Chemotherapy in Prostate Cancer- When, Why and How - Fred Saad

Until 2010, our treatment armamentarium for prostate cancer (PC) was fairly limited. Patients received local therapy for non-metastatic disease, androgen deprivation therapy (ADT) for hormone-naïve metastatic disease, denosumab and zoledronic acid for metastatic castration-resistant prostate cancer (mCRPC), and bisphosphonates or docetaxel for symptomatic mCRPC.

In the past 7 years, this list has grown to include drugs such as abiraterone, enzalutamide, and cabazitaxel, while docetaxel has expanded into the metastatic hormone-sensitive prostate cancer (mHSPC) setting. In my clinic, we now routinely see patients with advanced mCRPC survive 5 years and longer, and we can expect outcomes to continue to improve with the advent of novel, targeted, and multi-modal therapies.1

The results of seminal trials such as CHAARTED and STAMPEDE have made chemotherapy a standard option for the early treatment of metastatic prostate cancer (mPC).3,4,5 Urologists have decades of experience developing and refining medications and can translate these skills to the chemotherapy setting if they have sufficient case volume, infrastructure, and time. Case volume confers experience; infrastructure enables clinics to implement the same safety nets that medical oncologists use to quickly identify and treat chemotherapy-emergent adverse effects; time ensures appropriate case management and availability to answer questions.2

Advanced prostate cancer clinics are ideally suited to establish infusion clinics that offer chemotherapy when appropriate. Outside this setting, a collaborative effort is usually best. A critical priority is to efficiently transition mPC patients to their next line of treatment, avoiding delays because of poor or unreliable referral systems. When urologists or centers are uncomfortable administering chemotherapy, I advise establishing an excellent relationship with medical oncologists, including a smooth referral process. This is the best approach aside from a group that is equipped to handle chemotherapy internally.

OVERVIEW OF REGIMENS AND DOSING

The CHAARTED and STAMPEDE trials guide us in dosing chemotherapy for mPC. Patients should receive docetaxel (75 mg/ m2) every 3 weeks + prednisone (5 mg) twice daily after pre- medication with oral dexamethasone (8 mg at 12 hours, 3 hours, and 1 hour before docetaxel infusion.3,4 Although the CHAARTED trial did not include daily prednisone,3 adding this corticosteroid appears to lessen the adverse effects of docetaxel.6 For patients with mCRPC, I typically administer 6-10 treatment cycles. If patients respond well, I stop at 10 cycles instead of continuing treatment until failure. Patients with mHSPC receive 6 cycles of the same regimen except that prednisone is optional.

Granulocyte colony-stimulating factor (G-CSF) is associated with bone pain,7 and I do not use it in a first-line setting except when patients have a history of having developed neutropenic fever during their first or second cycle of chemotherapy.5 Compared with the castration-resistant state, HSPC is associated with significant increases in docetaxel absorption10 and risk of neutropenic fever.5,8,9 Thus, it’s important never to start docetaxel before patients are adequately castrated. I recommend at least 1 month and preferably 2-3 months of hormonal therapy before starting docetaxel. Peripheral neuropathy is another risk of chemotherapy, and it is potentially irreversible.11 If patients report warning signs and symptoms, it is recommended to reduce the dose of docetaxel to 60 mg/m2.12 If symptoms persist, further reduce the dose to 45 mg or stop treatment.

Twenty-four to 72 hours before each infusion, obtain a complete blood count to confirm that neutrophils are at least 1500 cells/μL, hemoglobin is at least 100 g/L, and platelets exceed 100 x 109/L. Also obtain liver function tests. Typically, docetaxel can be continued as long as results do not exceed three times the upper limit of normal.

The novel taxane cabazitaxel is an alternative for treating docetaxel-resistant mCRPC.13 In a recent non-inferiority study, a fixed dose of 20 mg cabazitaxel was equivalent to 25 mg/m2 in terms of overall survival (OS).14 Patients should receive prednisone (5 mg twice daily) during cabazitaxel treatment. I do not exceed 10 cycles, and I consider adding G-CSF if patients are older than 75 years or have a history of docetaxel-induced neutropenic fever.

Next, let’s consider chemotherapy in specific PC settings.

