ASCO 2018: Judicious Use of Therapeutics and Imaging in Early-Stage Prostate Cancer

Chicago, IL (UroToday.com) Following three excellent prostate cancer oral abstracts presented this afternoon at the ASCO 2018, Dr. Felix Feng from UCSF presented an engaging discussion of the implications of the findings presented today.
As Dr. Feng notes, there is rationale for intensifying therapies for prostate cancer patients. Mechanisms that confer resistance to ADT can be present prior to any treatment (innate) or can occur following treatment (acquired). Furthermore, resistant clones are either selected for or emerge when ADT is used. We have phase III evidence demonstrating that docetaxel confers an OS benefit in the metastatic hormone sensitivity setting [1-2], as well as in the mCRPC setting [3]. Similarly, there is level 1 evidence demonstrating that abiraterone confers an OS benefit in the metastatic hormone sensitivity setting [4-5], as well as in the mCRPC setting [6-7]. Thus, there is rationale that both docetaxel and abiraterone could be tested earlier in the adjuvant/early recurrence disease space.

As Dr. Feng notes that in the SPCG-13 trial presented today, there was no difference between adjuvant docetaxel and surveillance after intermediate/high risk radiotherapy with regards to the primary outcome of BDFS (p = 0.631). The HR for the docetaxel arm vs surveillance arm was 1.14 (95%CI, 0.79-1.64). Dr. Feng notes there is precedence for adding docetaxel in this setting, given that in the RTOG 0521 study (ADT + RT vs ADT + RT + docetaxel) there was no significant difference between the groups with regards to BCR (p=0.19) or OS (p=0.04, one-sided), however there was a separating of the curves in both outcomes after 3-4 years. These trials were similar, however RTOG 0521 had higher-risk patients than those in SPCG-13, and they used longer duration of ADT. Based on the use of docetaxel in other disease state settings, Dr. Feng has developed the following excellent pictorial representation of the benefit-risk ratio on the y-axis and stage of disease progression on the x-axis, with the parabola representing docetaxel treatment:
image.png

With regards to abiraterone, Dr. Efstathiou and colleagues showed that adding 8 months of AA to ADT resulted in a median PSA free survival of 28.3 months (range 24.2—35.4) vs 21.1 (19.1-27.2) for ADT patients alone (HR 0.62, 95%CI 0.44-0.88). Secondly, median time to testosterone recovery for AA + ADT was 13.1 months (95%CI 13.0-13.3) vs 12.9 (95%CI 11.0-13.1) for ADT, and finally median time to PSA relapse following testosterone recovery for AA + ADT was 13.8 months vs 9 months for ADT (HR 0.70, 95%CI 0.49-1.00). Several points that Dr. Feng made regarding this trial:
This trial was positive for its primary endpoint of PSA RFS
If this difference in PSA relapse-free survival meaningful? Ultimately and importantly, will this translate to differences in MFS or OS?
We need to improve upon a 21% in in PSA-relapse survival. Considerations for doing this include increasing the duration of each cycles, the number of cycles, intensifying androgen-directed therapy, etc
This is an important hypothesis-generating works that bears further exploration and optimization

Similar to the above diagram for docetaxel, Dr. Feng provides a pictorial representation of the benefit-risk ratio for abiraterone treatment:

image 35b

As noted at the peak of the parabola for both the docetaxel and abiraterone curves, there is opportunity to better define this disease space, which transitioned Dr. Feng into discussing the study presented by Dr. Fendler and colleagues using 68Ga-PSMA11 PET/CT to detect recurrent prostate cancer. Several highlights of this trial include:
• Detection of a lesion in ~40% of patients with PSA < 0.5
• 78% detected lesions were not a local recurrence
• The PPV was 85% validated by histopathology
• 78% of 23 patients receiving lesion-directed therapy had a PSA response of >50% or PSA undetectable

These are promising numbers, according to Dr. Feng and he postulates how these results would compare to Axumin PET in the same patients.
Dr. Feng concluded his discussion with several conclusions:
• While there is strong rationale for intensifying systemic therapy for M0 prostate cancer, better patient selection is necessary to optimize the benefit-to-risk ratio of treatment intensification
• Imaging and genomic approaches are promising strategies to improve patient selection
• Additional trials, with more robust endpoints, are needed to demonstrate the benefit of treatment intensification in earlier stage prostate cancer

Presented by: Felix Feng, Departments of Radiation Oncology, Urology, and Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md, at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References:
1. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
2. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177.
3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-1512.
4. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351.
5. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.d
6. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.
7. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.