Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial
Kyriakopoulos CE et al., J Clin Oncol. 2018 Jan 31:JCO2017753657..
PubMed ID: 29384722
Interim analysis of the phase III E3805 (CHAARTED) trial revealed that docetaxel with androgen deprivation therapy (ADT) significantly prolonged overall survival (OS) by 13.6 mos. (HR 0.61; p <0.001) over ADT alone as first line treatment in metastatic hormone-sensitive prostate cancer (mHSPC). The greatest OS benefit was observed in the group with high-volume disease (65%), where OS was extended by 17 mos. However, for low-volume disease, median OS was not reached at the time of analysis. The study was powered for OS analysis of the entire population and not the subgroups. Further follow-up was conducted and updated analysis for the study is summarized below.
- Patients: Prostate cancer (pathologically proven or significantly elevated PSA), radiologic evidence of metastatic disease, ECOG 0-2 (ECOG 2 allowed if functional decline was due to prostate Ca). Prior adjuvant ADT allowed if ≤24 mos. of therapy and progression occurred >12 mos. after completing therapy. Patients on ADT for metastatic disease were eligible in the absence of progression and if ADT commenced within 120 days prior to randomization.
- Study design: Phase III, RCT
Initially only high-volume disease: presence of visceral metastases or ≥ 4 bone lesions with ≥ 1 beyond vertebral bodies and pelvis. Subsequently low-volume patients also enrolled
- Control: ADT alone
- Experimental: ADT with Docetaxel 75 mg/m2 q3 wks. x 6 cycles
(daily prednisone not required)
- Primary: OS
- Secondary: PSA response, change in PSA over time, time to refractory disease, time to clinical progression, time to PSA progression, toxicity
- 790 randomised and analysed by ITT
- Interim analysis revealed Grade 3 or higher AE’s in docetaxel + ADT arm: neutropenic fever-6%, infection with neutropenia-2%, fatigue-4%, allergic reaction-2%, thrombotic event-1%, diarrhea, stomatitis, neuropathy (motor and sensory) - ≤1%
- No additional long-term side effects were reported.
TABLE 1: Efficacy Endpoints
Table 2: Overall Survival
Table 3: Clinical Outcomes
- Updated analysis of the CHAARTED trial at a median follow-up of 53.7 mos. demonstrated that survival benefit with the addition of docetaxel to ADT was sustained and undiminished with additional follow-up. Combination therapy extended survival by 10.4 mos. in patients with high-volume mHSPC.
- The advantage that was initially observed in the high-volume group was confirmed with longer follow-up, moreso for de novo disease than PLT. Overall, OS improved by 16.8 mos. while the risk of death was reduced by 37%. No survival benefit was found in the low-volume group even with longer follow-up.
- A similar trend was observed for time to CRPC and clinical progression, which both favored docetaxel with ADT compared to ADT alone. Time to PSA rise or disease progression was delayed by 7.7 mos. overall and by 6.3 mos. in the high-volume group.
- Patient accrual in CHAARTED was slow in the beginning and although the trial initially focused on high-risk patients, low-risk patients were later on added to the study population. Subgroup analysis by disease volume was not adequately powered, although it was preplanned. Heterogeneity test confirmed interaction between disease volume and treatment. The study defined high volume disease as visceral metastasis or ≥ 4 bone metastases to avoid misclassification to high-volume disease among patients with ≤ 3 sites, even if one lesion was beyond the vertebrae and pelvis.
- The phase III GETUG-AFU 15 trial randomized 380 patients with newly diagnosed metastatic prostate cancer to ADT with or without docetaxel (Eur Urol 70:256-262, 2016). Updated analysis at a median follow-up of 84 mos. showed nonsignificant improvement in OS with docetaxel and ADT vs. ADT alone (62.1 vs 48.6 mo, HR 0.88, p = 0.3). This result could be attributed to heterogeneity in the study population. CHAARTED trial had more patients with high-volume disease and poor prognosis [e.g. high Gleason score, higher PSA levels]; more patients in the ADT with docetaxel arm received subsequent therapy compared to GETUG-AFU 15 trial.
- GETUG-AFU 15 trial had a similar definition of disease volume and time at metastasis (at diagnosis or after prior local therapy) as the CHAARTED trial. Gravis and colleagues synthesized data from these two trials, focusing on OS by subgroups (Eur Urol , https:// doi.org/10.1016/j.eururo.2018.02.001). They found significant heterogeneity in effect sizes of ADT with docetaxel vs. ADT alone between low and high-volume disease (p=0.017) but not between upfront and PLT groups. Consistent OS advantage was found in patients with high volume disease who received docetaxel with ADT compared to ADT alone (pooled HR=0.68, p<0.001). No survival benefit was seen in the low-volume disease subgroup.
