Prostate Cancer Resource Center
Recent progress in treating advanced prostate cancer

Current Opinion in Oncology

Theodore Gourdin


Abstract

Purpose of review

Summarize recent advances in the treatment of advanced prostate cancer.

Recent findings

Recent randomized data suggest a survival advantage to early use of novel androgen receptor inhibitors in combination with androgen deprivation therapy both in the setting of hormone-sensitive metastatic prostate cancer and nonmetastatic castration-resistant disease. While ongoing analyses examine optimal sequencing of existing agents for treatment of advanced prostate cancer, additional research focuses on expanding treatment options through development of novel genomically targeted therapies, antibody–drug conjugates, and immune therapy combinations.

Summary

In this review, we summarize the recent data supporting the early use of novel androgen receptor inhibitors in advanced prostate cancer and aim to also frame how these drugs may fit within the existing context of docetaxel and abiraterone. We present recent series examining sequencing of approved therapies while searching for predictive biomarkers. Finally, we examine trials evaluating novel agents that target certain biological pathways to highlight the likely future directions for progress in the clinical management of advanced prostate cancer.


Introduction

Although prognosis for men with advanced prostate cancer is improving with the introduction of a growing number of systemic therapies, approximately 31 000 men died of the disease in 2019 in the United States [1]. Recent efforts to improve overall survival in patients with advanced prostate cancer have focused on optimizing use of existing systemic therapies while exploring novel interventions. Improving the utility of known therapeutics has centered on introduction of treatments earlier in the spectrum of disease and refining drug sequencing. Avenues of research to identify novel therapies for advanced prostate cancer have included targeting tumor-specific genomic anomalies, refining antibody–drug conjugates (ADCs), and continuing to try to develop effective immune therapies. The present review will focus on recent developments in the treatment of advanced prostate cancer with an eye toward research questions that must be answered to yield further progress.

Expanding Options In Metastatic Hormone-Sensitive Prostate Cancer


Although the CHAARTED (Chemo-hormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials established an overall survival (OS) advantage to early docetaxel and abiraterone respectively in the setting of metastatic hormone-sensitive prostate cancer (mHSPC), debate remains about choice between these agents [2–3,4▪]. Questions about optimal therapy in mHSPC have only become more complicated with recent randomized data showing survival advantage to use of novel androgen-receptor inhibitors in this disease space. Finally, questions about resource utilization/cost may start to play a larger role in influencing clinician decision making in newly diagnosed metastatic prostate cancer.

Androgen-Receptor Inhibitors In Metastatic Hormone-Sensitive Prostate Cancer


Enzalutamide, already FDA approved in the setting of metastatic castration-resistant prostate cancer (mCRPC), was demonstrated in two separate randomized trials published in the past year to convey an efficacy advantage when added to standard androgen deprivation therapy (ADT) in mHSPC. The ENZAMET (Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer) trial randomized 1125 men with newly diagnosed metastatic prostate cancer to standard ADT plus 160 mg daily enzalutamide versus ADT plus first-generation nonsteroidal antiandrogen therapy (bicalutamide, nilutamide, or flutamide). Interestingly, men were stratified by volume of metastatic disease and by planned use of early docetaxel (yes vs. no). After a median follow-up of 34 months, there were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group yielding a hazard ratio for death of 0.67; 95% confidence interval (CI), 0.52–0.86; P = 0.002. Of note, the effects of enzalutamide on overall survival were muted in patients with high volume disease and patients who received early docetaxel or antiresorptive therapy with P values for heterogeneity of the treatment effect of enzalutamide greater than 0.05 [5▪▪].

In the ARCHES (A Randomized, Phase III Study of Androgen Deprivation Therapy with Enzalutamide or Placebo in Men with Metastatic Hormone-Sensitive Prostate Cancer) trial, 1150 men with mHSPC were randomized to enzalutamide 160 mg daily or placebo plus ADT. Patients were again stratified by volume of disease and by use of early docetaxel. Primary endpoint for this trial was radiographic progression-free survival (rPFS) with a hazard ratio at 3 years favoring the enzalutamide group of 0.39; 95% CI, 0.33–0.47; P < 0.001). The treatment effect was maintained regardless of disease status or receipt of early docetaxel. Overall survival data were immature at time of first published analysis [6▪▪].

