effects. Even those who can tolerate it initially are seldom able to continue treatment beyond eight-to-10 months due to the cumulative nature of toxicities.
Apart from the commonly-utilised treatment options mentioned above, many others have been explored to treat prostate cancer. However, many anti-cancer agents showing promising results in other cancer types have failed to be effective in prostate cancer.
Since the revolutionary roll-out of herceptin in breast cancer in the 1990s, the landscape of cancer care has changed significantly. The dream of finding a treatment to selectively kill cancer cells with minimal side-effects has started to look more possible. In the last three decades, a tremendous amount of research has taken place to achieve this dream. Thousands of potential treatment targets have been identified, including gene mutations. Immune check point inhibitors, commonly known as immunotherapy, have revolutionised the prognosis of many cancers in the last decade. Most benefit has been seen in patients with metastatic melanoma, lung cancer, kidney cancers, and colorectal cancers. However, other cancers like prostate are lagging behind.
With regard to the BRCA gene mutation, first discovered in 1994, this can be inherited and is associated with an increased risk of breast, prostate, ovarian, pancreatic, and other cancers. PARP (poly ADP ribose polymerase) inhibitors are used to target BRCA mutations and treat cancers associated with BRCA gene mutations. They are widely used in ovarian cancer and breast cancer, but heretofore have not been commonly used in prostate cancer. The reason for this has been the lack of evidence for efficacy compared to current standard-of-care therapies. In Ireland, at present, no BRCA-targeting agents have been approved for treatment of advanced prostate cancer in the first-line setting.
To summarise, there are good treatment options for metastatic prostate cancer including androgen deprivation therapy, novel anti-androgen therapy, and chemotherapy, but they have their limitations. Most importantly, their use is limited by the development of resistance or toxicity. Keeping this in mind, we will now discuss the just-published TRITON3 prostate cancer trial results.
The multicentre, randomised, open label phase 3 study TRITON3 compared the efficacy and side-effects of the PARP inhibitor rucaparib with standard-of-care treatment (docetaxel or novel anti-androgen) in patients with BRCA or ATM mutations.
As a part of this multinational study, the clinical trials team in Tallaght University Hospital (TUH) recruited and screened patients from February 2017 to February 2022 under the supervision of Prof Ray McDermott, Consultant Medical Oncologist and Clinical Professor of Medical Oncology at TUH. Prof McDermott is one of the principal investigators for TRITON3, and is the National Cancer Control Programme lead in guideline development for prostate cancer.
St Vincent’s University Hospital, Mater Misericordiae University Hospital, St James’s Hospital, Dublin, and Cork University Hospital were other centres in Ireland to participate in the study. Even during the Covid -19 pandemic, our teams continued the process of screening, recruitment, and treatment of patients.
Around 5,000 patients were screened in 12 countries and 143 cancer centres over the period of five years. Out of those, 405 patients were found to harbour BRCA or ATM deleterious alterations. In a 2:1 randomisation, 270 patients received rucaparib tablets and 135 received either docetaxel chemotherapy or a novel anti-androgen.
The results were widely anticipated as a previously trial (TRITON2) had shown good activity of this new drug in treating metastatic prostate cancer after prior chemotherapy. The hard work of our trials team made it possible to offer this new promising drug to our patients. At the same time, the stakes were high because the trial was designed to compare rucaparib with standard-of-care treatment at an earlier stage of the disease process.
Results were published in the New England Journal of Medicine on 23 February, 2023.5 The trial was positive, with rucaparib showing remarkably better activity in patients, with manageable side-effects. In patients carrying BRCA mutations, the rucaparib arm controlled disease for 11 months compared to six months in the control arm. Among patients who had radiographically measurable disease, shrinkage (objective response rate) was observed in 45 per cent of cases of the rucaparib arm compared to only 17 per cent in the control arm. These figures clearly demonstrate the superior efficacy of rucaparib compared to present treatment options in BRCA-associated prostate cancer.
Comparing the side-effect profile, 15 per cent of patients in the rucaparib arm discontinued treatment due to side-effects compared to 22 per cent in the control arm. The most commonly reported side-effects were fatigue, nausea, and anaemia, which were manageable and reversible compared to diarrhoea and peripheral neuropathy in the docetaxel arm.
TRITON3 is a major step towards the goal of selective treatment of cancer. We expect, in the near future, that this new drug will get approvals from regulatory bodies in Europe and the US. After these approvals, we will be able use it earlier in the treatment of BRCA-associated prostate cancer. Once in general use, rucaparib should improve the prognosis in these patients.
A positive clinical trial has a hugely beneficial impact on the research staff involved in cancer trials and for patients. Managing a patient on a clinical trial is burdensome due to the necessity for extensive paper work and frequent visits to the relevant facility. The last few years have been particularly difficult for healthcare staff due to the Covid-19 pandemic, succeeded by a surge in delayed cancer diagnosis and upstaging. Successful trials in this situation boost the energy and motivation of staff working in trials, as well as the patients and families involved.
Most recently our team leader in TUH, Ms Ashley Bazin, was awarded Support Staff member of the year by the Irish Cancer Society in acknowledgement of these efforts. This again is a big success for our team, patients, and the families who are vital to this process of the continuing development of cancer care.
With another positive trial, we are progressing towards our goal of improving cancer care. The hunt for a sliver bullet will continue with even more commitment and persistence in our trials unit and the units around Ireland, in conjunction with Cancer Trials Ireland.
Irish Cancer Society. Cancer statistics. 2023. Available at: www.cancer.ie/cancer-information-and-support/cancer-information/about-cancer/cancer-statistics
Huggins CB, Stevens RA. The effect of castration on benign hypertrophy of the prostate in man. J Urol. 1940;43:105
Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: Progress in understanding mechanisms of resistance and optimising androgen depletion. Nat Clin Pract Urol 2009. Feb;6(2):76-85
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12
Fizazi K, Piulats JM, Reaume MN, Ostler P, McDermott R, Gingerich JR, et al. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023 Feb 23;388(8):719-732
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