MCRPC

As the Prostate Cancer Clinical Trials Working Group 3 has noted, localized PC progresses to biomedical recurrence or to mHSPC, both of which ultimately become resistant to hormone therapy and are potential candidates for successive treatments.16 Thus, our concept of advanced prostate cancer has evolved beyond pre- and post-docetaxel to encompass multiple lines of therapy (Figure 1).16




Figure 1: Prostate Cancer Clinical States Model as Updated by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) Guidelines. CRPC = castration-resistant prostate cancer; mCRPC = metastatic castration-resistant prostate cancer; PSA = prostate-specific antigen.

In 2004, the pivotal, randomized phase III TAX 327 trial confirmed that docetaxel was superior to mitoxantrone for patients with mCRPC.17 In an updated survival analysis, patients who received docetaxel (75 mg/m2 every 3 weeks) + prednisone (5 mg twice daily) had about a 25% lower risk of death and about a 3-month longer median OS compared with patients who received prednisone + mitoxantrone (12 mg/m2 every 3 weeks).18

In 2010, cabazitaxel became the first agent to demonstrate a survival advantage among patients whose PC had progressed after docetaxel therapy.13 In the large, randomized multicenter TROPIC trial, patients with mCRPC who received cabazitaxel (25 mg/m2 every 3 weeks) had a median OS of 15.1 months compared with 12.7 months among patients who received mitoxantrone, a 2.4-month difference. This translated to about a 30% reduction in risk of death (hazard ratio [HR], 0.70; 95% con dence interval [CI], 0.59 to 0.83; P < .0001).13

Events that occurred at the beginning of the TROPIC study are worth noting: Clinics in countries that were not equipped to manage heavily pre-treated PC patients struggled to manage severe treatment-emergent adverse effects, such as neutropenic fever with concurrent diarrhea.13 Within the North American population, cabazitaxel conferred a more than 40% reduction in the risk of death, but in countries outside the United States and Europe, a number of deaths occurred before centers became informed about how to manage these patients.13 These events underscore the critical need to ensure adequate case volume, infrastructure, and time before venturing into chemotherapy.

EARLY PC

The clear survival advantage of chemotherapy in late-stage mCRPC inspired investigators to explore its use in newly diagnosed mPC and as a second-line treatment for mHSPC. In the latter case, experts posited that hormone-naïve tumors might already have hormone-insensitive clones, which ADT alone would not eliminate.

This hypothesis was the basis of the E3805 (CHAARTED) trial, in which patients with newly diagnosed (M1) PC received ADT alone or with 6 cycles of docetaxel (75 mg/m2 every 3 weeks) + 8 mg oral dexamethasone 12 hours, 3 hours, and 1 hour before infusion.3 Daily prednisone was not required.3 As has been widely reported, median OS was more than 1 year longer in the docetaxel+ADT arm compared with ADT alone (57.6 vs. 44.0 months) (HR for death, 0.61; 95% CI, 0.47 to 0.80; P = .0003).3 This OS difference was substantially better than the approximately 3-month improvement in OS when patients with mCRPC received exactly the same drug and dose.18

Among CHAARTED participants with high-volume mPC (visceral metastases or > 4 bone lesions, including > 1 located outside the vertebral bodies and pelvis), docetaxel + ADT led to an unprecedented 17-month improvement in median OS compared with ADT alone (median OS, 49.2 vs. 32.2 months, respectively) (HR, 0.6; 95% CI, 0.45 to 0.81; P = .0006).3 Not only was a result of this magnitude previously unknown for any metastatic solid tumor, but patients who were at least 70 years old also benefitted at least as much and possibly more than younger patients.3

In CHAARTED, the upfront addition of docetaxel to ADT also significantly improved every other secondary endpoint of relevance to patients. For example, combination therapy doubled the proportion of patients with undetectable PSA, a powerful predictor of long-term survival.3 Furthermore, undetectable PSA was maintained at 12 months twice as often in the docetaxel + ADT group compared with the ADT-only group. Docetaxel also significantly prolonged median time to CRPC (20.7 vs. 14.7 months; P < .0001) (HR for death, 0.56; 95% CI, 0.44 to 0.70) and median time to symptomatic or radiologic progression (32.7 vs. 19.8 months; P < .0001) (HR, 0.49; 95% CI, 0.37 to 0.65).3

Perhaps most crucially, these differences occurred even though 74% of ADT-only patients received docetaxel after progression and 97% received it after clinical progression.3 Obviously, waiting for mPC to become castration-resistant before administering docetaxel makes it almost impossible to catch up to the benefits of early, upfront treatment. Among men with high-volume mHSPC, upfront docetaxel maximizes the opportunity to kill the crucial minority of clones that are already ADT-insensitive.