Apalutamide, another next-generation androgen-receptor inhibitor, was also recently evaluated in the setting of mHSPC with the TITAN (Targeted Investigational Treatment Analysis of Novel Antiandrogen) trial, which randomized 1052 men with newly diagnosed mHSPC to apalutamide 240 mg daily plus ADT versus placebo plus ADT. Like in the ARCHES trial, the primary endpoint was rPFS and patients were stratified by disease volume status and prior use of docetaxel. At first interim analysis, with a median 22.7 months follow-up, the percentage of patients with rPFS in the apalutamide group was 68.2 versus 47.5% in the placebo group representing a hazard ratio for progression or death favoring apalutamide of 0.48; 95% CI, 0.39–0.60; P < 0.001. Notably, an overall survival advantage was also detected at 24 months with 82.4% of patients alive in the apalutamide group versus 73.5% in the placebo group representing a hazard ratio for death favoring apalutamide of 0.67; 95% CI, 0.51–0.89; P = 0.005. Although the rPFS advantage for patients receiving apalutamide was preserved regardless of volume status of disease or previous docetaxel, the statistically significant advantage in OS disappeared in the subgroup of patients who received previous docetaxel [7▪▪].

Remaining Questions In Metastatic Hormone-Sensitive Prostate Cancer


For a period of time, consensus interpretation of available data supported the use of docetaxel or abiraterone with ADT in the setting of newly diagnosed metastatic prostate cancer with results of the CHAARTED trial in particular suggesting that docetaxel be reserved for patients with high volume disease [3]. A recent update of data from STAMPEDE conflicts somewhat with this consensus with docetaxel conveying an overall survival advantage when combined with ADT in both low-volume and high-volume disease [8]. Three recent trials, ENZAMET, ARCHES, and TITAN, evaluating novel androgen-receptor inhibitors in mHSPC, suggest that there is also benefit to these drugs in combination with ADT in this disease space [5▪▪,6▪▪,7▪▪]. Unlike the earlier trials of abiraterone, these trials allowed concomitant use of early docetaxel. Although PFS endpoints did not seem influenced by use of early docetaxel in these trials, overall survival results were mixed in the relatively small subgroups of patients who received early docetaxel, suggesting that there may not be an additive benefit to cytotoxic chemotherapy plus novel androgen directed therapy in mHSPC. A recent meta-analysis of trials in the setting of mHSPC identified no indirect difference in relative overall survival advantage to docetaxel, abiraterone, enzalutamide, or apalutamide when combined with ADT as compared to ADT alone [9]. It may be that toxicity profile becomes a determining factor in clinician decision making in this disease space, and one particular side effect of note may become ‘financial toxicity [10]’. One recent analysis calculated an incremental cost effectiveness ratio or United States dollar per quality adjusted life year added of $34 723 for a regimen of early docetaxel plus ADT versus $295 212 for early abiraterone plus ADT representing a clear cost advantage to the cytotoxic agent [11].

