Historically, the initial treatment of metastatic castration sensitive prostate cancer (mCSPC) has been suppression of testicular production of testosterone by androgen deprivation therapy (ADT).2 While most patients initially respond to ADT, the majority develop castration resistance and disease progression - which is the lethal phenotype of the disease and is typically associated with worsening of HRQoL. Therefore, there is a need to delay progression to metastatic castration-resistant disease.
Concurrent inhibition of the androgen receptor (AR), in addition to ADT, may provide a more complete blockade of androgen signaling than ADT alone. Apalutamide is an oral nonsteroidal AR inhibitor that blocks androgen-induced AR activation, prevents nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription (Figure 1).3 TITAN is a phase 3 randomized, double-blind, placebo-controlled, multinational trial evaluating the addition of apalutamide or placebo to ADT in men with metastatic castration-sensitive prostate cancer (mCSPC). TITAN enrolled a broad patient population with mCSPC, including those with low- and high-volume disease, low- and high-risk disease, previous docetaxel use, and those who presented with de novo metastasis as well as who those who developed metastasis after prior therapy for localized prostate cancer.4 The addition of apalutamide to ADT provided a significant benefit in overall survival (33% reduction in the risk of death) and radiographic progression-free survival (52% reduction in the risk of progression or death (Figure 2) and 61% reduction in the need to initiate cytotoxic chemotherapy), compared with placebo plus ADT.4 Based on TITAN data, apalutamide is now approved in the United States for the treatment of patients with mCSPC in addition to its previous approval for nonmetastatic castration-resistant prostate cancer.5
Figure 1: Apalutamide mechanism of action.
This article was published in J Urol. Vol 200. Crawford DE, et al. Androgen Receptor Targeted Treatments of Prostate Cancer: 35 Years of Progress with Antiandrogens. p 956-66. Copyright Elsevier (2018).
Figure 2: Apalutamide significantly reduced the risk of radiographic progression and death compared with ADT alone.
A: TITAN radiographic progression-free survival: Apalutamide significantly reduced the risk of radiographic progression or death by 52% (HR = 0.48 [95% CI, 0.39-0.60]; p<0.001).
B: TITAN overall survival: Apalutamide significantly reduced the risk of death by 33% (HR = 0.67 [95% CI, 0.51-0.89]; p=0.005).
From The New England Journal of Medicine, Chi KM, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic Castration-Sensitive Prostate Cancer, 381:13-24. Copyright © (2019) Massachusetts Medical Society. Reprinted with permission
The time to pain progression was a secondary endpoint in TITAN; PRO-related endpoints for fatigue and HRQoL were prespecified exploratory analyses. PRO instruments were collected in a rigorous way using the Brief Fatigue Inventory (BFI), the Brief Pain Inventory-Short Form (BPI-SF), and the Functional Assessment of Cancer Therapy-Prostate (FACT-P).6 These instruments were administered at baseline, frequently during the treatment phase of the study, and at multiple time points after disease progression, providing an in-depth understanding of the patient experience.
Fatigue can be particularly debilitating and has been independently associated with pain and depression in patients with prostate cancer treated with ADT.7 Patients in TITAN were relatively asymptomatic at baseline with regard to fatigue. The group mean fatigue scores (based on the BFI) of patients on the TITAN trial remained stable throughout the trial in both the apalutamide- and placebo-treated groups, with no difference seen between the two groups (Figure 3).
Figure 3. Addition of apalutamide to ADT did not increase fatigue (intensity).
Group mean values for worst fatigue intensity. Median time to fatigue intensity progression not estimable. Time to progression in the 25th percentile, months (95% CI): apalutamide (APA), 9.2 (6.5-12.9); placebo (PBO), 11.0 (8.3-14.8); HR = 1.09 (95% CI, 0.88-1.35); p=0.4428.
Included with permission from Agarwal N, et al. European Society of Medical Oncology. 2019; Abstract #1910.
Multiple sensitivity analyses, as well as analysis of pain interference, showed that the time to pain progression consistently favored apalutamide (Figure 4).6 Median pain scores (BPI-SF) were low at baseline, and the median time to pain progression (worsening by ≥2 points with no decrease in opioid use, or initiation of chronic opioids) was not reached in either group. The 25th percentiles were 20.53 months (apalutamide) and 14.78 months (placebo).
Figure 4. Time to pain progression favored apalutamide.
Adapted with permission from Agarwal N, et al. Lancet Oncol. 2019;20:1518-1530.
Group mean HRQoL scores, based on FACT-P, were also similar between the treatment groups over time (Figure 5). The median time to deterioration of HRQoL was not different between the apalutamide and placebo groups.6
Figure 5. Based on FACT-P total scores, HRQoL was preserved with the addition of apalutamide to ADT.
Median time to deterioration, months (95% CI): APA, 8.9 (4.7-11.1); PBO, 9.2 (7.4-12.9); HR, 1.0 (95% CI, 0.9-1.2); p = 0.85.
Adapted with permission from Agarwal N, et al. Lancet Oncol. 2019; 20:1518-1530.
In conclusion, results from TITAN demonstrated that apalutamide plus ADT provided a significant improvement in overall survival and radiographic progression-free survival versus ADT alone,4 while preserving HRQoL.6 The improvements in survival and maintenance of HRQoL demonstrated in the TITAN trial indicate that treatment with apalutamide plus ADT is an excellent option for patients with mCSPC, regardless of disease burden and prior therapy.
Written by: Neeraj Agarwal,1 Kelly McQuarrie,2 Simon Chowdhury,3 Branko Miladinovic,4 Angela Lopez-Gitlitz,5 Kim N. Chi6
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
- Janssen Research & Development, Horsham, PA, USA
- Guy’s, King’s, and St Thomas’ Hospitals, and Sarah Cannon Research Institute, London, UK
- Janssen Research & Development, San Diego, CA, USA
- Janssen Research & Development, Los Angeles, CA, USA
- BC Cancer and Vancouver Prostate Centre, Vancouver, BC, Canada
- Aggarwal A, Ginsburg O, Fojo T. Cancer economics, policy and politics: what informs the debate? Perspectives from the EU, Canada and US. J Cancer Policy. 2014;2(1):1-11.
- Damodaran S, Lang JM, Jarrard DF. Targeting metastatic hormone sensitive prostate cancer: chemohormonal therapy and new combinatorial approaches. J Urol. 2019;201(5):876-885.
- Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72(6):1494-1503.
- Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24.
- ERLEADA [prescribing information]. Horsham, PA: Janssen Products, LP; 2019.
- Agarwal N, McQuarrie K, Bjartell A, et al. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2019;20(11):1518-1530.
- Storey DJ, McLaren DB, Atkinson MA, et al. Clinically relevant fatigue in men with hormone-sensitive prostate cancer on long-term androgen deprivation therapy. Ann Oncol. 2012;23(6):1542-1549.
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Watch: Patient-reported Outcomes from TITAN: Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer - Neeraj Agarwal