What about low-volume PC? CHAARTED investigators initially reported that median OS was not reached by this sub- group of patients in either treatment arm (HR for death, 0.63; 95% CI, 0.34 to 1.17).3 Many of us wondered, however, whether it was just a question of time for upfront docetaxel to create a survival advantage.

Our hypothesis was overturned at the 2016 meeting of the European Society for Medical Oncology (ESMO), when investigators presented 2 additional years of follow-up data from CHAARTED.19 Patients with low-volume disease had a statistically insignificant HR for death of 1.04 (95% CI, 0.70 to 1.55; P = .86); median OS was 63.5 months with ADT+docetaxel and was not reached with ADT only. Clearly, upfront docetaxel provided no inkling of an advantage for the average patient with low-volume HSPC. These patients probably lack sufficient numbers of hormone-insensitive clones for docetaxel to improve survival beyond what ADT alone confers.

Although chemotherapy can initially erode quality of life (QOL), CHAARTED participants who received upfront docetaxel ultimately reported improved QOL.19 Specifically, docetaxel + ADT led to a significant reduction in measurable QOL compared with ADT-only (P = .02) after 3 months of treatment, but this trend reversed at 6 months and persisted through 12 months of treatment (P < .01).19 Clearly, it is difficult to justify not at least discussing upfront chemotherapy for our patients who walk in the door with mPC.

Investigators achieved a holy grail in oncology with the simultaneous report of STAMPEDE trial results.4 Conducted in the United Kingdom, this trial also showed that adding docetaxel to ADT significantly improved OS compared with ADT alone in patients with HSPC.4 Most patients had high-volume disease, and results were almost identical to those of CHAARTED, including about a 15-month improvement in median OS (60 vs. 45 months, respectively).

Thus, whereas trials of mCRPC consistently reported that docetaxel improved median OS by about 3 to 4.5 months, CHAARTED and STAMPEDE read out a 13.9-month 3 to 15-month4 improvement in patients with earlier-stage, HSPC. These results suggest that other drugs with activity against mCRPC are likely to be used earlier in the disease course, which heightens the need for urologists to help manage advanced PC patients. Although ESMO guidelines recommend that every patient with mPC receive upfront chemotherapy,20 I disagree. In my opinion, most patients with low-volume mPC do not require chemotherapy.

NON-METASTATIC HSPC

Researchers also have studied chemotherapy in non-metastatic PC. In the Radiation Therapy Oncology Group (RTOG) 0521 trial, patients with high-risk (Gleason score > 7), localized, potentially curable prostate cancer were randomly assigned to receive ADT for 24 months + external beam radiotherapy for 8 weeks, with or without six 21-day cycles of docetaxel + prednisone beginning 28 days after radiotherapy. 21 At 6 years of follow-up, the rate of disease-free survival (DFS) was 65% in the docetaxel arm and 55% in the non-docetaxel arm, for a hazard ratio for death of 0.76.21 Docetaxel also appeared to improve metastasis-free survival (P = .05) and 4-year OS (93% vs. 89%; P = .04) (HR, 0.70; 95% CI, 0.51 to 0.98).21

In another recent study, experts reviewed randomized clinical trials of docetaxel + standard of care in men with HSPC.22 In a meta-analysis of 2,348 patients with M0 disease, docetaxel was associated with an 8% reduction in treatment failure at 4 years (from 70% to 62%). However, the HR for death did not favor docetaxel (0.70; 95% CI, 0.61 to 0.81; P < .0001).22 Such findings highlight the need to use techniques like genomics to better identify which patients with M0 PC are most likely to benefit from chemotherapy.

These results are a step in the right direction, but for now, this regimen is not ready for prime time. In our multidisciplinary tumor board, we discuss chemotherapy for relatively young patients with aggressive, locally advanced PC, especially if there are signs of pelvic lymph node involvement.

CHEMOTHERAPY IN THE ABIRATERONE/ ENZALUTAMIDE ERA

The emergence of effective non-chemotherapy therapies for mPC, such as abiraterone acetate and enzalutamide, raises the question of how best to sequence therapies. Do we start with chemotherapy, or with non-chemotherapy?

