{"product_id":"repurposing-existing-medicines-to-improve-prostate-cancer-outcomes-what-current-major-trials-are-testing","title":"Repurposing Existing Medicines to Improve Prostate Cancer Outcomes: What Current Major Trials Are Testing","description":"\u003cp\u003eThis review examines the strategy of using existing, already-licensed medicines (called drug repurposing) to treat prostate cancer at every stage of the disease. The authors describe current phase III randomised controlled trials testing drugs such as finasteride, aspirin, metformin, statins, beta-blockers, and transdermal oestradiol patches. The review highlights that while repurposed drugs offer advantages in safety knowledge and cost, they still require the same rigorous evidence from large randomised trials before becoming standard treatments. To date, few drugs have been successfully repurposed for prostate cancer despite considerable research effort.\u003c\/p\u003e\n\n\u003ch1\u003eRepurposing Existing Medicines to Improve Prostate Cancer Outcomes: What Current Major Trials Are Testing\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why Prostate Cancer Research Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#repurposing\"\u003eWhat Is Drug Repurposing and Why Is It Attractive?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#prevention\"\u003ePrimary Prevention of Prostate Cancer\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#active-surveillance\"\u003ePreventing Progression in Patients on Active Surveillance\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#radical-treatment\"\u003eRepurposing Drugs After Radical Treatment\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#adt\"\u003eImproving Outcomes During Long-Term Hormone Therapy\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#advanced-disease\"\u003eRepurposing Drugs for Locally Advanced and Metastatic Disease\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#challenges\"\u003eChallenges in Drug Repurposing\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Current Evidence\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Future Directions\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eDrug repurposing uses existing licensed medicines for prostate cancer, but they still require the same rigorous phase III randomised trial evidence as new drugs.\u003c\/li\u003e\n\u003cli\u003eIn the MAST trial of 407 men on active surveillance, metformin showed no difference in progression-free survival compared with placebo.\u003c\/li\u003e\n\u003cli\u003eIn the PCPT trial of 18,880 men, finasteride reduced prostate cancer diagnoses by 30% but did not improve overall survival at 18 years.\u003c\/li\u003e\n\u003cli\u003eIn the PATCH programme, transdermal oestradiol patches achieved equivalent cancer control to standard hormone therapy, with improved quality of life and fewer hot flushes.\u003c\/li\u003e\n\u003cli\u003ePatients should discuss clinical trial participation with their healthcare team, as trials are testing repurposed drugs at every stage of prostate cancer.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why Prostate Cancer Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eProstate cancer remains a major cause of illness and death in men worldwide. In the United Kingdom alone, prostate cancer is responsible for 55,000 new cases and 12,000 deaths each year. The number of cases globally is projected to rise from 1.4 million in 2020 to 2.9 million by 2040. This increase is driven by changing population demographics and improving life expectancy.\u003c\/p\u003e\n\n\u003cp\u003eUntil the turn of the last century, treatment for prostate cancer typically consisted of surgical removal of the prostate (radical prostatectomy) for the earliest, localised cases. For the remaining patients, treatment consisted of androgen deprivation therapy (ADT), which reduces male hormone levels. Radiotherapy was added for men without clear evidence that the cancer had spread (metastatic disease).\u003c\/p\u003e\n\n\u003cp\u003eOver the last 20 years, several key developments have improved outcomes dramatically. The availability of the Prostate Specific Antigen (PSA) blood test significantly increased the detection of early disease. However, PSA testing alone had low specificity for clinically significant disease, which made over-diagnosis a challenge. The addition of multi-parametric MRI (mpMRI) to the diagnostic pathway for men with early PSA-based detection can now reliably exclude clinically insignificant cancers without the need for biopsy.\u003c\/p\u003e\n\n\u003cp\u003eAdvances in treating localised, intermediate-risk disease have also improved outcomes. Surgical techniques have progressed from laparoscopic to robotic-assisted radical prostatectomy, reducing operative complications and hospital stay. Radiotherapy schedules have been optimised through sequential large-scale phase III trials. These trials took the previous standard of care through moderate hypofractionation to stereotactic radiotherapy techniques. The previous standard of care was 74 Gy external beam radiotherapy in 37 fractions over 7.5 weeks. Moderate hypofractionation was 60 Gy in 20 fractions over four weeks. Stereotactic radiotherapy techniques treat the prostate in just 5 fractions.