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- In summary, longer follow-up of the CHAARTED trial confirmed initial findings of survival benefit with early addition of docetaxel to ADT compared to ADT alone in patients with mHSPC and high burden of disease. For low-volume disease, ADT alone seems to be adequate treatment, until studies reveal OS benefit with newer drugs or drug combinations. There are no head-to-head comparisons of docetaxel to abiraterone which is now also approved for this indication with high risk disease. Certainly abiraterone is likely better tolerated than docetaxel, however it is much more expensive
Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer
Van Driel WF et al., N Engl J Med. 2018 Jan 18;378(3):230-240..
PubMed ID: 29342393
Cytoreductive surgery and chemotherapy is standard of care treatment in newly diagnosed advanced ovarian cancer, with the goal of reducing tumor burden and enhancing drug penetration in the peritoneum. Hyperthermic intraperitoneal chemotherapy (HIPEC) was shown to induce apoptosis and inhibit angiogenesis. Cytoreductive surgery with HIPEC is feasible in stage III ovarian cancer. However. the efficacy of this combination has not been well investigated. To address this issue, researchers conducted a trial looking at the efficacy and safety of interval cytoreductive surgery with or without HIPEC in advanced ovarian cancer.
- Patients: histologically confirmed newly diagnosed stage III epithelial ovarian, fallopian tube, or peritoneal cancer not eligible for primary cytoreductive surgery due to extensive abdominal disease or with one or more residual tumors measuring >1 cm in diameter postop, ECOG 0-2.
- Study design: Phase III, Open-label RCT
- Experimental: Interval cytoreductive surgery + HIPEC (Cisplatin 100 mg/m2)
- Control: Interval cytoreductive surgery
* Patients who received neoadjuvant Carboplatin AUC 5 or 6 + Paclitaxel 175
mg/m2 x 3 cycles could be registered prior to cytoreductive surgery.
- Primary: RFS
- Secondary: OS, HRQOL, safety
- 245 patients randomized to surgery + HIPEC (n=122) and surgery alone (n=123)
- Baseline patient characteristics: median age 62 yrs., 90% high grade serous type, 90% no previous surgery, 68% with 0 to 5 regions affected prior to cytoreductive surgery, 68% R.1, no visible tumor, complete cytoreduction, 76% with no bowel resection, 32 days median time between surgery and first cycle of adjuvant chemotherapy, 92% completed 3 cycles of adjuvant chemotherapy.
Table 1: Efficacy Outcomes
Table 2: Adverse Events and Treatment Summaries
- Most common grade 3-4 adverse events in both arms: abdominal pain, infection, ileus
- Rates of postop complications did not differ between treatment arms.
- QOL was comparable between both treatment arms.
- At a median follow-up of 4.7 yrs., the addition of HIPEC to cytoreductive surgery delayed disease recurrence by 3.5 mos. compared to surgery alone in stage III ovarian cancer with at least stable disease after neoadjuvant chemotherapy.
- Surgery with HIPEC resulted in better survival compared to surgery alone. OS was extended by 11.8 mos. and treatment reduced the risk of death by 33%. This advantage was consistent across all pre specified subgroups.
- The addition of HIPEC with surgery did not appear to increase toxicity. No significant differences in grade 3-4 adverse events and bowel resection rates were observed between treatment arms. However, more patients had a colostomy/ileostomy with surgery + HIPEC (p=-0.04). QOL was maintained despite the addition of HIPEC with surgery.
- In the GOG-172 trial, patients with stage III ovarian carcinoma or primary peritoneal carcinoma with no residual mass greater than 1.0 cm were randomized to paclitaxel IV followed by either cisplatin IV or intraperitoneal cisplatin (N Engl J Med 2006; 354: 34-43). Intraperitoneal therapy improved PFS (23.8 vs. 18.2 mos., p=0.05) and OS (65.6 vs. 49.7 mos.; p=0.03) compared to IV therapy with cisplatin. Although OS was longer compared to the van Driel trial, only 42% completed the planned 6 cycles of intraperitoneal therapy. Furthermore, patients in the van Driel trial received a single intraperitoneal infusion and the study design and patient characteristics were different.
- In summary, this study revealed that HIPEC with surgery provided significantly better survival outcomes, leading to a 3-yr. OS rate of 62% compared to surgery in patients with stage III ovarian cancer not eligible for primary cytoreduction and with response to neoadjuvant chemotherapy.
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