The phase III FIRSTANA study helped inform this question by testing docetaxel’s effects in a truly first-line setting: Less than 2% of patients had received abiraterone or enzalutamide prior to study enrollment.23 In the study, which included 159 centers worldwide, 1,168 patients with chemotherapy-naïve mCRPC were randomly assigned to one of three regimens: cabazitaxel 20 mg/ m2, cabazitaxel 25 mg/m2, or docetaxel 75 mg/m2 every 3 weeks + daily prednisone (10 mg).23

Median OS was very similar among groups: 24.3 months (95% CI, 22.2 to 27.6) for docetaxel, 24.5 months (95% CI, 21.7 to 27.2) for cabazitaxel 20 mg, and 25.2 months (95% CI, 22.9 to 27.0) for cabazitaxel 25 mg/m2. Thus, in 2017, we continue to project a survival time of only about 24 months when first treating mCRPC with docetaxel. In contrast, in the randomized, phase III COU-302 trial of patients with chemotherapy-naïve mCRPC, starting with abiraterone + prednisone and then proceeding to chemotherapy after progression led to a median OS of about 34.5-month, compared with 30.3 months in the placebo+prednisone arm (HR, 0.81; 95% CI, 0.70 to 0.93; P = .003.24

What about progression-free survival (PFS)? In the FIRSTANA trial, median PFS was 5.3 months (95% CI, 4.9 to 5.8) with docetaxel, which was similar to results in the cabazitaxel 20 mg/m2 (4.4 months; 3.9 to 5.1) and cabazitaxel 25 mg/m2 (5.1 months; 4.6 to 5.7) arms.23 In the COU-302 trial, median time to radiographic progression was 16.5 months among patients who received abiraterone+prednisone.24 In a separate trial of patients with chemotherapy-naïve mCRPC who received enzalutamide,25 and median time to progression was 18 months. In FIRSTANA, PSA response rates were 68% in the docetaxel group, 69% in the cabazitaxel 25 mg/m2 (P = .99), and 61% in the cabazitaxel 20 mg/m2 group (P = .052 vs. docetaxel)23— the best results we had ever seen in a first-line setting. The rate of tumor response based on RECIST criteria was 31% with docetaxel, 32% with cabazitaxel 20 mg/m2, and 42% with cabazitaxel 25 mg/m2.23 In contrast, rates of PSA response were 78% with abiraterone and 69% with enzalutamide.24,25

Thus, abiraterone and enzalutamide appear to be at least as effective as docetaxel in treating mCRPC. We must also consider safety. Chemotherapy toxicities can be serious, but are relatively simple to manage given appropriate experience, infrastructure, and vigilance. In FIRSTANA, chemotherapy not infrequently led to grade 3-4 treatment-emergent adverse events, such as febrile neutropenia and diarrhea, toxicity stopped about a third of patients from completing treatment.23 In addition, 25% of patients developed docetaxel-emergent grade 1-2 peripheral neuropathy, which will progress without dose reduction or cessation. Rates of death linked to adverse events were 2% in the docetaxel group, 0.8% in the cabazitaxel 20 mg/m2 group, and 2.8% in the 25 mg/ m2 group,23 underscoring the importance of selecting patients who are well enough to receive chemotherapy.

So, in the abiraterone and enzalutamide era, is there still a role for upfront chemotherapy in the mCRPC setting? I would definitely say yes. Robust data support upfront chemotherapy in patients with mCRPC who have a clear disconnect between PSA and burden of disease. Tumors in patients who have a low PSA but a high burden of mPC clearly lack an androgen receptor therefore pose a much higher risk of treatment failure on hormonal therapy. Additional considerations for upfront chemotherapy include high burden of visceral metastases, rapidly progressive moderate to severe symptoms, minimal response to primary AD, or androgen receptor splice variant-7 (AR-V7) in circulating tumor cells, which predicts worse outcomes in mCRPC.26 Together, these groups comprise about 10% to 20% of patients who walk through our doors.

Finally, we should keep in mind that chemotherapy can remain effective after mCRPC patients receive hormonal therapy. In a post-hoc analysis of COU-302, 265 patients received chemotherapy a median of 3 months (interquartile range, 1 to 5 months) after abiraterone.27 In all, 47% of these patients experienced at least a 50% decline in PSA, with a median time to PSA progression of 7.6 months.27 In other studies, between 30% and 43% of patients who received cabazitaxel after abiraterone or enzalutamide had at least a 50% decline in PSA.28,29,30

CONCLUSIONS

Before venturing into the realm of chemotherapy, urologists should be accustomed to treating patients with prednisone and their clinics should already have infusion capabilities. A clinic that focuses on incontinence, vasectomies, and uroliths is not an appropriate setting for chemotherapy. It’s important that all clinic members establish a group mindset and commitment. When financially feasible, it also makes biological sense to stack therapies, such as by adding radium-23 therapy to hormonal or chemotherapy. For high-volume visceral metastatic disease, biopsies can help clarify whether tumor tissue is poorly differentiated and whether non-androgen-responsive disease that requires upfront chemotherapy.