\u003c\/p\u003e\n\n\u003cp\u003eThe benefit of adding radiotherapy to 2–3 years of ADT in patients with locally advanced but non-metastatic (M0) disease was also demonstrated. This combination is now a standard of care.\u003c\/p\u003e\n\n\u003cp\u003eFor systemic treatments (drugs that travel through the bloodstream), efficacy has typically been demonstrated first in patients with metastatic, castrate-resistant disease. Later, the same drugs were tested in the \"upfront\" setting before patients experienced progression on ADT. In this way, the chemotherapy agent docetaxel was shown to improve survival in patients progressing on ADT. Docetaxel was subsequently shown to improve survival in patients commencing ADT for metastatic disease in the CHAARTED and STAMPEDE trials.\u003c\/p\u003e\n\n\u003cp\u003eA group of drugs called androgen receptor pathway inhibitors (ARPIs) followed a similar path. These include abiraterone acetate, enzalutamide, apalutamide, and darolutamide. These drugs are now typically considered standard of care in newly diagnosed, hormone-sensitive patients. They are used for patients presenting with locally advanced disease (abiraterone) or metastatic disease (all of these drugs).\u003c\/p\u003e\n\n\u003cp\u003eThe second-generation taxane chemotherapy drug cabazitaxel has efficacy in patients previously treated with docetaxel. There is also increasing interest in more targeted approaches. This includes radiopharmaceuticals. Radium 223 initially demonstrated benefit in patients with extensive bone metastases. More recently, Prostate Specific Membrane Antigen (PSMA)-Lutetium offers metastases-directed therapy. Molecularly targeted agents include Poly ADP ribose polymerase (PARP) inhibitors in patients with DNA damage repair defects. Immune checkpoint inhibitors may also benefit the small number of patients whose tumours harbour deficiencies in mismatch repair (dMMR).\u003c\/p\u003e\n\n\u003cp\u003eDespite this progress, specific clinical areas still have open questions. These include primary prevention. These include patients undergoing active surveillance where treatments might reduce the requirement for active intervention. These include improving outcomes after radical treatment. These include mitigating the side-effects of ADT. These include improving outcomes for patients who still develop locally advanced or metastatic disease.\u003c\/p\u003e\n\n\u003cp\u003eWhile new targets and corresponding drugs continue to emerge, the global burden of prostate cancer makes it not just an opportunity but a necessity. The global burden of prostate cancer makes it a necessity to assess currently licensed medicines for their potential benefits in this population. A range of different approaches and mechanisms have been suggested. The authors use a series of current phase III trials testing repurposed medicines to demonstrate this strategy and discuss methods taken to investigate this approach in men with prostate cancer.\u003c\/p\u003e\n\n\u003ch2 id=\"repurposing\"\u003eWhat Is Drug Repurposing and Why Is It Attractive?\u003c\/h2\u003e\n\n\u003cp\u003eRepurposed drugs are existing medicines that are already licensed for other conditions. These drugs have attracted interest in the treatment of prostate cancer. A number of agents have been proposed with a range of mechanisms of action suggesting potential benefits.\u003c\/p\u003e\n\n\u003cp\u003eA major advantage of such drugs is the wealth of pre-existing patient safety data typically available. This means repurposed agents would be expected to have a known and often low toxicity profile. Additionally, because these drugs are often late in their developmental pathway and generic versions are available, they are attractive in terms of cost-effectiveness.\u003c\/p\u003e\n\n\u003cp\u003eHowever, the evidence required for repurposed drugs to become accepted standards of care and enter the treatment formulary is no less arduous than conventional development pathways. Confirmatory results from randomised phase III trials remain the absolute requirement. Additionally, these efforts are often led by academic trial groups rather than pharmaceutical companies. This creates challenges in the steps to licensing that are typically undertaken by industry.\u003c\/p\u003e\n\n\u003cp\u003eTo date, despite large-scale initiatives, there is a paucity of drugs successfully repurposed in this way for prostate cancer.\u003c\/p\u003e\n\n\u003ch2 id=\"prevention\"\u003ePrimary Prevention of Prostate Cancer\u003c\/h2\u003e\n\n\u003cp\u003eAs a major health challenge, prevention of prostate cancer could have multiple benefits. Drugs in this space are intended for individuals without cancer but at high risk. These drugs would potentially be administered over many years, so safety is of utmost importance. The established long-term safety profiles from repurposed agents make them particularly well-suited for preventive interventions.\u003c\/p\u003e\n\n\u003cp\u003eVarious classes of drugs have been proposed or investigated for their potential role in prostate cancer prevention. These work primarily through hormonal modulation, anti-inflammatory effects, and metabolic modulation.