Prostate cancer is the second most common cancer in men worldwide. It has been estimated that 175,000 men will be diagnosed with prostate cancer and 32,000 will die from the disease in 2019 in the USA.1 The majority (around 95%) of men have localised disease, diagnosed through prostate-specific antigen (PSA) screening. Most cases are cured by surgery or radiation, and some need no treatment. The remaining 5% are diagnosed with aggressive disease, and many other patients relapse after treatment for localised disease but tend to have slower disease progression.1
Since the discovery of androgen deprivation therapy (ADT) by Charles B. Huggins in 1966, hormonal therapy has been a mainstay in the treatment of advanced prostate cancer.2 However, many prostate cancers ultimately fail to respond to ADT and are termed castrate-resistant prostate cancer (CRPC). The past decade has seen the emergence of highly effective treatment options, including docetaxel, and the androgen receptor-axis-targeted therapies abiraterone acetate (ZytigaÒ, Janssen), enzalutamide (XtandiÒ, Astellas Pharma) and apalutamide (ErleadÒ, Janssen) for CRPC.3 More recently, these agents have shown efficacy in the earlier, hormone-sensitive prostate cancer (HSPC) treatment setting.4
One of the major talking points at the 2019 ASCO meeting, which was held from 31 May to 4 June 2019 in Chicago, Illinois, was an interim analysis of the ENZAMET trial (NCT02446405), which is investigating the efficacy and safety of enzalutamide, compared with a conventional non-steroidal anti-androgen (NSAA; bicalutamide, nilutamide or flutamide) when combined with standard-of-care ADT for newly diagnosed metastatic HSPC (mHSPC).5 Investigators randomly assigned 1,125 men to receive enzalutamide or NSAA plus standard-of-care therapy. The treatment groups were well balanced for all important baseline factors.
The results showed that after 3 years the overall survival (OS) was 80% in men who received enzalutamide, compared with 72% of men who received a NSAA (hazard ratio [HR] 0.66; p=0.002). In addition, time to PSA rise, clinical progression or death (HR 0.39; 95% CI, 0.33–0.47) and time to clinical progression (HR 0.40; 95% CI, 0.33–0.49) were both higher in the enzalutamide group than the NSAA group. Among the men with high-volume disease the OS was 71% and 63% for the enzalutamide and NSAA arms, respectively (HR 0.78). Among the 529 men with low-volume disease, the OS was 90% and 82% in the enzalutamide and NSAA groups, respectively (HR 0.48). Among the patients who received enzalutamide without docetaxel, the OS was 83% compared with 70% in those taking another NSAA (HR 0.51), and the time to clinical progression was longer in the enzalutamide group (HR 0.34). Of those taking docetaxel, enzalutamide significantly improved time to clinical progression among men receiving docetaxel (HR 0.48; 95% CI, 0.37–0.62), but did not improve OS (HR 0.90). At the time of this analysis, 64% of the enzalutamide group remained on treatment compared with only 36% of men in the NSAA group. Serious adverse events (AEs) were reported in 42% of the men receiving enzalutamide and 34% of the men taking one of the other NSAAs.5
One important question that the trial aimed to answer was whether enzalutamide would be beneficial for men who are candidates for docetaxel, which was given to about 45% of the trial participants. The results showed that in this population, enzalutamide and docetaxel were both effective, and the choice of therapy will depend on side effects, costs, risks and benefits. Early analysis indicates that, among men with lower disease burden, enzalutamide may be more beneficial than docetaxel, but longer follow-up is needed.6
Lead author Christopher Sweeney of the Dana-Farber Cancer Institute, Boston, Massachusetts, commented: ‘Physicians and patients with prostate cancer now have a new treatment option with enzalutamide, and this is especially relevant for men who cannot tolerate chemotherapy and have a lower burden of disease seen on scans’.6
The first results were also presented from TITAN (NCT02489318), a Phase III study that investigated apalutamide in the same treatment setting.7 In this study, 1,052 patients with metastatic castrate-sensitive prostate cancer were randomly assigned to receive apalutamide or placebo plus ADT, regardless of the extent of disease. At the 22.6-month follow-up, progression-free survival (PFS) was not reached in the apalutamide treatment group compared with 22.8 months in the placebo group (HR 0.48; p<0.0001). Patients treated with apalutamide also had an increased OS compared with placebo (82.4% vs 73.5%; HR 0.67; p=0.0053) and an improvement in time to initiation of chemotherapy (HR 0.59; p<0.0001). At the time of this analysis, 66% of patients in the apalutamide group and 46% of patients in the placebo group were still receiving treatment. Grade 3/4 AEs were similar in both groups (42% in the apalutamide group and 41% in the placebo group). These led to treatment discontinuation in 8% in the apalutamide group and 5% in the placebo group.7 Based on the trial results, the independent data monitoring committee have recommended unblinding the study in order to allow those patients on placebo and ADT to receive the combination of apalutamide and ADT.
