Castration Resistant Prostate Cancer: Role of Chemotherapy

C H A P T E R

54 Castration Resistant Prostate Cancer: Role of Chemotherapy Marijo Bilusic, MD, PhD Department of Medical Oncology, Fox Chase Cancer Center/Temple University, Philadelphia, PA, USA

INTRODUCTION Prostate cancer is the second most common cancer (after skin cancer) and one of the major causes of cancer mortality in the United States with an expected 29,720 deaths in 2013.1,2 About 40% of prostate cancer patients will fail surgical or radiation therapy and will develop metastatic disease.3,4 Testosterone suppression is an effective frontline treatment in newly diagnosed metastatic disease; however, cancer will ultimately progress to castration-resistant disease. Androgen deprivation therapy (ADT) is the backbone of treatment in castration-resistant disease; although, additional agents, such as antiandrogens, immunotherapy, radiopharmaceuticals, and chemotherapy, are necessary in order to palliate symptoms and prolong survival. Historically, chemotherapy was considered ineffective for metastatic castration resistant prostate cancer (mCRPC) with a response rate of less than 20% and without any significant impact on overall survival (OS). Surprisingly in the last decade a few chemotherapy agents have demonstrated improvement in OS, establishing chemotherapy as a standard treatment option in advanced disease.

FDA-APPROVED CHEMOTHERAPY REGIMENS FOR mCRPC Mitoxantrone Mitoxantrone is a DNA-intercalating derivative of an anthracenedione antibiotic, which binds to topoisomerase II, thus causing inhibition of DNA and RNA replication. Based on the encouraging early phase trials, a phase III trial enrolled 161 patients with symptomatic mCRPC to mitoxantrone 12 mg/m2 IV every-3-weeks

plus prednisone arm and to prednisone alone arm. Mitoxantrone with prednisone significantly improved pain control compared to prednisone alone (29% vs. 12%) with the median duration of response of 7.6 versus 2.1 months (p = 0.0009). No significant improvement in OS was reported.5 Another phase III trial (CALGB 9182) randomized 244 mCRPC patients to mitoxantrone plus hydrocortisone arm and to hydrocortisone alone. This study also showed improvement in pain control with no significant survival advantage (12.3 vs. 12.6 months, p = 0.3298).6 Mitoxantrone was approved by the FDA in 1996 for the palliative treatment of mCRPC. Mitoxantrone is generally well-tolerated. Cardiotoxicity was observed in 5.5% of patients (defined as any decrease in left ventricle ejection fraction below the normal range, congestive heart failure, or myocardial ischemia), while secondary leukemia was reported in 1% of the treated patients. Today, mitoxantrone is used with the goal of improving quality of life and pain control as second- or third-line chemotherapy.

Docetaxel Docetaxel is a taxane derivate, which prevents androgen receptor (AR) nuclear translocation by binding to microtubules7,8 and causing apoptosis through Bcl-2 phosphorylation.9 Single-agent docetaxel or in combination with estramustine demonstrated objective response rates (ORR) in up to 38% patients, PSA decline >50% in up to 69% patients with a median OS between 20 months and 23 months.10–12 These exciting findings prompted two phase III trials (TAK 327 and SWOG 99-16) that independently confirmed that docetaxel chemotherapy improved OS in mCRPC. The TAX 327 study randomized 1006 mCRPC patients to three arms (all with daily oral prednisone):

Prostate Cancer. http://dx.doi.org/10.1016/B978-0-12-800077-9.00054-2 Copyright © 2016 Elsevier Ltd. All rights reserved.