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFinasteride and the Prostate Cancer Prevention Trial (PCPT)\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eAndrogens (male hormones) play a key role in the development and progression of prostate cancer. The Prostate Cancer Prevention Trial (PCPT) evaluated finasteride, a 5-alpha-reductase inhibitor, in a preventative setting. This is analogous to the repurposing of the aromatase inhibitor anastrozole for the prevention of breast cancer in women at high risk of developing the disease.\u003c\/p\u003e\n\n\u003cp\u003ePCPT was designed to have 92% power to detect a 25% reduction in prevalence of biopsy-proven prostate cancer. The trial used a two-sided test with a significance level (alpha) of 0.05. A total of 18,880 men were randomised to finasteride versus placebo.\u003c\/p\u003e\n\n\u003cp\u003eWith 18 years of follow-up, prostate cancer was diagnosed in 989 of 9,423 men (10.5%) in the finasteride group and 1,412 of 9,457 men (14.9%) in the placebo group. The relative risk in the finasteride group was 0.70 (95% confidence interval [CI], 0.65 to 0.76; P \u0026lt; 0.001). This means finasteride reduced the risk of being diagnosed with prostate cancer by 30%.\u003c\/p\u003e\n\n\u003cp\u003eInterestingly, high-grade disease was diagnosed more frequently in the finasteride arm. The 15-year survival was 78.0% in men randomised to finasteride and 78.2% in the placebo group. The hazard ratio for death was 1.02 (95% CI, 0.97 to 1.08; P = 0.46). Even at 18 years of follow-up, there was no significant difference in overall survival or survival after a prostate cancer diagnosis between the finasteride and placebo groups. This highlights the complex relationship between prostate cancer incidence and ultimate impact on survival.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAspirin for Prevention\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eAspirin has been suggested to affect multiple mechanisms that could confer an anti-cancer effect. These include immunomodulation, cell metabolism, gene repair, inflammation reduction, platelet activation, and gut microbiota improvement.\u003c\/p\u003e\n\n\u003cp\u003eRecent work has begun to elucidate a mechanism whereby aspirin reduces the production of thromboxane A2 (TXA2) through the inhibition of cyclo-oxygenase 1 (COX1) in platelets. In preclinical models, the abolition of TXA2 signalling reduces metastatic dissemination. Perhaps most strikingly, inhibition of platelet-derived TXA2 has been shown to enhance T-cell immune-mediated clearance of metastases in mouse models.\u003c\/p\u003e\n\n\u003cp\u003eThe strongest data supporting a role for aspirin in cancer prevention comes from randomised studies investigating aspirin to prevent cancers in patients with Lynch syndrome. Prior data came from patients randomised in trials testing aspirin in the context of cardiovascular disease. These prior data concerned long-term outcomes. The prior data showed aspirin use was associated with a lower risk of cancer-related death.\u003c\/p\u003e\n\n\u003cp\u003eWith respect to primary prevention in particular, aspirin reduced the risk of a cancer diagnosis (hazard ratio 0.88, 95% CI 0.80–0.98, P = 0.017), with the effect proportional to time on treatment. Overall, pooled data from case-control and cohort studies suggest that aspirin reduces the risk of a diagnosis of several common cancers including prostate cancer (relative risk 0.90, 95% CI 0.85–0.96, P \u0026lt; 0.001).\u003c\/p\u003e\n\n\u003cp\u003eOne piece of contrasting data is the results from the ASPREE trial (Aspirin in Reducing Events in the Elderly, NCT01038583), where cancer-related deaths were actually higher in the aspirin group. With a relatively small effect size, a primary prevention study for prostate cancer alone would likely be prohibitively large. Whether this might be included as a composite of numerous other potential health benefits of any future study remains to be seen.\u003c\/p\u003e\n\n\u003cp\u003ePrimary prevention of prostate cancer remains a challenge, with a paucity of ongoing clinical trials. The design and appropriate outcome measures to balance clinically pertinent results with achievable and affordable projects is not straightforward.\u003c\/p\u003e\n\n\u003ch2 id=\"active-surveillance\"\u003ePreventing Progression in Patients on Active Surveillance\u003c\/h2\u003e\n\n\u003cp\u003eAs an alternative to primary prevention, and with the diagnosis of early, low-risk disease rising through increased use of PSA testing, researchers are investigating repurposed agents. Researchers are investigating whether repurposed agents can treat prostate cancer at this early stage. The goal is to prevent progression to situations that require radical treatment.\u003c\/p\u003e\n\n\u003cp\u003eActive surveillance is routinely offered to patients diagnosed with low-risk prostate cancer. This approach is used in lieu of validated biomarkers to predict progression, where a significant proportion of patients might avoid radical treatment. Active surveillance schedules must ensure comprehensive monitoring. Future strategies could use personalised deep-learning-based algorithms to predict grade reclassification.