Lead author, Kim Chi, MD, of BC Cancer, Vancouver, British Columbia, said: ‘In the TITAN study in patients with metastatic castration-sensitive prostate cancer, including patients with high- and low-volume disease and prior docetaxel, [the] addition of apalutamide to ADT significantly improved, radiographic progression-free survival and overall survival, and the safety profile was tolerable. These results support the addition of apalutamide to ADT for [the] treatment of patients with metastatic castration-sensitive prostate cancer’.8
Although neither of these studies have given a definitive answer to which therapy should be used, it is clear that patients with newly diagnosed advanced HSPC will benefit from ADT plus a next-generation androgen receptor-axis-targeted therapy. These data will be combined with those of similar studies to provide a dataset of over 10,000 men. It is hoped that this will enable comparisons between different therapies to determine which men are likely to benefit the most from these treatments.6
There was also good news at ASCO for men with metastatic castration-resistant prostate cancer (mCRPC). Approximately 20–25% of mCRPC patients have alterations in DNA repair genes, particularly BRCA2, which means that they are likely to respond to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor therapy. The first part of a Phase II study (TOPARP-A; NCT01682772) involving unselected mCRPC patients, found a high response rate to the PARP inhibitor olaparib (LynparzaÒ AstraZeneca) in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes, including BRCA1/2, ATM, Fanconi’s anaemia genes, and CHEK2.9 At ASCO 2019, the results of TOPARP-B, in which patients were preselected for DNA damage repair gene alterations, were presented. All of the 92 evaluable patients had progressed on ADT; 99% had received docetaxel, 90% abiraterone/enzalutamide and 38% cabitaxel. Patients were randomly assigned to receive 400 mg or 300 mg of olaparib twice daily. At a median follow-up of 17.6 months, the ORR was 54% in the 400 mg cohort and 39% in the 300 mg cohort. Over a median follow-up of 17.6 months, the overall median PFS was 5.4 months. Response rates were highest in patients with BRCA1/2 mutations (ORR 80%; PFS 8.1 months). Among patients treated with the 300 mg dose, 12.2% required a dose reduction, while 26.7% discontinued therapy due to AEs. Among patients treated with the 400 mg dose, 36.7% required a dose reduction, while 10.4% discontinued therapy. Anaemia was the most common AE in both groups.10 These findings support the further investigation of olaparib in this treatment setting.
In summary, these presentations have highlighted the evolving treatment paradigm for mHSPC. In addition, advances in genetic profiling continue to identify clinically actionable mutations in men with mCRPC. In future, it is likely that further genetic alterations will be identified, allowing the development of new targeted therapies and elucidating mechanisms of resistance to existing agents. The therapeutic landscape in advanced prostate cancer is increasingly diverse, allowing a more personalised treatment approach.
- NIH Surveillance, Epidemiology and End Results Program (SEER). Cancer stat facts: prostate cancer. Available at URL https://seercancergov/statfacts/html/prosthtml Accessed 5 June 2019.
- Hansson N, Moll F, Schultheiss D, et al. Remembering Charles B. Huggins’ Nobel Prize for hormonal treatment of prostatic cancer at its 50th anniversary. Eur Urol. 2016;69:971–2.
- Albala DM. Imaging and treatment recommendations in patients with castrate-resistant prostate cancer. Rev Urol. 2017;19:200–2.
- Shah H, Vaishampayan U. Therapy of advanced prostate cancer: targeting the androgen receptor axis in earlier lines of treatment. Target Oncol. 2018;13:679–89.
- Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. J Clin Oncol. 2019;37(Suppl. 15):abstr LBA2.
- ASCO: ENZAMET. Addition of enzalutamide to standard of care in metastatic hormone-sensitive prostate cancer. 2019. Available at URL https://ascopostcom/News/60104 Accessed 5 June 2019.
- Chi KN, Agarwal N, Bjartell A, et al. First results from TITAN: A phase III double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). J Clin Oncol. 2019;37(Suppl. 15):abstr 5006.
- ASCO: TITAN study assesses apalutamide vs placebo during androgen-deprivation therapy for metastatic castration-sensitive prostate cancer. 2019. Available at URL www.ascopostcom/News/60096 Accessed 5 June 2019.
- Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708.
- Mateo J, Porta N, McGovern UB, et al. TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations. J Clin Oncol. 2019;37(Suppl. 15):abstr 5005)
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