Actual Benefit of Chemo-hormonal Therapy in Non-castrate Metastatic Prostate Cancer

Mehmet AN Şendur; Muhammed Bülent Akıncı; Nuriye Yıldırım Ozdemir; Sercan Aksoy; Didem S Dede; Arife Ulas; Nurullah Zengin; Bülent Yalçın

Disclosures

Future Oncol. 2015;11(8):1141-1143. 

Prostate cancer is the most common diagnosed cancer and second leading cause of cancer deaths in men.[1] In advanced or metastatic prostate cancer, androgen deprivation therapy (ADT) is universally accepted as the initial treatment choice.[2] However, many patients will relapse and become resistant to further hormone manipulations and the outcomes of these patients are poor. Duration of response to hormonal manipulation is generally between 24 and 36 months.[3] ADT can be done with surgical castration (bilateral orchiectomy) or medical castration (luteinizing hormone-releasing hormone). Although ADT is the gold standard of initial therapy for patients with metastatic prostate cancer, most of the patients become resistant to castration.

In the randomized Phase III SWOG 99-16 trial, the primary end point overall survival (OS) was improved from 15.6 to 17.5 months in the docetaxel plus estramustine arm compared with the mitoxantrone and prednisone arm in 674 castration-resistant metastatic prostate cancer patients (p = 0.02).[4] In another randomized Phase III TAX 327 trial, the primary end point OS was also improved from 16.5 to 18.9 months in the docetaxel plus prednisone every 3-week arm compared with the mitoxantrone plus prednisone arm in 1006 castration-resistant metastatic prostate cancer patients (p = 0.009).[5] In the survival update data of TAX 327 trial, the survival benefit was still continued in the docetaxel plus prednizone every 3-week arm compared with mitoxantrone plus prednisone arm (19.2 vs 16.3 months; p = 0.004).[6] Thus, taxanes is the standard treatment approach in metastatic castration-resistant prostate cancer.[2]

Due to most of the patients becoming resistant to castration with ADT, two randomized trials that were recently published aimed to investigate the combination of docetaxel with ADT in treatment-naive metastatic castration prostate cancer.[7,8] In a randomized, open-label, Phase III (GETUG-AFU 15) trial, 385 patients with treatment-naive hormone-sensitive metastatic prostate cancer were randomized to either ADT plus docetaxel or ADT alone.[8] Docetaxel was permitted to give up to nine cycles. The primary end point of this study was OS, whereas secondary end points were time to clinical progression or death (clinical progression-free survival [PFS]) and time to prostate-specific antigen (PSA) progression, clinical progression, or death and biochemical PFS. The median age of the participants were 63 years (range: 57–84 years), median PSA was 26.7 ng/ml (range: 5.0–26.9 ng/ml), Gleason score ≥8 was reported in 57% of the patients. Bone metastasis were reported in 81% of the patients and visceral organ metastasis were reported in 14.5% of the patients. The median number of applied docetaxel cycles was 8. Median OS was 58.9 months and 54.2 months in ADT plus docetaxel and ADT arms, respectively, with a median 50-month follow-up (p = 0.955). The median time to subsequent treatment was significantly improved with ADT plus docetaxel compared to ADT alone arm (20.0 vs 15.4 months; p = 0.0015). Median biochemical PFS was significantly longer in ADT plus docetaxel group compared with ADT alone group (22.9 vs 12.9 months; p=0.005). In addition, median clinical PFS was also significantly longer in ADT plus docetaxel group compared with ADT alone group (23.5 vs 15.4 months; p = 0.015). Grade 3–4 adverse events were reported significantly higher in ADT plus docetaxel arm. The most common grade 3–4 adverse events were neutropenia (32%), febrile neutropenia (7%) and fatigue (7%) in ADT plus docetaxel arm. Doses of docetaxel were reduced in 21 (11%) of the patients who received docetaxel.

In a recent reported randomized, Phase III E3805 trial, 790 patients with treatment-na-ve hormone-sensitive metastatic prostate cancer were randomized to either ADT plus docetaxel or ADT alone.[7] The primary end point of this study was OS. Patients were stratified according to the high-volume (visceral metastases and/or four or more bone metastases) versus low-volume disease, anti-androgen use beyond 30 days, age ≥70 versus <70 years, European Cooperative Oncology Group performance score 0–1 versus 2 and prior adjuvant ADT >12 versus ≤12 months. Median age of the patients was 63 years (range: 36–91) and 98% of the patients had European Cooperative Oncology Group performance score 0 or 1. High-volume disease was reported in 67 and 64% ADT plus docetaxel and ADT alone arms, respectively. The primary end point median OS was 57.6 and 44.0 months in the ADT plus docetaxel and ADT alone arms, respectively, with a median 29-month follow-up (hazard ratio [HR]: 0.61; 95% CI: 0.47–0.80; p = 0.0003). In the subgroup analyses patients with high-volume disease, median OS was 49.2 months and 32.2 months with docetaxel plus ADT and ADT arms alone, respectively (HR: 0.60, 95% CI: 0.45–0.81; p = 0.0006). In patients with low-volume disease, median OS had not been reached at the time of the primary analysis. Median time to clinical progression was also significantly improved from 19.8 to 32.7 months in the docetaxel plus ADT arm compared with ADT alone arm (HR: 0.49; 95% CI: 0.37–0.65; p < 0.0001).

Although both E3805 and GETUG-AFU 15 trials aimed to investigate the effect of addition of docetaxel to ADT in patients with non-castrate metastatic prostate cancer, two studies had obviously different results with same end point.[7,8] In the GETUG-AFU 15 trial, bone metastases were reported in 81% of the patients and visceral organ metastases were reported in 14.5% of the patients, whereas in the E3805 trial, high-volume disease, which defined visceral metastases and/or four or more bone metastases, was found in 67% of the patients. In the GETUG-AFU 15 trial, the secondary end points, such as PSA increase, biochemical PFS and clinical PFS, were improved with addition docetaxel to ADT. However, docetaxel is associated with some toxicities, the risk–benefit ratio for its early use in combination with ADT is clearly favor it for using in patients with high-volume metastatic prostate cancer despite no benefit in the GETUG-AFU 15 trial. Further follow-up of the E3805 trial and the subgroup analyses will define the exact role of this treatment combination on these patients.

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