\u003c\/p\u003e\n\n\u003cp\u003eA 15-year follow-up of 1,643 men in the ProtecT trial (NCT02044172) found no difference in mortality between those offered active monitoring, prostatectomy, or radiotherapy. However, prostatectomy and radiotherapy reduced disease progression and the development of metastases. While there is no detriment to survival associated with active surveillance, there is a potential opportunity for interventions that prevent progression. Such interventions would improve outcomes without the toxicity associated with conventional treatments. The safety net of curative treatment upon signs of progression makes men on active surveillance a unique population to trial repurposed drugs that may delay disease progression.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eMetformin and the MAST Trial\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eHyperinsulinemia (high insulin levels) promotes metastasis and treatment resistance. This occurs through upregulation of intracellular testosterone levels and androgen receptor activation in prostate cancer cells in laboratory studies. Some metabolic modulators, such as metformin, aim to reduce hyperinsulinemia and can influence other cancer signalling pathways due to their antineoplastic properties.\u003c\/p\u003e\n\n\u003cp\u003eMetformin was originally investigated as a treatment for malaria and influenza, and is now used for type 2 diabetes. Metformin was shown to reduce cancer incidence and cancer-specific mortality in people with diabetes compared to insulin in an observational cohort study.\u003c\/p\u003e\n\n\u003cp\u003eMetformin's mechanism of action is multifaceted. It involves inhibition of cell proliferation, cell cycle progression, and cellular invasion. Metformin regulates energy function in cancer stem cells (CSCs) by activating AMP-activated protein kinase (AMPK), a metabolic regulator. This inhibits oxidative phosphorylation and reduces mitochondrial ATP production. This forces tumour cells to increase glycolysis. Since CSCs rely heavily on oxidative phosphorylation, this creates an energy crisis that increases their sensitivity to anti-cancer treatment.\u003c\/p\u003e\n\n\u003cp\u003eThe Metformin Active Surveillance (MAST) trial (NCT01864096) investigated whether metformin affected progression-free survival in men with prostate cancer on active surveillance. Eligible patients had biopsy-proven, low-risk, localised prostate cancer. Specifically, they had a Gleason score of 6 or less observed in one-third or fewer cores. They had less than 50% positivity in any one core. They had PSA of 10 ng\/ml or less. They had clinical stage T1c-T2a. Patients were diagnosed within the past 6 months.\u003c\/p\u003e\n\n\u003cp\u003ePatients were randomly assigned (1:1) to metformin (850 mg twice daily) versus placebo for 3 years. Patients underwent repeat prostate biopsy at 18 and 36 months. The primary outcome was progression-free survival (time to primary therapy such as prostatectomy, radiation, hormonal therapy, or pathological progression).\u003c\/p\u003e\n\n\u003cp\u003eA total of 141 of 407 patients experienced disease progression. No difference in progression-free survival (PFS) was observed between patients treated with metformin and those receiving placebo (p = 0.63). An exploratory subgroup analysis even suggested potential detriment in patients on metformin with a higher BMI and a Gleason score of at least 8 at disease progression.\u003c\/p\u003e\n\n\u003cp\u003eA meta-analysis of observational studies suggested that metformin might be of benefit as an adjuvant therapy after radical treatment. Trials have also tested the addition of metformin in the advanced setting.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eStatins and Beta-Blockers\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eEpidemiological data suggests statins may reduce the risk of advanced and fatal prostate cancers. In a meta-analysis of trials of men undergoing radical treatment, patients taking statins had improved outcomes when treated with radical radiotherapy. This effect was not seen in patients treated with surgery.\u003c\/p\u003e\n\n\u003cp\u003eStatin prescription for cardiovascular disease is highest in men over 70. This is the demographic of men with the highest incidence of prostate cancer. The significant burden of cardiovascular disease among men with prostate cancer offers a risk-benefit profile in favour of statin use. However, current observational data does not support an effect in patients on active surveillance. It remains to be seen whether the community will deem a randomised controlled trial worthwhile.\u003c\/p\u003e\n\n\u003cp\u003eBeta-blockers have also been proposed as a potential adjunct for men on active surveillance. Their cardioprotective function occurs due to inhibition of beta-adrenergic receptors, which may also have anti-neoplastic benefits. In vivo studies suggest beta-adrenergic stimulation has a role in apoptosis, angiogenesis, and metastases. A retrospective study showed atenolol use was associated with a reduced risk of pathologic upgrade to Gleason grade 3 or higher in men on active surveillance. However, prospective trials are needed to determine causality.