The word is out that a survival benefit accrues when either abiraterone (Zytiga) plus prednisone (AA/P) or docetaxel (Taxotere) are added to standard androgen deprivation therapy (ADT) in the treatment of de novo metastatic hormone sensitive prostate cancer and also in advanced non-metastatic disease at diagnosis. Two recently published major trials, STAMPEDE and LATTITUDE, and an earlier 2014 trial, CHAARTED, demonstrated this point.
The second development is the newly available Axumin® PET/CT imaging which yields a high detection rate in recurrent disease after primary therapy, and, potentially, in staging high-risk disease at diagnosis. The Axumin scan PCa Commentary Vol 116 (control+click link to follow) has demonstrated that the tumor burden in prostate cancer is often more extensive than is detected by the less sensitive traditional imaging techniques, such as CT or technetium bone scans.
This Commentary will explore the management implications of combining the greater sensitivities of the Axumin scan with the application of either of the new systemic treatments for de novo metastatic prostate cancer and recurrent disease.
Metastatic Cancer at Diagnosis:
The incidence of de novo metastatic prostate cancer in the US is estimated to be ~4-6%, but will be on the increase due to the 2011 USPSTF recommendation to avoid PSA screening. Already studies have shown a greater percentage of Gleason 8-10 cancers since 2014 (Gejerman et al., Investigative and Clinical Urology, Nov 2017). If staging of aggressive cancer on biopsy utilized the Axumin scan the detection of early metastasis would likely be significantly higher.
There is sound biologic rationale for moving the bigger guns earlier in the regimen of treatment, as opposed to sequential usage. At all stages of prostate cancer the mutational clock is ticking, with the cancer acquiring random or therapy induced mutations that may confer increased aggressiveness and frustrate effective treatment. This progressive acquisition of adverse mutations is a recognized downside of ADT, during which depressed androgen levels induce treatment-resistant permutations in the androgen receptor. Hence the rationale of the strategy of applying the most effective therapy early so as to optimally pre-empt the mutational cascade.
The early inclusion of docetaxel potentially may address the heterogeneity of prostate cancer wherein some cells are resistant to ADT at the onset. A practical consideration arguing for up-front chemotherapy is that it may be better tolerated at the beginning of treatment.
Current Axumin Usage:
The role of Axumin PET/CT imaging in men at PSA relapse after primary therapy has been extensively studied. These men can be diagnosed with significant metastatic disease when scanned at PSA levels slightly above the conventional PSA relapse thresholds of >0.2 ng/mL for surgery and well below the metric of PSA nadir + 2.0 ng/mL for radiation.
A recent report addressed this issue: “Multisite Experience of the Safety, Detection Rate and Diagnostic Performance of Fluciclovine (18F)PET/CT [i.e. Axumin] Imaging in the Staging of Biochemically Recurrent Prostate Cancer,” Bach-Gansmo et al., J Urol, Mar 2017. A total of 596 men with predominantly high-risk cancer had received the Axumin scan “for the detection of suspected BCR [i.e. PSA relapse] after surgery or radiation. The validity of the scan interpretation was checked against post-prostatectomy histologic findings in 143 men.
- “Positive scans were detected in the prostate/bed and pelvic lymph nodes in 38.7% (232 of 599) and 32.6% of scans (194 of 596), respectively.”
- Metastatic involvement outside of the pelvis was detected in 26.2% of scans, including skeletal sites in 9% (55 of 610), although an eligibility requirement for inclusion in the study was a negative bone scan.
- The detection rate in the men with baseline PSA values of 0.79 ng/mL or less was 41.4% (53 of 128) and of this group 24% had distant metastases. In the PSA cohort with PSA values 0.8-2.0 ng/mL the whole body detection rate was 60%.
A View to the Future:
Although the Axumin scan is currently FDA approved for use only in men with recurrent prostate cancer, its capabilities would seem to offer valuable information in staging men with high-risk and aggressive disease at biopsy, thus providing data that might influence management decisions. A substantial number of these men would likely show “de novo” metastatic disease, making them candidate for early treatment with one of the combination therapies to be discussed below.
