Update on taxanes for prostate cancer

From the 2013

Genitourinary Cancers Symposium

Recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC) have led to new agents demonstrating overall survival (OS) advantages, including autologous cellular immunotherapy (sipuleucel-T), a new taxane (cabazitaxel), 2 therapies further targeting the androgen axis (abiraterone acetate and enzalutamide), and a bone-seeking alpha emitter (radium-223 chloride). This brief review discusses recent clinical trials utilizing the 2 FDA-approved taxanes that were presented in Orlando, Fla., in February at the 2013 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncologists (ASCO), American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO).

Docetaxel updates 

Multiple agents have appeared promising based upon pre-clinical and early-stage clinical trials, but none have been successfully combined with docetaxel in phase 3 studies. Two additional phase 3 studies were presented at the 2013 Genitourinary Cancers Symposium.

Aflibercept is a recombinant fusion protein of vascular endothelial growth factor (VEGF) R1 and R2 binding regions that is FDA approved for advanced colorectal carcinoma. The VENICE (Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer) study was a randomized phase 3 trial utilizing docetaxel, prednisone, and aflibercept/placebo in men with CRPC who had not received prior chemotherapy.¹ The study was designed to show a 20% improvement in survival, but did not demonstrate a difference in OS with additional toxicity in the investigational (aflibercept-containing) arm. Dasatinib is an oral multikinase inhibitor, including the Src family. The READY (Randomized Study Comparing Docetaxel Plus Dasatinib to Docetaxel Plus Placebo in Castration-Resistant Prostate Cancer) study was a randomized, placebo-controlled phase 3 study of docetaxel, prednisone, and dasatinib/placebo in chemo-naïve men with metastatic CRPC.²  It failed to meet its primary end point of improved OS (21.5 vs 21.2 months; HR=0.99; P=.90), with secondary end points also negative (see Table 1).

Two additional combinations with docetaxel were presented.  Heath et al presented a randomized phase 2 study of docetaxel/prednisone with or without cediranib, an oral multikinase inhibitor, including VEGF receptors.³ The combination may have resulted in increased response, but also had significant enough toxicity to warrant dose reductions. A phase 1 study of the combination of docetaxel/prednisone and enzalutamide was also presented.⁴  This single-cohort study of full-dose drugs demonstrated that the combination was reasonably well-tolerated compared to historical controls and that the addition of enzalutamide did not significantly affect docetaxel pharmacokinetics.

Table 1:  Docetaxel combination studies

Abbreviations: Objective response rate (ORR); progression free survival (PFS)

Formulary/Source: Refs 1–4

Additional docetaxel studies examined different settings or schedules. A phase 3 trial of docetaxel-estramustine in high risk localized prostate cancer (GETUG 12 trial) tested 3-years of hormonal therapy and 72 Gy of radiation with or without 4 cycles of docetaxel-estramustine in 413 patients with high-risk PC.⁵ Investigators presented longer-term safety data showing that docetaxel-estramustine chemotherapy did not seem to have adverse long-term impact on serum testosterone, weight, and sexual function.⁶

Docetaxel administered every 3 weeks is the standard regimen for men with metastatic CRPC. A phase 3 study testing 50 mg/m² q2 week vs 75 mg/m² q3 week docetaxel was recently published showing decreased toxicity with a possible improvement in survival for the q2 week arm.⁷ Malhotra et al presented a retrospective study of 41 patients that received docetaxel 30 mg/m² weekly, 60 mg/m² q3 weeks, and 75 mg/m² q3 weeks.⁸ Due to the retrospective nature of the small study, only feasibility of each schedule can be concluded, but q2 week schedule was associated with trends for longer PFS and OS. Italian investigators presented a randomized phase 2 trial of continuous vs intermittent docetaxel with or without estramustine.⁹  Subjects received 8 cycles continuously or 4 cycles with a 3-month break before completing 4 additional cycles and patient reported outcomes (PRO) were reported using EORTC QLQ-C30 (which assesses the quality of life of cancer patients). No significant difference in PRO were demonstrated with intermittent therapy.