Hormonally-based therapy should be used early in the mCRPC setting and should be first-line therapy for almost all patients. However, chemotherapy remains appropriate for some patients with mPC, and upfront chemotherapy should be considered for some patients with mCRPC and almost all patients with mHSPC. The role of chemotherapy in low-volume and non-metastatic prostate cancer remains questionable. Molecular classification should help guide future treatments. In the meantime, early recognition of resistance remains a critical priority in the clinic, enabling patients to access multiple lines of therapy and achieve better outcomes.

Written by: Fred Saad, MD, FRCS

REFERENCES

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  2. Saad F. Should urologists give chemotherapy? Can Urol Assoc J 2008; 2(2): 135-136.
  3. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373(8):737-746.
  4. James ND, Sydes MR, Clarke NW, et al; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387(10024):1163-1177.
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  12. Highlights of prescribing information. Taxotere (docetaxel) injection concentrate, intravenous infusion (IV). https:/www.accessdata.fda.gov/drugsatfda_docs/label/2010/020449s059lbl.pdf Accessed November 28, 2017.
  13. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomized open-label trial. Lancet 2010;376:1147-1154.
  14. Eisenberger M, Hardy-bessard AC, Kim CS, et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J Clin Oncol 2017;35(28):3198-3206.
  15. Highlights of prescribing information. Jevtana (cabazitaxel) injection, 60 mg/1.5 mL, for intravenous infusion only. https:/www.accessdata.fda.gov/drugsatfda_docs/label/2010/201023lbl.pdf. Accessed November 28, 2017.
  16. Geethakumari PR, Cookson MS, Kelly WK. The evolving biology of castration-resistant prostate cancer: review of recommendations from the Prostate Cancer Clinical Trials Working Group 3. Oncology (Williston Park, NY) 2016;30(2):187-95, 199.
  17. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351(15):1502-1512.
  18. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008;26(2):242-245.
  19. Sweeney C, Chen Y-H, Liu G, et al. Long term efficacy and QOL data of chemohormonal therapy (C-HT) in low and high volume hormone naïve metastatic prostate cancer (PrCa): E3805 CHAARTED trial. Ann Oncol 2016;27(suppl_6):720PD.
  20. Parker C, Gillessen S, Heidenreich A, et al. Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26 Suppl 5:v69-77.
  21. Sandler HM, Hu C, Rosenthal SA. A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with doxetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521) Proc Am Soc Clin Oncol 2015;33(suppl) abstr LBA5022.
  22. Vale CL, Burdett S, Rydzewska LHM, et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol 2016;17(2):243-256.
  23. Oudard S, Fizazi K, Sengeløv L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase iii trial-FIRSTANA. J Clin Oncol 2017;35(28):3189-3197.
  24. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus predni- sone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16(2):152-60.
  25. [No authors listed] NICE guidance: Enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. BJU Int 2017;120(2):168-184.
  26. Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen receptor splice variant-7 mrna detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol 2017;35(19):2149-2156.
  27. De Bono JS, Smith MR, Saad F, et al. Response to taxane chemotherapy as first subsequent therapy after abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post-hoc analysis of COU-AA-302. J Clin Oncol 2015;33(suppl 7):abstr 184. http:/ascopubs. org/doi/abs/10.1200/jco.2015.33.7_suppl.184
  28. Pezaro CJ, Omlin AG, Altavilla A, et al. Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents. Eur Urol 2014;66(3):459-465.
  29. Avishay Sella, Tal Sella, Avivit Peer, et al. Activity of cabazitaxel following docetaxel and abiraterone acetate in patients with castration-resistant prostate cancer. J Clin Oncol 2013;31 (suppl 6):abstr 186. http:/ascopubs.org/doi/abs/10.1200/jco.2013.31.6_suppl.186
  30. Saad F, Miller K. Treatment options in castration-resistant prostate cancer: current therapies and emerging docetaxel-based regimens. Urol Oncol 2014;32(2):70-79.
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