An Expanding Treatment Space: Nonmetastatic Castration-Resistant Prostate Cancer


Nonmetastatic castration resistant prostate cancer (nmCRPC), a disease entity characterized by a rising PSA on ADT with no overt evidence of metastatic disease on CT scans/nuclear bone scan, represents a heterogeneous disease space with until recently no accompanying FDA approved therapies [12]. As rapid PSA doubling time in patients with nmCRPC has historically been linked with rapid development of radiographic metastases and eventually death, a group of recent trials have evaluated the novel androgen receptor directed therapies in the setting of nmCRPC with short PSA doubling time [13]. The SPARTAN (A Study of Apalutamide (ARN-509) in Men with nmCRPC), PROSPER (A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Enzalutamide in Patients with nmCRPC), and ARAMIS (Efficacy and Safety Study of Darolutamide (ODM-201) in Men with High-risk nmCRPC) randomized trials demonstrated respective efficacy advantages to apalutamide, enzalutamide, and darolutamide versus placebo in combination with ADT in patients with nmCRPC and PSA doubling times less than 10 months [14▪▪,15,16]. All three of these trials initially reported statistically significant advantages in a rather novel endpoint of metastasis-free survival (mFS), with hazard ratios for metastasis or death of 0.28; 95% CI, 0.23–0.35; P < 0.001 favoring the apalutamide combination group, 0.29; 95% CI, 0.24–0.35; P < 0.001 favoring the enzalutamide combination group, and 0.41; 95% CI, 0.34–0.50; P < 0.001 favoring the darolutamide combination group. Upon a second interim analysis of data from the SPARTAN trial at a median follow-up of 41 months, 22% of patients in the apalutamide group had died versus 27% in the placebo group representing a hazard ratio for death favoring the apalutamide group of 0.75; 95% CI 0.59–0.96; P = 0.0197 [17▪▪]. All three of these novel androgen-receptor inhibitors are now FDA approved for nmCRPC with only limited indirect comparative data available to guide clinician selection [18].

Metastatic Castration-Resistant Prostate Cancer: Drug Sequencing


Although novel therapeutics are being incorporated earlier into the treatment paradigm for advanced prostate cancer, most patients will still inevitably develop metastatic castration-resistant prostate cancer (mCRPC). Upfront therapies will certainly inform choice of subsequent intervention, but research continues into optimal sequencing strategies. In a phase II crossover trial, Khalaf et al. randomized 202 men with mCRPC naïve to second-generation androgen-directed therapies to abiraterone followed by enzalutamide at progression versus enzalutamide followed by abiraterone at progression. Time to second PSA progression was longer when the second agent was enzalutamide and similarly responses were seen in 36% of men who received enzalutamide as a second-line agent but only 4% of men who received second-line abiraterone [19▪]. In the context of poor responses to a second androgen signaling-targeted therapy (ASTT), another prospective trial randomized men with mCRPC who had failed docetaxel and either enzalutamide or abiraterone to cabazitaxel 25 mg/m2 intravenously every 3 weeks or the alternative ASTT. Statistically significant advantages were detected to cabazitaxel versus an alternative ASTT in PFS, PSA response rate, and OS [20▪▪]. Building on a potentially increased role for cabazitaxel, a phase II trial in men with mCRPC demonstrated an improved median PFS with combination carboplatin AUC 4 plus cabazitaxel 25 mg/m2 of 7.3 months as opposed to cabazitaxel alone of 4.5 months for a hazard ratio for progression of 0.69; 95% CI, 0.50–0.95; P = 0.018 [21].

As opposed to rote sequencing of therapies, an alternative construct has been investigating genomic predictors of prognosis and response. Chen et al.[22▪] performed prospective whole genome sequencing and RNA sequencing in a cohort of 101 patients with mCRPC revealing anomalies in the Wnt/β-catenin pathway as predictive of enzalutamide resistance and poor overall prognosis. In a finding confirmed in a second larger series, genomic alterations in RB1, particularly multiple anomalies in tandem, predicted poor overall survival and lack of treatment response in mCRPC [22▪,23]. In fact, RB1 anomalies along with loss of expression of the androgen receptor were shown in a separate series to be characteristic of the small cell neuroendocrine carcinoma that can be identified as a novel morphology in response to treatment failure [24]. In addition to particular genomic mutations, splice variants such as androgen receptor splice variant 7 (AR-V7) continue to correlate with disease response/prognosis in advanced prostate cancer. Building on earlier data, Armstrong et al. prospectively analyzed disease response to abiraterone or enzalutamide in a cohort of 118 men with mCRPC correlating treatment response to baseline AR-V7 detection via two separate assays. After adjusting for well validated prognostic factors, AR-V7 detection was associated with inferior PFS, OS, and relative lack of response to either ASTT [25▪]. Although further randomized trials will be required before routine clinical decisions about sequencing can be made based on existing genomic interrogation techniques, the more important underlying message may be that novel treatment strategies are required to tackle the full spectrum of advanced prostate cancer.