Finally, investigators at the National Cancer Institute presented retrospective data on the safety of docetaxel administration in patients with prior hypersensitivity reactions.¹⁰ Utilizing their clinical management guideline involving H1 and H2 blockers, higher doses of corticosteroids, slower infusion rates, and lower concentrations, 61 patients safely received docetaxel without need for treatment discontinuation.

Cabazitaxel updates 

The TROPIC (XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer) trial demonstrated a survival benefit for cabazitaxel/prednisone compared to mitoxantrone/prednisone in patients with CRPC and prior docetaxel¹¹ PSA declines were more frequent with cabazitaxel, as were objective responses, but significant toxicity was reported, including an approximate 5% toxic death rate in the setting of an international prospective randomized, controlled study, leading to apprehension from some with transition into a community setting.

Several studies presented safety and efficacy of cabazitaxel/prednisone post-FDA approval. Bracarda et al reported the Italian experience with 165 patients treated in the expanded access program (EAP).¹² Reported adverse events were similar to that reported in TROPIC, providing safety data from a community setting.  Bahl et al presented the UK EAP safety and PRO data from 108 patients treated at 12 centers.¹³ In the setting of 85% prophylactic white blood cell (WBC), growth factor, toxicity seemed less than reported in TROPIC, with 31% receiving at least 10 cycles. PRO data revealed stability with trends toward improvement.  Kelly et al reported a single-center experience with frequent WBC growth factor use, with numerically lower toxicity rates compared to TROPIC.¹⁴ In these studies, efficacy seemed at least as good as reported in TROPIC. Two additional studies reported efficacy data. Oudard reported retrospective data on 84 patients, demonstrating baseline characteristics that might be predictive of response to second-line hormonal therapies did not impact efficacy of cabazitaxel.¹⁵ Another French study reported PSA flare in patients treated with cabazitaxel, supporting the recommendation of PCWG2 to not abandon therapy solely for PSA increase in the initial cycles of treatment.¹⁶

With the approval of additional non-cytotoxic options, sequencing has become one of the most pertinent issues to the treating physician (and patients).  Schnadig et al presented a retrospective study examining prescribing patterns following docetaxel from 2010-2012.¹⁷ Cabazitaxel use declined following availability of abiraterone, but the overall treatment of cabazitaxel→abiraterone was more prevalent than abiraterone→cabazitaxel following docetaxel in this community-based study over the time period studied. An Israeli study retrospectively reviewed 24 patients who received cabazitaxel (14/24 at 20 mg/m²) following docetaxel and abiraterone.¹⁸ Prior docetaxel sensitivity and performance status were associated with longer survival with cabazitaxel, but abiraterone sensitivity was not.

In summary the cabazitaxel studies confirmed reasonable safety and efficacy data in various settings, but none answered taxane sequencing or cabazitaxel dosing questions. We await the results of PROSELICA trial (NCT01308580) examining 20 mg/m² vs 25 mg/m² of cabazitaxel in combination with prednisone following docetaxel and FIRSTANA (NCT01308567) examining cabazitaxel plus prednisone at two dose levels versus docetaxel plus prednisone in patients with chemo-naïve mCRPC. In the meantime, we expect limited chemo-naïve  cabazitaxel data in addition to the more interesting sequencing and biomarker examinations from TAXYNERGY (NCT01718353). ■

References:

Tannock I, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): results from the multinational phase III trial (VENICE). 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;13(Suppl 6);abstr 13.

Arujo JC, Trudel GC, Saad F, et al. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): results from the randomized phase III READY trial. 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;13(Suppl 6):abstr LBA8.

Heath EI, Mannuel HD, Liu G, et al. Randomized phase II trial of docetaxel (Doc) and prednisone (Pred) with or without AZD2171 (cediranib), in chemotherapy-naive, metastatic castrate-resistant prostate cancer (mCRPC) (NCI 7451). 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 38.

