Post-docetaxel therapy in castration resistant prostate cancer – the forest is growing in the desert

Introduction

In Europe, prostate cancer is the most common cancer among men with 382,000 new cases and 89,000 deaths annually [Ferlay et al. 2010]. Androgen deprivation therapy (ADT) is the cornerstone for recurrent or metastatic prostate cancer, but it is estimated that almost all patients will develop progressive castration-resistant prostate cancer (CRPC) in future [Miyamoto et al. 2004].

In 2004, the TAX327 study changed the paradigm of prostate cancer treatment, reporting for the first time a survival benefit for docetaxel-based chemotherapy compared with mitoxantrone in patients affected by CRPC [Tannock et al. 2004]. After docetaxel progression, there was no standard of care in the second-line setting. Mitoxantrone plus prednisone or ketoconazole have improved the quality of life without any significant impact on the survival in the first-line setting [Kantoff et al. 1999; Procopio et al. 2011; Tannock et al. 1996]. Docetaxel rechallenge seems to be an effective strategy in patients who have previously responded to first line, but there are no data supported by a comparative phase III study [Eymard et al. 2010].

New trials have been published in the last year regarding the management of CRPC after docetaxel failure [Antonarakis and Armstrong, 2011]. For the first time, second-line therapies have been demonstrated to improve survival and the concept of sequential therapies in docetaxel-progressed CRPC (DP-CRPC) has been introduced. The relevance of these trials is the reintroduction of chemotherapy and hormonal therapy in a disease once considered chemotherapy and castration resistant.

Cabazitaxel

Cabazitaxel is a semisynthetic derivative of the natural taxoid 10-deacetylbaccatin III with potential antineoplastic activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase and the inhibition of tumor cell proliferation. Unlike other taxane compounds, this agent is a poor substrate for the membrane-associated, multidrug resistant (MDR), P-glycoprotein (P-gp) efflux pump and may be useful for treating MDR tumors. In addition, cabazitaxel penetrates the blood–brain barrier [Mita et al. 2009].

In a recent phase III trial, 775 DP-CRPC patients were randomized to receive cabazitaxel 25 mg/m² or mitoxantrone 12 mg/m² every 3 weeks, both in combination with prednisone [De Bono et al. 2010]. The primary endpoint was overall survival (OS) and the secondary endpoints included progression-free survival (PFS), prostates-specific antigen (PSA) response rate (RR), time to PSA progression (TTPP), objective tumor response rate (TRR), pain response rate (PRR), time to pain progression (TPP), time to tumor progression (TTP) and safety. Cabazitaxel has been demonstrated to prolong OS compared with mitoxantrone (15.1 versus 12.7 months) and the hazard ratio (HR) for death was 0.70 (95% confidence interval [CI] 0.59–0.83, p < 0.0001). Median PFS (2.8 versus 1.4 months, HR 0.74, 0.64–0.86; p < 0.0001), PSA RR (39.2% versus 17.8%, p= 0.0002), TTPP (6.4 versus 3.1 months, p = 0.001), TRR (14.4% versus 4.4%, p = 0.0005) and TTP (8.8 versus 5.4 months, p < 0.0001) were also increased. PRR (9.2% versus 7.7%, p = 0.63) and TPP were similar in the two groups. Most common adverse events were neutropenia and diarrhea reported in 82% and 6% of patients, respectively. Eighteen cabazitaxel toxicity-related deaths were reported, primarily due to neutropenia and its clinical consequences (seven cases) and to cardiac events (five cases). Considering these data, the authors recommend that every effort should be taken to avoid or reduce bone marrow toxicity with dose modifications as well as prophylactic treatment with granulocyte colony stimulating factor in high-risk selected patients.

Abiraterone

Emerging evidence also suggests that CRPC remains hormone driven and androgen receptor (AR) signaling plays an important role. The molecular basis for AR reactivation is still unclear but possible mechanisms include reactivation by androgens converted from the adrenal glands or synthesized intratumorally, overexpression of AR protein, AR mutations or amplifications and increase of cofactors levels [Zivi et al. 2010]. In this setting, the inhibition of steroidogenesis at adrenal levels could represent one of the possible antitumor mechanisms targetable.