Novel Treatment Strategies In Advanced Prostate Cancer: Targeted Therapies


Further data were presented in the last year supporting the use of targeted therapies in men with advanced prostate cancer and DNA damage response (DDR) gene aberrations. In the open-label phase II TOPARP-B (A Phase II Trial of Olaparib in Patients with Advanced Castration Resistant Prostate Cancer) trial, 98 men with progressive mCRPC after previous taxane therapy possessing confirmed DDR gene aberrations were randomized to 400 mg twice per day or 300 mg twice per day dosing of the oral poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. At median follow-up of 24.8 months, disease responses (radiographic, PSA, and defined circulating tumor cell metrics) were obtained in 54.3% of patients in the 400 mg cohort and 39.1% of patients in the 300 mg cohort [26]. Like olaparib, two additional PARP inhibitors, rucaparib and niraparib, have also received FDA breakthrough designation for patients with mCRPC with DDR genetic anomalies based on phase II trials showing clinical efficacy in this population [27]. Although full FDA approval for PARP inhibition in patients with prostate cancer possessing DDR genetic anomalies is likely imminent, additional antibody-conjugated therapies will hopefully be beneficial to a broader group of patients with prostate cancer.

The PSMA-targeted radiopharmaceutical 177Lu-PSMA-617 continues to be evaluated in several studies showing its potential utility in patients with heavily treated mCRPC [28,29,30▪]. One prospective analysis of 90 men with mCRPC, almost all refractory to chemotherapy and an ASTT, demonstrated a more than 50% decline in PSA in response to 177Lu-PSMA-617 in 45.5% of patients with no clearly predictive biomarkers identified on univariate analysis including degree of 68Ga-PSMA uptake on pretherapy 68Ga-PSMA PET/CT [30▪]. A separate dose escalation phase I trial evaluated a cytotoxic (monomethyl auristatin E/MMAE) bound to an anti-PSMA monoclonal antibody as opposed to a radioisotope. A total of 52 men with refractory mCRPC were treated with this PSMA ADC revealing an acceptable toxicity profile and preliminary signs of efficacy supporting further development [31].

Not Giving Up On Immunotherapy


Although modern checkpoint inhibitors have shown reproducible results in treating other genitourinary malignancies, prostate cancer has initially proven to be fairly resistant to immunotherapy. A phase III trial of PROSTVAC, a viral vector-based immunotherapy, disappointingly demonstrated no OS advantage compared to placebo in men with mCRPC despite encouraging phase II data [32▪]. An attempt in a randomized phase II trial to improve on the one existing FDA approved immunotherapy in prostate cancer, sipuleucel-T, by combining the vaccine with sensitizing radiation therapy also demonstrated no statistically significant efficacy advantage over sipuleucel-T alone [33]. Pembrolizumab did yield durable responses by RECIST criteria in a small percentage of men (3–5%) with mCRPC in several cohorts of the open label Phase II KEYNOTE-199 study. Neither PD-L1 expression nor presence of mutation in a DDR gene clearly correlated with response [34▪▪]. Interestingly, a retrospective series of patients with mCRPC treated with pembrolizumab at Duke University identified an LRP1b mutation in two of four men with at least 90% PSA decline suggesting a biomarker that may warrant prospective testing [35]. A way forward with immunotherapy in prostate cancer will be to test combination therapies; preliminary data with ipilimumab/nivolumab in mCRPC are sparking interest and multiple ongoing trials are evaluating checkpoint inhibitors in combination with other therapeutics [36].

Conclusion

Treatment options for men with newly diagnosed metastatic prostate cancer continue to expand, with clinicians now deciding between docetaxel, abiraterone, and androgen-receptor inhibitors as part of combination therapy with gonadal androgen deprivation. A trio of androgen receptor inhibitors are now also FDA approved in nonmetastatic castration resistant prostate cancer essentially opening a new therapeutic window. While existing therapies are being moved earlier in the treatment paradigm, the real way forward in advanced prostate cancer will be through novel interventions. A variety of genomically-targeted agents, antibody-conjugates, and immune therapies are poised to further improve outcomes for men with prostate cancer in the future.


Financial support and sponsorship

The authors of this review have received no source of funding in relation to creation of this manuscript. T.G. has received research funding from Ferring Pharmaceuticals for purposes of conducting an investigator initiated trial.