Fleming MT, Rathkopf DE, Gibbons J, et al. Enzalutamide in combination with docetaxel in men with prostate cancer (PC): preliminary results from a phase I study. 2013 Genitourinary Cancers Symposium, Feb.14-16.
J Clin Oncol. 2013;31(Suppl 6):abstr 63.

Fizazi K, Lesaunier F, Delva R, et al. A phase III trial of docetaxel-estramustine in high-risk localised prostate cancer: a planned analysis of response, toxicity and quality of life in the GETUG 12 trial. Eur Cancer. 2012;48:209-217.

Bosset PO, Albiges L, Laplanche A, et al. Long-term tolerance of neoadjuvant docetaxel/estramustine chemotherapy in patients with high-risk localized prostate cancer treated at IGR in the GETUG 12 phase III trial. 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 168.

Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, et al; PROSTY Study Group. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 2013;14:117–124.

Malhotra A, Poiesz BJ. Efficacy and toxicity of q 2 weeks versus weekly versus q 3 weeks docetaxel in metastatic castration-resistant prostate cancer (CRPC). 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 206.

Caffo O, Sava T, Basso U, et al. Impact of intermittent (I) first-line docetaxel (D)-based chemotherapy on quality of life (QL) of patients (pts) with castration-resistant prostate cancer (CRPC): results of a phase II randomized trial. 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 90.

Couvillon A, Beatson MA, Harold N, et al. Feasibility of continuing docetaxel-based therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC) that experience hypersensitivity reactions (HSR). 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 132.

de Bono JS, Oudard S, Ozguroglu M, et al; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–1154.

Bracarda S, Marchetti P, Gasparro D, et al. Which data for cabazitaxel (Cbz) from the real world? The safety experience from the Italian centres participating in the Expanded Access Programme (EAP). 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 189.

Bahl A, Masson S, Malik ZI, et al. Cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC): final quality-of-life (QOL) results with safety data from the United Kingdom (UK) Early Access Programme (EAP) (NCT01254279). 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 91.

Kelly CLS, Hague CJ, Cornthwaite SA, Birtle AJ. Cabazitaxel in patients with metastatic castrate-resistant prostate cancer previously treated with a docetaxel-containing regimen: a single U.K. cancer center’s experience using Early Access Programme and Cancer Drugs Fund. 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 224.

Oudard S, Mercier F, Flechon A, et al. Efficacy of cabazitaxel and its relationship with predictors of poor response to second hormonal therapies (2d HT) in metastatic castration-resistant prostate cancer (mCRPC). 2013 Genitourinary Cancers Symposium, Feb.14-16.
J Clin Oncol. 2013;31(Suppl 6):abstr 137.

Angelergues A, Mercier F, Flechon A, et al. Retrospective registry evaluating the PSA flare phenomenon with cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC). 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 122.

Schnadig I, Bhor M, Vogelzang N, et al. Sequencing of cabazitaxel and abiraterone acetate following docetaxel in metastatic castration-resistant prostate cancer (mCRPC). 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 79.

Sella A, Sella T, Peer A, et al. Activity of cabazitaxel following docetaxel and abiraterone acetate in patients with castration-resistant prostate cancer. 2013 Genitourinary Cancers Symposium, Feb.14-16. J Clin Oncol. 2013;31(Suppl 6):abstr 186.

Dr Akhtar is a research fellow, hematology/oncology, Weill Cornell Medical College, New York. Dr Tagawa is medical director, Genitourinary Oncology Research Program, and associate professor of medicine & urology, Weill Cornell Medical College.

Disclosure Information: Dr Akhtar reports no financial disclosures as related to products discussed in this article. Dr Tagawa reports that he is a member of the speakers bureau of sanofi-aventis, Janssen, and Medivation/Astellas.