A protocol, NCT03081884, at Emory University addresses the earlier application of the Axumin scan (also known as FACBC). The protocol’s goal: “… is to determine if FACBC PET will detect significant occult metastatic disease in patients with high-risk primary prostate carcinoma who have negative or equivocal conventional imaging such as CT and/or MRI and bone scan.”
STAMPEDE AND LATTITUDE Trials:
Two very large, well done recent studies agree on a straightforward message: the combination of standard androgen deprivation therapy (ADT) with abiraterone (Zytiga)/prednisone or ADT plus docetaxel both prolong overall survival (OS) compared to ADT alone as treatment for men diagnosed de novo with metastatic prostate cancer.
1) STAMPEDE (ADT + docetaxel vs ADT alone): James et al, Lancet, Mar 2016 reported on overall survival in 2962 men treated between 2005 and 2013, 52% metastatic disease at diagnosis and 48% with non-metastatic locally advanced cancer, of which 28% had no nodal spread. Docetaxel was given for six 3-week cycles. ADT was continued for a minimum of 2 years in both arms.
- The study found a 37% improved overall survival (OS) in the group receiving docetaxel /ADT vs ADT alone in men with metastatic disease at diagnosis resulting in a median 10 month increase in OS. Prostate-cancer specific survival and skeletal-related events also were improved in the combined therapy group.
Authors’ conclusion: “Standard of care should be updated to include docetaxel chemotherapy in suitable patients with metastatic disease [at diagnosis] …”
- A recent 2017 update of the STAMPEDE study was presented at the European Society of Medical Oncology. Dr. James detailed the outcome for 915 men who had locally advanced cancer at diagnosis but were staged free of metastases. In this more favorable group OS data is immature. The intermediate endpoint used is “failure-free survival” (FFS) defined as PSA progression, progression locally, in lymph nodes, or distant metastases or death from prostate cancer.
Findings: At 3 years, FFS for men on combined therapy was 98% vs 80% for ADT alone, suggesting to the authors that “docetaxel may be considered for men with high-risk
non-metastatic prostate cancer with or without radiotherapy.”
The STAMPEDE trial was conducted using CT and technetium bone scans for staging at diagnosis and recurrence. In keeping with greater sensitivity of Axumin PET/CT scan (as is also the case with the (68)Gallium-PSMA PET/CT scans), many men in the “non-metastatic” group could be expected to have shown metastases, especially since inclusion in this cohort of the study required at least 2 of 3 features: clinical stage,T3/4; Gleason score 8 – 10; or PSA > 40 ng/ml.
A presentation at ASCO in June 2014 gave the first indication of the survival benefit for the combination regimen of docetaxel/ADT vs ADT alone in men with metastases at diagnosis. The “CHAARTED” study of 790 men reported an OS of 52.7 months for combined therapy vs 44.0 months, ADT alone. This outcome was best seen in men with a heavy burden of disease.
“Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated with upfront chemo-hormonal therapy for metastatic hormone-naive prostate cancer,” as was reported in a European study similar to STAMPEDE. (Lavaud et al., European Urology, 2017)
2) LATTITUDE (abiraterone/prednisone plus ADT vs ADT alone): Fizazi et al., NEJM June 2017, echoes the conclusions in STAMPEDE and CHAARTED. The LATTITUDE study only enrolled men with newly diagnosed, metastatic castration-sensitive prostate cancer. Randomization of 1199 men was 1:1 between the two treatment arms. The end points were overall survival and radiographic progression.
At 30.4 months of follow-up the combination treatment showed a 38% better overall survival. Radiographic progression was delayed in the combined therapy group to a median of 33 months vs 14.8 months for ADT alone. Men failing ADT alone were allowed crossover to the combined treatment.
Staging of prostate cancer at diagnosis and recurrence with conventional CT and bone scans substantially underestimates the burden of disease. The greater sensitivity of the Axumin scan, or ((68)Ga-PSMA PET/CT scan), can provide an earlier detection of metastatic disease at PSA recurrence in men with rising PSA following definitive therapy, and, potentially in men with high risk prostate cancer at diagnosis. Three studies document the benefit of early application of combined therapy in men in these situations resulting in a survival advantage as compared to ADT alone.
Integrating new imaging technology and new research findings promises to improve the clinical management of prostate cancer.