Abiraterone acetate is an orally active acetate salt of the steroidal compound abiraterone with anti-androgen activity. Abiraterone inhibits the enzymatic activity of steroid 17alphamonooxygenase (17alpha-hydrolase/C17,20 lyase complex), a member of the cytochrome p450 family that catalyzes the 17alpha-hydroxylation of steroid intermediates involved in testosterone synthesis. Administration of this agent may suppress testosterone production by both the testes and the adrenal glands to castrate-range levels.

Three phase II studies have tested the activity of abiraterone acetate in CRPC patients who received docetaxel or not [Attard et al. 2009; Danila et al. 2010; Reid et al. 2010]. A phase III trial randomized a total of 1195 CRPC patients who have progressed after one or two line chemotherapeutic agents (included docetaxel) to either abiraterone or placebo (in a 2:1 fashion) both in combination with prednisone [De Bono et al. 2011]. OS was the primary endpoint of the study and the secondary endpoints were TTPP, PSA RR, radiographic progression-free survival (rPFS) and TRR. The study was unblinded following the first planned interim analysis showing a significant improvement in OS from 10.4 to 14.8 months (HR 0.65, 95% CI 0.54–0.77; p < 0.0001) in the abiraterone arm. Abiraterone therapy also yielded superior outcomes with respect to TTPP (10.2 months versus 6.6 months, p < 0.0001), rPFS (5.6 months versus 3.6 months, p < 0.0001), PSA RR (29% versus 6%, p < 0.0001) and TRR (14% versus 3%, p < 0.001). The most severe abiraterone-related adverse events were fluid retention (31% versus 22% in placebo arm), hypokalemia (17% versus 8%) and cardiac disorders (13% versus 11%).

Sipuleucel-T

Another interesting area in the treatment of CRPC is immunotherapy, wherein the aim is to harness and enhance the body’s immune system to elicit an antitumor effect. Sipuleucel-T is a dendritic cell-based vaccine designed to stimulate T-cell immunity against prostatic acid phosphatase (PAP), an enzyme localized to prostate cell membranes. Dendritic cells are removed from the patient by leukapheresis, pulsed with PAP, purified and reintroduced to the patient.

In the IMPACT study, the autologous vaccine sipuleucel-T was compared with placebo for asymptomatic or minimally symptomatic patients affected by CRPC, reporting an improvement in the OS [Kantoff et al. 2010]. Only 18.2% of patients enrolled have received prior chemotherapy, included docetaxel, so the efficacy in this setting should be further evaluated in a larger study.

Radiopharmaceuticals

About 90% of patients with metastatic CRPC have radiologic evidence of bone metastases [Tannock et al. 2004]. Current bone-targeted therapies have been shown to reduce risk for skeletal related events (SREs), but do not improve OS. Radium-223 is an alpha-emitting pharmaceutical that delivers high linear energy, with a range of less than 100 µm. Compared with the beta-emitting radiopharmaceuticals, radium-223 induces double-stranded DNA breaks with lower penetration to surrounding tissues, reducing the toxicity to the bone marrow.