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510 54.  Castration Resistant Prostate Cancer: Role of Chemotherapy (1) mitoxantrone 12 mg/m2 IV every 3 weeks, (2) docetaxel 30 mg/m2 IV weekly, and (3) docetaxel 75 mg/m2 IV every 3 weeks. Eight milligrams of dexamethasone was prescribed 12, 3, and 1 h prior treatment in order to minimize toxicity. Only the docetaxel every-3-weeks arm showed significant median OS advantage compared with weekly docetaxel and mitoxantrone (19.2 vs. 17.8 vs. 16.3 months, respectively), with additional improvement in pain and quality of life.13,14 Subset analyses confirmed survival advantage in all subgroups. Docetaxel toxicity was acceptable. The most common toxicity in the docetaxel every-3-weeks group was grade 3/4 neutropenia compared with weekly docetaxel and mitoxantrone group (32% vs. 2% vs. 22%). Neutropenic infections were rare (3% vs. 0% vs. 2%, respectively). Treatment discontinuation due to side effects was relatively uncommon in all arms (11% vs. 16% vs. 10%, respectively). This trial has established docetaxel (75 mg/m2 every-3-weeks) plus daily prednisone (5 mg twice a day) as the standard treatment option for mCRPC and was approved by the FDA in 2004. The SWOG 99-16 phase III trial enrolled 770 mCRPC patients to two arms: (1) docetaxel (60 mg/m2 IV every3-weeks) plus estramustine (280 mg PO TID days 1–5) and (2) mitoxantrone (12 mg/m2 IV every-3-weeks) plus prednisone (5 mg BID). The docetaxel plus estramustine arm demonstrated improvement in median OS (17.5 vs. 15.6 months, p = 0.02).15 Pain improvement was similar in both groups. Grade 3/4 toxicity (gastrointestinal, cardiovascular/thromboembolic events, infections, pain, and neuropathy) was significantly higher and was reported in 54% patients (compared to 34% on mitoxantrone and prednisone arm); however, study discontinuation due to toxicities and treatment-related deaths (2% vs. 1%) were similar in both groups. Despite demonstrated survival advantage, the combination of docetaxel plus estramustine is rarely used due to significant toxicity of the regimen.

Docetaxel Combinations It is a widely accepted rule in oncology that chemotherapy drugs are most effective when given in combination since using agents that work by different mechanisms can improve the treatment effect while decreasing the risk of resistance development. Several large phase III studies have combined docetaxel plus prednisone with different agents such as bevacizumab,16 aflibercept,17 lenalidomide,18 dasatinib,19 atrasentan,20 zibotentan,21 and calcitriol.22 Surprisingly, none of the combinations were superior. The majority of combination studies demonstrated significant toxicities requiring docetaxel dose reduction and delays as well as potentially compromising survival. Several ongoing phase II and III studies are testing the combination of docetaxel with other agents; however, none of them have established a role yet (Table 54.1).

Cabazitaxel Cabazitaxel is a derivative of docetaxel, which is cytotoxic for docetaxel-resistant cell lines due to gp-1 overexpression and has a better blood–brain barrier penetration.23 Based on the results of a phase I study that enrolled 25 patients (only eight patients with mCRPC),24 a decision was made to test this drug in mCRPC. TROPIC was a phase III study that enrolled 755 docetaxel pretreated mCRPC patients to two groups: (1) mitoxantrone 12 mg/m2 IV every-3-weeks plus prednisone 10 mg and (2) cabazitaxel 25 mg/m2 IV every-3-weeks plus prednisone 10 mg daily. The vast majority of patients had advanced mCRPC: 25% of the patients had visceral disease and 92% of the patients previously received a >225 mg/m2 cumulative dose of docetaxel. At the first interim analysis, the cabazitaxel arm demonstrated significant improvement in median OS (15.1 vs. 12.7 months), with a 30% decrease in relative risk of dying (HR = 0.7, p < 0.0001). Interestingly, subset analysis demonstrated

TABLE 54.1 Ongoing Phase II and III Studies Combining Docetaxel with Other Agents Disease stage

Drug

Phase

Number of pts

End point

Clincaltrials.gov

mCRPC; chemo naive

Custirsen

III

1023

OS

NCT01188187 (SYNERGY)

mCRPC; chemo naive

DCVAC/PCa

III

1170

OS

NCT02111577 (VIABLE)

mCRPC; chemo naive

Dendritic cell vaccine

II

40

Immune response

NCT01446731

mCRPC; chemo naive

Imatinib

II

17

Disease progression

NCT00251225

mCRPC; chemo naive

Cediranib

II

84

PFS

NCT00527124

mCRPC; chemo naive

Reolysin

II

80

Disease progression

NCT01619813

mCRPC; chemo naive

Bevacizumab, thalidomide

II

73

PSA response

NCT00089609

mCRPC; prior docetaxel

Tasquinimod

II

140

PFS radiographic

NCT01732549

Pts, Patients; mCRPC, metastatic castration resistant prostate cancer; OS, overall survival; PSA, prostate specific antigen; PFS, progression free survival.