\u003c\/p\u003e\n\n\u003cp\u003eWhile retrospective and observational studies provide suggestions of drugs to repurpose in this area, clinical trials testing the efficacy of repurposed agents in men on active surveillance remain vital. Clinical trials testing the efficacy of repurposed agents in men on active surveillance remain vital in producing definitive data. Patients on active surveillance are potentially an attractive group to study because they have well-characterised disease, regular follow-up, and clear patient benefits from positive findings.\u003c\/p\u003e\n\n\u003cp\u003eInterestingly, although not strictly repurposed drugs in the conventional sense, there are strong parallels here with efforts to investigate dietary intervention in this setting. One example is a high omega-3, low omega-6 diet in combination with fish oil supplementation, as tested in the phase 2 CAPFISH-3 trial (NCT02176902). Given the range of possible interventions and surrogate outcome measures, there is arguably an opportunity for a multi-arm multi-stage (MAMS) trial to improve efficiency in this approach.\u003c\/p\u003e\n\n\u003ch2 id=\"radical-treatment\"\u003eRepurposing Drugs After Radical Treatment\u003c\/h2\u003e\n\n\u003cp\u003eAfter radical treatment (surgery or radiotherapy), some patients experience a rise in PSA levels, which is called biochemical recurrence. This indicates the cancer may be returning. The ADD ASPIRIN trial (NCT02804815) is testing aspirin in this setting.\u003c\/p\u003e\n\n\u003cp\u003eThe primary outcome measure for the ADD ASPIRIN trial is biochemical recurrence-free survival. Given the very long lead time and uncertain association between recurrence after radical treatment and the development of metastases or death, this was considered the optimal outcome. This was considered the optimal outcome by the trial group with patient input.\u003c\/p\u003e\n\n\u003cp\u003eA total of 1,917 men treated for localised prostate cancer have been randomly allocated in this trial. The primary outcome analysis is expected in 2027. Long-term follow-up and the large sample size will also produce evidence of the effects of aspirin unrelated to the primary cancer. These include prevention of deaths related to vascular events and second malignancies. Rates of serious toxicity (especially haemorrhage), as well as other secondary health outcomes, will be available. Ultimately, aspirin is a low-cost drug available generically.\u003c\/p\u003e\n\n\u003ch2 id=\"adt\"\u003eImproving Outcomes During Long-Term Hormone Therapy\u003c\/h2\u003e\n\n\u003cp\u003eADT, traditionally achieved using luteinising hormone-releasing hormone analogues (LHRHa), is central to prostate cancer management. While LHRHa effectively suppress testosterone, they also reduce circulating oestrogens. This contributes to many significant toxicities including hot flushes, osteoporosis, increased fracture risk, adverse metabolic changes, increased cardiovascular risk, and reduced quality of life.\u003c\/p\u003e\n\n\u003cp\u003eOral oestrogens, although previously used as ADT, were abandoned due to high rates of cardiovascular thromboembolic effects linked to hepatic first-pass metabolism. Transdermal oestradiol (tE2) patches, which allow oestradiol to pass through the skin, avoid this problem. These patches are licensed for hormone replacement therapy in post-menopausal women. Repurposing tE2 patches results in suppression of testosterone levels while avoiding those side-effects associated with oestrogen deficiency.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eThe PATCH Programme\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eThe PATCH (Prostate Adenocarcinoma Transcutaneous Hormones) repurposing programme (NCT00303784) is evaluating the repurposing of tE2 patches for ADT in men with locally advanced (M0) or metastatic (M1) prostate cancer. This adaptive, multi-stage trial investigates the safety and efficacy of tE2 patches compared to LHRHa.\u003c\/p\u003e\n\n\u003cp\u003eParticipants have been recruited through the PATCH and STAMPEDE (NCT00268476) trials. A randomisation to tE2 was included as a comparison with eligibility and design aligned. Analyses will be combined using a meta-analysis approach. This evaluation assesses tE2 patches for equivalent androgen suppression while minimising treatment-related toxicities. Importantly, the tE2 evaluation uses a non-inferiority design with respect to prostate cancer outcomes.\u003c\/p\u003e\n\n\u003cp\u003eInitial results from PATCH have demonstrated equivalent androgen suppression, improved quality of life, bone mineral density, and superior metabolic profiles in the tE2 arm. There was no significant increase in cardiovascular events (HR 1.11, 95% CI: 0.80–1.53, p = 0.54).