Dr. Karim Fizazi then provided the argument for abiraterone in this clinical setting. As Dr. Fizazi points out, this patient fits the criteria of >95% men enrolled in the LATITUDE study: Gleason ≥8 disease, PS 0, and widespread metastases. LATITUDE demonstrated a 38% risk reduction of death and 53% risk reduction of progression/death for men treated with abiraterone + prednisone + ADT compared to ADT alone [1]. Additionally, STAMPEDE demonstrated a 39% risk reduction of death among patients treated with abiraterone + prednisone + ADT vs ADT alone [2].
Dr. Fizazi argues that in a meta-analysis of aggregate data among clinical trials assessing docetaxel in the mHSPC setting, the risk reduction of death was only 23% (HR 0.77, 95%CI 0.68-0.87) [3]. Additionally, in an updated survival analysis among CHAARTED patients [4], at a median follow-up 53.7 months the HR for OS was 0.72 (95%CI 0.59-0.89) favoring docetaxel over ADT standard of care, a 28% risk reduction of death compared to 39% in the first analysis [5]. Furthermore, using an indirect comparison approach to determine the relative efficacy of abiraterone vs docetaxel in mHSPC, abiraterone + prednisone + ADT had a greater reduction in risk of progression and death compared to docetaxel + ADT (Bayesian probabilities for abiraterone + prednisone + ADT: 86.8% probability of preferred treatment for OS and 99.2% for rPFS) [6]. Given the STAMPEDE trial design, recruitment of patients for the comparison of docetaxel + prednisone plus ADT versus ADT overlapped for 16 months with recruiting patients for abiraterone acetate + prednisone + ADT versus ADT. This allowed a comparison of randomized patients receiving docetaxel + ADT to those receiving abiraterone + ADT [7]. The analysis showed that failure free survival HR was 0.51 (95%CI 0.39-0.67), favoring abiraterone + prednisone + ADT.
A recently published analysis of the LATITUDE data assessing patient reported outcomes showed that patients receiving abiraterone + prednisone + ADT had improved overall outcomes showing a clinical benefit in the progression of pain, prostate cancer symptoms, fatigue, functional decline, and overall health-related quality of life [8]. Furthermore, as presented by Dr. Fizazi earlier during today’s prostate cancer poster session, the discontinuation of abiraterone was rare in LATITUDE, with only 1% of patients discontinuing therapy secondary to mineralcorticoid-related adverse events [9]. Dr. Fizazi concluded by highlighting the ongoing PEACE-1 phase III trial assessing standard of care (ADT +/- docetaxel) vs standard of care + abiraterone + prednisone vs standard of care + local radiotherapy vs standard of care + local radiotherapy + abiraterone + prednisone for men with de novo M1 prostate cancer. With an accrual target of 1156 patients, Dr. Fizazi reports that 963 patients have already been recruited. This trial will ultimately test whether ADT + abiraterone + docetaxel is even better than abiraterone + ADT or docetaxel + ADT.
Dr. Christopher Sweeney then had the opportunity to provide the argument for docetaxel in mHSPC. He notes that when choosing between docetaxel and abiraterone we must ask: (i) is the patient fit for docetaxel? (ii) does the patient have a high enough burden of disease to potentially benefit from early docetaxel?
Dr. Sweeney highlighted several interesting observations of the ADT + docetaxel trials with longer follow-up:
- GETUG15 [10] was conducted in an era when there was less access to life-prolonging CRPC therapies than when CHAARTED and STAMPEDE were conducted, however there was a similar impact on time to progression
- Long-term follow-up of CHAARTED patients shows that the hazard ratio for OS lessens with time as the lack of treatment effect in low volume patients diluted the overall effect, solidifying that there is no benefit in low volume patients [4]
- Tests for heterogeneity of impact from docetaxel within M1 patients – there is a differential effect seen in M1 high volume vs low volume within CHAARTED and GETUG15, showing that CHAARTED and GETUG15 are homogenous. Conversely, STAMPEDE had no test for heterogeneity despite low volume and high volume patients being grouped within M1
Utilizing the STAMPEDE data indirectly comparing randomized patients receiving docetaxel + ADT vs abiraterone + ADT [7], Dr. Sweeney notes that conclusions from this study included (i) strong evidence favoring abiraterone acetate + prednisone + ADT to delay PSA rise, and (ii) weak evidence favoring abiraterone acetate + prednisone + ADT to delay radiographic progression. However, Dr. Sweeney argues that there is proportionately different amount of time spent in each disease state because the androgen receptor is targeted more intensely and longer with abiraterone compared to the shorter treatment duration for docetaxel. Several network meta-analyses [6,11] indirectly comparing docetaxel and abiraterone have suggested that abiraterone is favored, however Dr. Sweeney points out that these studies are limited by including GETUG15 which had limited access to life prolonging therapies in CRPC and that abiraterone had an inherent positive bias by having a greater proportion of poor risk patients with a clear treatment effect with short follow-up.
Dr. Sweeney notes that there are significant cost differences when considering docetaxel or abiraterone. Using a hypothetical example of 100 patients with mHSPC, six cycles of upfront docetaxel (including visits, infusion and cost of the drug) would cost $10,000 per patient. By subsequently adding abiraterone for an eventual rising PSA associated with CRPC ($8,000/month USD; with a median time to progression to CRPC of 18 months), this would cost $144,000 per patient, thus roughly $15 million to treat 100 patients with upfront docetaxel. If one were to consider upfront abiraterone at median time to progression of 36 months (at $8,000/month USD) + $10,000 for post-abiraterone docetaxel, the total cost would be $30 million to treat 100 patients.
Dr. Sweeney acknowledges that it is “unfashionable” to propose the more “toxic” therapy upfront, but for the patients with high volume disease and fit for chemotherapy, docetaxel is completed in 18 weeks, as are short term adverse events. Furthermore, he argues that we need to get the docetaxel in before the patient becomes too frail, considering that abiraterone can be added on more easily than docetaxel at a later time point if the patient becomes frail. Finally, there is less overall long-term treatment and cost burden with upfront docetaxel with similar OS efficacy.
Presented by: Karim Fizazi, MD, PhD Institut Gustave Roussy, Villejuif, France; Christopher Sweeney, MBBS, Dana-Farber Cancer Institute, Boston, MA
Moderator: Nicholas van As, MBBCH, MRCP, FRCR, MD(res), The Royal Marsden Hospital, London, UK
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
References:
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3. Vale CL, Burdett S, Rydzewska LHM, et al. Addition of docetaxel or bisphosphonates to standard of care in men with localized or metastatic, hormone-sensitive prostate cancer: A systematic review and meta-analyses of aggregate data. Lancet Oncol. 2016;17(2):243-256.
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