IX.  Advanced prostate cancer



OTHER CHEMOTHERAPY REGIMENS FOR mCRPC

the greatest survival advantage in heavily pretreated patients.25 Recently published updated analyses showed that survival benefit was sustained with >2 years survival in 27% of patients treated with cabazitaxel versus 16% in the control arm.26 Cabazitaxel treatment was quite toxic: 94% of patients had neutropenia, 97% anemia, and 47% thrombocytopenia. Neutropenic fever occurred in 8% of the patients and five patients died. Other common toxicities were diarrhea (47%), nausea (34%), and vomiting (22%). Cabazitaxel was FDA approved in 2010 for patients who progressed after docetaxel treatment. Due to significant toxicities, prophylaxis with colony-stimulating factors is recommended for high-risk groups and patients older than 65 years of age. An ongoing randomized phase III study will evaluate the safety and efficacy of a lower dose of cabazitaxel (20 mg/m2) (NCT01308567) and the role of cabazitaxel as the frontline therapy (NCT01308580).

OTHER CHEMOTHERAPY REGIMENS FOR mCRPC There are no standard chemotherapy regimens for patients with mCRPC who progressed or did not respond to docetaxel and cabazitaxel. The majority of those patients will eventually be treated with other novel agents such as abiraterone, enzalutamide, or radium-223; however, some may be candidates for additional chemotherapy. Several phase II trials tested different cytotoxic chemotherapies in prostate cancer patients and a few of them are presented in the subsequent section.

Estramustine Estramustine is a conjugate of estradiol and alkylating agent, which binds to microtubule-associated proteins and tubulin, thereby inhibiting activity of microtubules and leading to anaphase arrest. It also has additional anticancer benefit given antiandrogen effects due to the estradiol component. Although it was one of the first effective chemotherapeutics that demonstrated PSA response, this drug has rarely been used due to arterial and venous thromboembolic events.1 Several prophylactic measures have been tried, such as prophylaxis with daily aspirin or low-dose warfarin, however, without any significant impact.27–29

Cisplatin Cisplatin is an alkylating agent that binds with DNA and forms intrastrand cross-links affecting DNA replication. Other cytotoxic mechanisms include decreased ATPase activity, mitochondrial damage, and altered cellular transport mechanisms. Several phase II studies

511

tested single-agent cisplatin in mCRPC and showed a response rate of up to 19%.30,31 Cisplatin is used today mostly in combination with etoposide in patients with small cell neuroendocrine prostate carcinoma.

Carboplatin Carboplatin activity is very similar to cisplatin as it binds with DNA and affects replication; however, it has a more favorable adverse effect profile. Single-agent carboplatin demonstrated stable disease in 50% of patients with mCRPC.32 The combination of carboplatin, paclitaxel, and estramustine demonstrated antitumor activity in up to 45% mCRPC patients.33 Carboplatin (AUC 4) and docetaxel 60 mg/m2 were tested in 34 patients and demonstrated 50% PSA declines in six (18%) and a partial response in three (14%) patients.34 The combination of carboplatin plus paclitaxel was also tested in 38 patients (24 were pretreated with ≥2 chemotherapy regimens). The median OS was 10 months with clinical and/or PSA response observed in 26% of patients.35 Another phase II study evaluated carboplatin and docetaxel combination in 34 men who had progressed after the completion or during docetaxel chemotherapy. PSA responses were observed in 18% patients, the median PFS was 3 months with the median OS of 12 months.36