\u003c\/p\u003e\n\n\u003cp\u003eUltimately, 2,490 patients were randomised from both trial networks. Patients with locally advanced, non-metastatic (M0) disease and patients presenting with metastatic disease (M1) were considered separately for the phase III analyses. The primary outcomes were metastasis-free survival (MFS) for M0 patients and overall survival (OS) for M1 patients. Non-inferiority margins were set to rule out a 4% detriment in 3-year MFS (HR 1.27) and 5% in OS (HR 1.19). Secondary outcomes include overall survival (for M0 patients only), progression-free survival (PFS), prostate cancer-specific survival, cardiovascular morbidity, hormone levels, and quality of life.\u003c\/p\u003e\n\n\u003cp\u003eResults from the phase III evaluation are approaching maturity. Results presented in 2024 demonstrated that tE2 patches achieved a 3-year MFS of 87% compared to 86% with LHRHa. The hazard ratio (HR) was 0.96 (95% CI 0.81–1.14) in favour of tE2, excluding a 2% reduction in MFS. Overall survival also favoured tE2 with a HR of 0.90 (95% CI 0.75–1.07). Sustained castration rates were similar between groups (85%). The tE2 arm showed a reduction in patients experiencing hot flushes.\u003c\/p\u003e\n\n\u003ch2 id=\"advanced-disease\"\u003eRepurposing Drugs for Locally Advanced and Metastatic Disease\u003c\/h2\u003e\n\n\u003cp\u003eThe STAMPEDE trial (NCT00268476) is a large multi-arm multi-stage trial that has tested several repurposed drugs in patients with locally advanced or metastatic prostate cancer. These include zoledronic acid, celecoxib, and metformin.\u003c\/p\u003e\n\n\u003cp\u003eFor patients with locally advanced disease (M0), metastasis-free survival is a validated surrogate outcome for overall survival. This allows an earlier answer and a realistic sample size to influence standards of care. Overall survival remains the key outcome in patients with metastatic disease (M1). STAMPEDE is powered for superiority of these outcome measures.\u003c\/p\u003e\n\n\u003cp\u003eThe STAMPEDE trial design allows multiple drugs to be tested simultaneously against a common control group. This approach improves efficiency and speeds up the evaluation of repurposed agents in prostate cancer.\u003c\/p\u003e\n\n\u003ch2 id=\"challenges\"\u003eChallenges in Drug Repurposing\u003c\/h2\u003e\n\n\u003cp\u003eDespite the theoretical advantages of repurposed drugs, several significant challenges exist. These challenges explain why few drugs have been successfully repurposed for prostate cancer to date.\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRegulatory requirements:\u003c\/strong\u003e The evidence required for repurposed drugs to become accepted standards of care is no less arduous than conventional development pathways. Confirmatory results from randomised phase III trials remain the absolute requirement.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLack of industry leadership:\u003c\/strong\u003e These efforts are often led by academic trial groups rather than pharmaceutical companies. This creates challenges in the steps to licensing that are typically undertaken by industry.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFunding and resources:\u003c\/strong\u003e Large randomised trials are expensive and time-consuming. Academic groups may have limited resources compared to industry.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eOutcome measure selection:\u003c\/strong\u003e Choosing the right outcome measures to balance clinically pertinent results with achievable and affordable projects is not straightforward.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLong follow-up requirements:\u003c\/strong\u003e Some trials, such as the ADD ASPIRIN trial, require very long follow-up periods to detect differences in outcomes like biochemical recurrence-free survival.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eComplex relationships between incidence and survival:\u003c\/strong\u003e As seen in the PCPT trial with finasteride, reducing cancer incidence does not always translate into improved overall survival.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis review has several important implications for patients with prostate cancer and their families.\u003c\/p\u003e\n\n\u003cp\u003eFirst, repurposed drugs are being actively investigated at every stage of prostate cancer. This includes prevention, active surveillance, after radical treatment, during long-term hormone therapy, and for advanced disease. Patients may have opportunities to participate in clinical trials testing these agents.\u003c\/p\u003e\n\n\u003cp\u003eSecond, repurposed drugs offer potential advantages in terms of safety and cost. Because these drugs are already licensed for other conditions, their side-effect profiles are well known. This means patients and doctors can make more informed decisions about the risk-benefit balance.\u003c\/p\u003e\n\n\u003cp\u003eThird, not all repurposed drugs have shown benefit. The MAST trial found no difference in progression-free survival between metformin and placebo in men on active surveillance. The PCPT trial found that finasteride reduced prostate cancer diagnoses but did not improve overall survival at 18 years. These findings highlight the importance of rigorous testing.\u003c\/p\u003e\n\n\u003cp\u003eFourth, some repurposed drugs have shown promising results. The PATCH trial demonstrated that transdermal oestradiol patches achieved equivalent cancer control compared to standard hormone therapy. The tE2 patches also improved quality of life and bone mineral density, with fewer hot flushes.