A randomized, multicenter, placebo-controlled phase II trial of 64 patients demonstrated that radium-223 had significant effects on bone-alkaline phosphatase (ALP) and time to SREs. Furthermore, TTPP and OS, the secondary endpoints, were also positive [Nilsson et al. 2007]. Based on these results, the ALSYMPCA phase III trial evaluated radium-223 in patients with symptomatic CRPC progressed after first-line docetaxel or unfit for docetaxel therapy, with at least two bone metastases on bone scan and no visceral metastases [Parker et al. 2011]. The results were presented at last ECCO-ESMO Meeting in Stockholm: 922 patients have been randomly assigned 2:1 to radium-223 50 kBq/kg every 4 weeks or placebo. The primary endpoint of the study was OS, the secondary endpoints were time to first SRE, time to total ALP progression, total ALP response and normalization, TTPP, safety and quality of life. In June 2011, the study was stopped early after the first preplanned interim analysis. Compared with placebo, radium-223 improved OS (14.0 versus 11.2 months, HR 0.69, 95% CI 0.55–0.87; p = 0.0018) and delayed time to first SRE (13.6 versus 8.4 months, HR 0.61, 95% CI 0.46–0.80; p = 0.00046). A beneficial effect has also been shown in all of the secondary endpoints. Radium-223 was well tolerated: the most common adverse events included bone pain (43% versus 58% in placebo arm), nausea (34% versus 32%), anemia (27% versus 27%), diarrhea (22% versus 13%), constipation (18% versus 18%) and vomiting (17% versus 13%).

Discussion

Despite all of the new trials in DP-CRPC, current guidelines are far from helping clinicians to find the best way to treat patients. All of these data may change the traditional approach to DP-CRPC but so far no evidence has came out from the recently closed or ongoing clinical trials about the therapeutic algorithm. How to get oriented in this forest?

The efficacy of cabazitaxel and abiraterone allows us to enlarge the spectrum of patients that may receive a second-line therapy after docetaxel failure; therefore, every effort should be made in order to anticipate first-line docetaxel after ADT progression. The choice of subsequent therapy in DP-CRPC is influenced by patient’s conditions, response and toxicities reported with previous treatments and, above all, by dynamics and evolution of disease (Figure 1). In asymptomatic patients, timing of treatment is not clear and it should be tailored individually, even the treatment should be considered when high PSA serum levels or a PSA doubling time of less than 6 months are found [Mottet et al. 2011]. This subgroup of patients is potentially eligible for all therapies although an oral treatment may have a better impact on quality of life. Symptomatic patients need a rapid response rate to improve pain and disease-related symptoms. For them, both cabazitaxel and abiraterone should be considered as an appropriate treatment, reporting the same TRR (14.4% for cabazitaxel and 14% for abiraterone). For patients with symptomatic bone metastases without visceral lesions, radium-223 should also be considered. Patients with an ECOG Performance Status of 2 represent only a small part (less than 10%) of the study population of the main phase III trials. For them, given the limited benefit in survival reported, best supportive care is still a feasible option.

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Figure 1.

Possible algorithm for treatment of docetaxel progressed CRPC [Iacovelli R et al. 2011].PD= progression of disease; CRPC=castration resistant prostate cancer. ECOG PS=Eastern Cooperative Oncology Group Performance Status; RR= Response Rate.*Unlike other drugs approved for CRPC patients progressing during or after docetaxel-based chemotherapy, Sipuleucel-T has been approved for patients with metastatic, asymptomatic or minimally symptomatic, hormone-refractory prostate cancer.§Radium 223 has been tested only in patients with bone metastases, without visceral lesions.

As the ongoing trials are based on interesting molecules such as MDV3100 [ClinicalTrials. gov Identifier: NCT00974311], TAK700 [ClinicalTrials.gov Identifier: NCT01193257] and ipilimumab [ClinicalTrials.gov Identifier: NCT00861614], in a few years the prognosis of CRPC patients could further improve. Recently, it was announced that positive results have been reported from an interim analysis of the phase III AFFIRM trial of MDV3100 versus placebo in DP-CRPC. MDV3100 met the study’s prespecified interim efficacy stopping criteria, demonstrating an improvement in OS compared with placebo. The full results from the AFFIRM trial will be presented at an upcoming scientific congress, according to the company. In the near future, given the new treatment options available, it will no longer be possible to perform placebo or mitoxantrone controlled trials in DP-CRPC.

Nowadays, we have more opportunities than in the past, so the next challenge should be to find out the best sequential therapy after docetaxel failure and a possible third line for selected patients.

The forest is continuing to grow.