Oxaliplatin Two studies have evaluated oxaliplatin after docetaxel-based chemotherapy. The first study enrolled 47 mCRPC patients treated with oxaliplatin and pemetrexed and demonstrated PSA response in 64%, objective response in 25% of the patients with the median PFS of 6 months and median OS of 12 month.37 Another phase II study of oxaliplatin plus capecitabine in 14 patients showed PSA response in 57% of the patients with median OS of 24 weeks.38

Ixabepilone The epothilones are tubulin-polymerizing agents with broad spectrum activity.39 Initial study of ixabepilone in prostate cancer showed promising antitumor activities,40 which led to phase II studies. A SWOG phase II study enrolled 48 taxane-naïve mCRPC patients. Fourteen patients had PSA responses (33%) and two patients had an undetectable PSA. The median PFS was 6 months and the median OS was 18 months. Hematologic toxicity, infection, flu-like symptoms, and neuropathy were among the most commonly reported grade 3/4 adverse events.41 Another trial randomized taxane-refractory mCRPC patients to ixabepilone and mitoxantrone. Partial responses were observed in one ixabepilone patient (out of 24) and in two mitoxantrone treated patients (out of 21) with

IX.  Advanced prostate cancer

512 54.  Castration Resistant Prostate Cancer: Role of Chemotherapy PSA declines >50% demonstrated in 17% of ixabepilone treated patients.42

Vinorelbine Vinorelbine is a semisynthetic vinca alkaloid that affects microtubule activity. Initial studies with vinorelbine alone showed ≥50% PSA decline in up to 17% of patients.43,44 A phase III study randomized 414 chemo naïve patients to vinorelbine 30 mg/m2 IV on days 1 and 8 every-3-weeks plus hydrocortisone versus hydrocortisone alone. The PSA response (defined as ≥50% decline of PSA lasting for at least 6 weeks) was 30.1% in the vinorelbine arm and 19.2% in the control arm. The median PFS was 3.7 versus 2.8 months and the treatment was well-tolerated.45

WHEN TO START CHEMOTHERAPY? Since predictive and prognostic biomarkers are still in their infancy, the decision to start cytotoxic chemotherapy in mCRPC is based on several factors, including the presence of disease symptoms, performance status and other comorbidities, available treatment options, and patients’ preference. There is limited evidence that patients who developed castration-resistant disease in <16 months will respond better to chemotherapy.46 Chemotherapy is frequently offered earlier to patients with aggressive and symptomatic disease (such as younger patients with visceral metastases and a higher Gleason score), although trials supporting this practice are still lacking. In newly diagnosed metastatic disease, the situation is now clearer. The Eastern Cooperative Oncology Group (ECOG) phase III study randomized 790 newly diagnosed patients with metastatic disease to six cycles of docetaxel 75 mg/m2 IV every-3-weeks plus ADT and to ADT alone. This trial (CHAARTED) demonstrated significant improvement in median OS: 57.6 months versus 44.0 months (HR = 0.61, p = 0.0003). The median OS in the high-risk group (N = 514), defined as presence of visceral metastases, ≥4 bone metastases including ≥1 bone lesion beyond the vertebral column or pelvis improved from 32.2 months to 49.2 months (HR = 0.60, p = 0.006).47 Based on this study, six cycles of docetaxel with ADT are treatment of choice for metastatic prostate cancer patients with a high volume of metastases commencing ADT who are suitable for docetaxel therapy.

DURATION OF CHEMOTHERAPY The optimal duration of chemotherapy in metastatic CRPC is also unclear. Studies have suggested that >10 cycles of docetaxel did not significantly improve OS;

although, some patients still had some benefit after 1 year of therapy.48 The previously mentioned TAX 327 study allowed chemotherapy beyond 10 cycles, which did not demonstrate survival improvement; however, it seems that continuation of treatment, despite pain or PSA progression, was associated with longer postprogression survival. Alternative therapies should be used if the patient exhibits signs of disease progression such as pain, PSA, or radiographic progression.48 The hypothesis of intermittent docetaxel treatment was evaluated in the ASCENT-1 study. Patients with mCRPC who achieved a PSA level of ≤4 ng/mL following induction treatment with a docetaxel-based regimen had their treatment suspended until the PSA level increased by ≥50% and >2 ng/mL, or on evidence of progressive disease. The first treatment holiday duration was 18 weeks (range 4–70 weeks) and once the treatment was again restarted, 45.5% of patients had again ≥50% PSA decline for more than 12 weeks. This study suggested that chemotherapy holidays may be considered for some patients; however, this approach needs to be validated.49