\u003c\/p\u003e\n\n\u003cp\u003eFifth, participation in clinical trials remains vital. The authors emphasise that clinical trials testing the efficacy of repurposed agents remain vital in producing definitive data. Patients who participate in these trials contribute to knowledge that may benefit future patients.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Current Evidence\u003c\/h2\u003e\n\n\u003cp\u003eThis review has several limitations that patients should understand.\u003c\/p\u003e\n\n\u003cp\u003eFirst, many of the studies discussed are ongoing, and final results are not yet available. The ADD ASPIRIN trial's primary outcome analysis is expected in 2027. The PATCH trial's phase III results are approaching maturity but final analyses are pending.\u003c\/p\u003e\n\n\u003cp\u003eSecond, some evidence comes from observational studies rather than randomised controlled trials. Observational studies can suggest associations but cannot prove cause and effect. For example, the suggestion that statins may reduce the risk of advanced prostate cancer comes from epidemiological data, not randomised trials.\u003c\/p\u003e\n\n\u003cp\u003eThird, the review notes a paucity of drugs successfully repurposed for prostate cancer to date. This means that despite considerable research effort, few repurposed drugs have become standard treatments.\u003c\/p\u003e\n\n\u003cp\u003eFourth, the relationship between intermediate outcomes (such as cancer incidence or biochemical recurrence) and ultimate outcomes (such as overall survival) is complex. The PCPT trial demonstrated that reducing prostate cancer diagnoses did not translate into improved survival at 18 years.\u003c\/p\u003e\n\n\u003cp\u003eFifth, the review focuses on phase III trials, which are the gold standard for proving efficacy. However, earlier-phase trials and preclinical studies also inform this field, and their limitations are not fully discussed in this review.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Future Directions\u003c\/h2\u003e\n\n\u003cp\u003eBased on this comprehensive review, several recommendations and future directions emerge.\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eContinue rigorous testing:\u003c\/strong\u003e Repurposed drugs must be tested in randomised phase III trials before becoming standard treatments. The evidence bar is the same as for new drugs.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eImprove trial efficiency:\u003c\/strong\u003e Multi-arm multi-stage (MAMS) trials, such as STAMPEDE, allow multiple drugs to be tested simultaneously. This approach improves efficiency and speeds up evaluation.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSelect appropriate outcome measures:\u003c\/strong\u003e Researchers must balance clinically meaningful outcomes with achievable and affordable trial designs. Patient input is valuable in this process.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAddress regulatory and licensing challenges:\u003c\/strong\u003e New pathways are needed to help academic-led trials navigate the licensing process typically undertaken by industry.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eConsider combination approaches:\u003c\/strong\u003e Future trials may test repurposed drugs in combination with each other or with standard treatments.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eExplore personalised approaches:\u003c\/strong\u003e Future strategies could use personalised deep-learning-based algorithms to predict which patients are most likely to benefit from specific repurposed drugs.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eInclude patient-reported outcomes:\u003c\/strong\u003e Quality of life and other patient-reported measures should be included as secondary outcomes in trials of repurposed drugs.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSupport long-term follow-up:\u003c\/strong\u003e Some trials require very long follow-up periods to detect differences in outcomes. Continued support for these trials is essential.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eFor patients currently undergoing treatment for prostate cancer, the most important recommendation is to discuss clinical trial participation with their healthcare team. Clinical trials offer access to promising treatments and contribute to the knowledge that will improve care for future patients.\u003c\/p\u003e\n\n\u003cp\u003eFor patients on active surveillance, the authors note that this group is potentially attractive for studying repurposed drugs. Patients on active surveillance have well-characterised disease, regular follow-up, and clear potential benefits from positive findings.\u003c\/p\u003e\n\n\u003cp\u003eFor patients receiving long-term ADT, the PATCH trial results suggest that transdermal oestradiol patches may offer equivalent cancer control with improved quality of life and fewer side effects. Patients should discuss whether this approach might be appropriate for their situation.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is drug repurposing for prostate cancer?