References and Recommended Reading

& of special interest

&& of outstanding interest

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4. & Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol 2019; 20:686–700. The OS advantage demonstrated with combining abiraterone and ADT in mHSPC in the LATITUDE trial is updated with longer term follow-up.

5. && Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. New Engl J Med 2019; 381:121–131. Combining enzalutamide with ADT versus a standard nonsteroidal antiandrogen with ADT improved OS in the randomized phase III ENZAMET trial in men with mHSPC. Of note, the effects of enzalutamide on OS were muted in patients with high volume disease and patients who received early docetaxel.

6. && Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2019; 37:2974–2986. Enzalutamide in combination with ADT improves rPFS versus placebo with ADT in men with mHSPC in the randomized phase III ARCHES trial. The treatment effect was maintained regardless of disease status or receipt of early docetaxel. OS data were immature at time of first published analysis.

7. && Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castrationsensitive prostate cancer. New Engl J Med 2019; 381:13–24. The randomized phase III TITAN trial demonstrated rPFS and OS advantages to apalutamide plus ADT versus placebo plus ADT in mHSPC. Although the rPFS advantage for patients receiving apalutamide was preserved regardless of volume status of disease or previous docetaxel, the statistically significant advantage in OS disappeared in the subgroup of patients who received previous docetaxel.

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20. && de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. New Engl J Med 2019; 381:2506–2518. The authors of this prospective trial randomized men with mCRPC refractory to docetaxel and either abiraterone or enzalutamide to cabazitaxel or the other androgen-signaling-targeted inhibitor. Cabazitaxel significantly improved PFS, PSA response rate, and OS.

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24. Aggarwal RR, Quigley DA, Huang J, et al. Whole-genome and transcriptional analysis of treatment-emergent small-cell neuroendocrine prostate cancer demonstrates intraclass heterogeneity. Mol Cancer Res 2019; 17:1235–1240.

25. & Armstrong AJ, Halabi S, Luo J, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in highrisk castration-resistant prostate cancer: the PROPHECY study. J Clin Oncol 2019; 37:1120–1129. Detection of AR-V7 via two distinct assays in a prospective study correlated with shorter PFS and OS in a cohort of men with mCRPC initiating therapy with abiraterone or enzalutamide.

26. Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2020; 21:162–174.

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28. Emmett L, Crumbaker M, Ho B, et al. Results of a prospective phase 2 pilot trial of (177)Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer including imaging predictors of treatment response and patterns of progression. Clin Genitourinary Cancer 2019; 17:15–22.

29. Hofman MS, Violet J, Hicks RJ, et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol 2018; 19:825–833.

30. & Yadav MP, Ballal S, Bal C, et al. Efficacy and safety of 177Lu-PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer patients. Clin Nucl Med 2020; 45:19–31. Treatment with the radiopharmaceutical (177)Lu-PSMA-617 yielded at least 50% PSA declines in 45.5% of this cohort of 90 men with mCRPC largely refractory to chemotherapy and enzalutamide/abiraterone.

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32. & Gulley JL, Borre M, Vogelzang NJ, et al. Phase III trial of PROSTVAC in asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. J Clin Oncol 2019; 37:1051–1061. Despite earlier intriguing phase II data, a phase III trial of PROSTVAC, a viral vectorbased immunotherapy, disappointingly demonstrated no OS advantage compared to placebo in men with mCRPC.

33. Twardowski P, Wong JYC, Pal SK, et al. Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-T alone in patients with metastatic castrate resistant prostate cancer. Cancer Treat Res Commun 2019; 19:100116.

34. && Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol 2020; 38:395–405. Treatment with pembrolizumab yielded durable radiographic responses in a small number (3–5%) of men from several cohorts of patients with mCRPC treated on the phase II KEYNOTE-199 study. Neither PD-L1 expression nor presence of DNA repair defects clearly correlated with response.

35. Tucker MD, Zhu J, Marin D, et al. Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. Cancer Med 2019; 8:4644–4655.

36. Sharma P, Pachynski RK, Narayan V, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). J Clin Oncol 2019; 37(7_suppl):142.

 

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