THE FUTURE OF CHEMOTHERAPY IN mCRPC Several ongoing randomized trials should define which agent should be used as frontline chemotherapy; however, the optimal sequences of other therapies, such as abiraterone, enzalutamide and radium-223, are not clear yet. A few phase III trials are now evaluating cabazitaxel and its role in mCRPC. FIRSTANA (NCT01308567) will randomize 1170 chemotherapy naïve mCRPC to docetaxel 75 mg/m2 IV every-3-weeks, cabazitaxel 25 mg/m2 IV every-3-weeks, or cabazitaxel 20 mg/m2 IV every-3-weeks as firstline chemotherapy to evaluate whether a similar efficacy can be achieved with less drug. PROSELICA (NCT01308580) will randomize 1200 previously treated mCRPC patients to cabazitaxel 20 mg/m2 IV every-3-weeks and cabazitaxel 25 mg/m2 IV every3-weeks to evaluate the noninferiority in median OS. TAXYNERGY (NCT01718353) is a randomized phase II study, which evaluates an early change of chemotherapy from firstline docetaxel to cabazitaxel, or vice versa, if patients do not achieve >30% PSA decline after four cycles. This trial is also evaluating mechanisms of taxane resistance and biomarkers. AFFINITY (NCT01578655) is a phase III study, which is evaluating the role of custirsen (OGX-011 – an antisense oligonucleotide that blocks the expression of clusterin, a prosurvival protein associated with drug resistance) in combination with cabazitaxel plus prednisone as second-line chemotherapy. Eribulin mesylate (nontaxane halichondrin-B analogue microtubule inhibitor) demonstrated ≥50%

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513

REFERENCES

TABLE 54.2 Ongoing Phase II and III Studies Combining Chemotherapy with Biological Agents Disease

Chemotherapy

Biological agent

Number of pts

End point

Clincatrials.gov

mCRPC; mitoxantrone naive

Mitoxantrone

IMC-3G3

123

PFS

NCT01204710

mCRPC; postdocetaxel

Cabazitaxel

Custirsen

630

OS

NCT01578655 (AFFINITY)

mCRPC; mitoxantrone and cabozantinib naive

Mitoxantrone

Cabozantinib

246

Pain response at 12 weeks

NCT01522443

Pts, Patients; mCRPC, metastatic castration resistant prostate cancer; OS, overall survival; PFS, progression free survival.

PSA decrease in 22.4% of taxane-naïve and in 8.5% of taxane-treated mCRPC patients with an excellent toxicity profile.50 Other combinations of chemotherapy with biological agents are currently being tested in mCRPC (Table 54.2).

CONCLUSIONS Chemotherapy has an important role in castrationsensitive and castration-resistant prostate cancer. Due to the lack of validated predictive biomarkers, optimal sequence, selection, and ideal timing of chemotherapy is still unclear. With the recently approved drugs such as abiraterone, enzalutamide, radium 223, and sipuleucelT, the perfect timing of chemotherapy is even more complicated than before. Although both docetaxel and cabazitaxel demonstrated significant improvements in median OS, their responses are relatively short. Second-line chemotherapeutic options are still limited. In the future, the combinations of agents with proven survival advantage may be the most beneficial, such as the combination of enzalutamide plus abiraterone, chemotherapy plus androgen inhibitors (abiraterone or enzalutamide), or radium-223 and androgen inhibitors. Future novel drug combination therapies with the use of synergistic chemotherapy, better understanding of the drug resistance mechanisms, and targeting new pathways will hopefully change the treatment paradigm. Predictive biomarkers are urgently needed to guide the most feasible sequence of therapeutic agents and their combination for personalized treatment that will ultimately provide better survival for prostate cancer patients.

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IX.  Advanced prostate cancer