\u003c\/h3\u003e\n\u003cp\u003eDrug repurposing means using medicines already licensed for other conditions to treat prostate cancer. Examples being tested in phase III trials include finasteride, aspirin, metformin, statins, beta-blockers, and transdermal oestradiol patches. These drugs have known safety profiles and are often cheaper, but they still need the same rigorous randomised trial evidence as new drugs before becoming standard treatments.\u003c\/p\u003e\n\u003ch3\u003eCan I join a clinical trial of a repurposed drug?\u003c\/h3\u003e\n\u003cp\u003ePossibly. Repurposed drugs are being investigated at every stage of prostate cancer: prevention, active surveillance, after radical treatment, during long-term hormone therapy, and for advanced disease. Eligibility depends on your specific situation. The most important step is to discuss clinical trial participation with your healthcare team, who can tell you what is available and whether you might qualify.\u003c\/p\u003e\n\u003ch3\u003eDoes metformin stop prostate cancer from getting worse?\u003c\/h3\u003e\n\u003cp\u003eIn the MAST trial, 407 men on active surveillance with low-risk prostate cancer were randomly assigned to metformin or placebo for three years. There was no difference in progression-free survival between the groups. An exploratory analysis even suggested possible harm in men with a higher BMI and a Gleason score of at least 8 at progression. Metformin is not proven to delay progression in this setting.\u003c\/p\u003e\n\u003ch3\u003eDoes finasteride prevent prostate cancer?\u003c\/h3\u003e\n\u003cp\u003eIn the Prostate Cancer Prevention Trial, 18,880 men were randomly assigned to finasteride or placebo. Finasteride reduced the risk of being diagnosed with prostate cancer by 30%. However, high-grade disease was diagnosed more often in the finasteride group, and after 18 years there was no difference in overall survival between the groups. Finasteride is not a proven way to prevent prostate cancer.\u003c\/p\u003e\n\u003ch3\u003eWhat are transdermal oestradiol patches and do they work?\u003c\/h3\u003e\n\u003cp\u003eTransdermal oestradiol (tE2) patches are licensed for hormone replacement therapy in post-menopausal women and are being tested as hormone therapy for prostate cancer. In the PATCH programme, tE2 patches achieved equivalent androgen suppression and similar cancer control compared with standard hormone injections. They also improved quality of life and bone mineral density, with fewer hot flushes. Final phase III results are still pending.\u003c\/p\u003e\n\u003ch3\u003eDoes aspirin prevent prostate cancer or its return?\u003c\/h3\u003e\n\u003cp\u003ePooled data from case-control and cohort studies suggest aspirin may reduce the risk of a prostate cancer diagnosis, but one trial in older adults found higher cancer-related deaths in the aspirin group. The ADD ASPIRIN trial is testing aspirin after radical treatment in 1,917 men, with results expected in 2027. Aspirin is not yet proven for either purpose.\u003c\/p\u003e\n\u003ch3\u003eWhy do repurposed drugs still need large trials?\u003c\/h3\u003e\n\u003cp\u003eEven though repurposed drugs have known safety profiles and are often cheaper, they must show benefit in randomised phase III trials before becoming standard treatments. The evidence bar is the same as for new drugs. Many repurposed drugs have failed to show benefit, and reducing cancer diagnoses does not always translate into improved overall survival, as seen with finasteride.\u003c\/p\u003e\n\u003ch3\u003eI have low-risk prostate cancer on active surveillance — when should I get a second opinion about joining a trial of a repurposed drug like metformin?\u003c\/h3\u003e\n\u003cp\u003eA second opinion is reasonable when you are weighing active surveillance against a trial of an existing medicine such as metformin. The MAST trial tested metformin 850 mg twice daily versus placebo in men with low-risk, localised disease and found no difference in progression-free survival, so the option is not established. A review can confirm your Gleason score, core involvement and PSA fit trial eligibility, and clarify whether surveillance alone or a trial is appropriate. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Drug re-purposing to improve outcomes in the management of prostate cancer - aims, outcome measures and design of current phase III trials.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Gilbert DC, Langley RE, Ayadi D, Berhanu M, Hemanth LK, Kwon S, Abdallah H, Meade A, Clarke N, Gillessen S, James N, Bouche G, Parmar M, Nankivell M, Murphy L.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e BMC Pharmacology and Toxicology (2026) 27:35\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e https:\/\/doi.org\/10.1186\/s40360-025-01077-w\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c\/strong\u003e Not applicable (this is a review article)\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eKeywords:\u003c\/strong\u003e Prostate cancer, Repurposing, Phase III randomised controlled trials\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research. 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