Prostate Cancer Resource Center

Optimization of therapies for men with advanced prostate cancer

a review of recent developments with a look toward the future

Current Opinion in Oncology

Theodore Gourdin


Purpose of review: Summarizes the rapid progress being made in treatment of advanced prostate cancer.

Recent findings: Debate remains regarding the optimal sequencing of therapies in metastatic castration-sensitive prostate cancer with attention focused on the use of abiraterone versus docetaxel. Randomized trials now show a potential advantage to next-generation antiandrogens in the setting of nonmetastatic castration-resistant prostate cancer. Patient-specific genomic anomalies, in particular DNA repair defects, provide targets for therapy with poly(ADP-ribose) polymerase inhibitors alone and in combination with other interventions. Adjustments in the dose and administration schedule of the accompanying steroid may improve the efficacy of abiraterone. Novel radiopharmaceuticals and immunotherapies suggest progress is on the horizon for men with castration-resistant prostate cancer.

Summary: In this review, we will highlight the avenues of research leading to optimization of therapies for men with advanced prostate cancer. Known therapeutics, such as docetaxel and abiraterone, are being used earlier in the disease course in the setting of metastatic castration-sensitive prostate cancer, and next-generation antiandrogens in the setting of nonmetastatic castration-resistant disease. Existing interventions are being optimized, including a maneuver to salvage abiraterone response with steroid switch. Finally, individualized therapies directed at specific genomic aberrations, a radiopharmaceutical targeting prostate-specific membrane antigen, and immune therapy combinations are providing potentially additional treatment options for patients with refractory disease.


Introduction

Average survival for men with metastatic prostate cancer has improved over the last decade because of an expanding armamentarium of therapeutics initially evaluated in men whose cancers developed resistance to standard androgen deprivation [1]. Nonetheless, it is predicted that 32 000 men will die of prostate cancer in the United States in 2019 [2]. Continuing efforts to improve overall survival (OS) of men with advanced prostate cancer focus on optimizing the sequencing of existing therapies and moving treatments that have activity in the castration-resistant disease state to earlier disease settings. Additional attention has focused on individualizing interventions based on patient-specific genomic anomalies and development of novel therapeutics. The goal of this review is to summarize recent progress in the management of advanced prostate cancer with a look toward future realms for research.

Sequencing Therapies in Metastatic Castration-Sensitive Prostate Cancer: Docetaxel Versus Abiraterone

A majority of men with newly diagnosed metastatic prostate cancer obtain response to androgen deprivation therapy (ADT), but castration-resistant disease almost inevitably develops at an average of 18–24 months [3]. When metastatic castration-resistant prostate cancer (mCRPC) emerges, cytotoxic chemotherapy with docetaxel and second-generation androgen-receptor (AR)-targeted therapy with enzalutamide or abiraterone have emerged as standard treatment options. Recent randomized trials have demonstrated a survival advantage to moving these therapies earlier in the treatment paradigm. The question in many patients has become which of these interventions, chemotherapy or second-generation hormonal therapy, is preferred in addition to ADT in a patient with newly diagnosed metastatic disease.

An updated look at follow-up from the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) trial confirms an OS advantage to combining six cycles of docetaxel with ADT in newly diagnosed metastatic prostate cancer with a hazard ratio (HR)of 0.72 (95% confidence interval (CI), 0.59 to 0.89; P = .0018) favoring combined therapy versus ADT alone in the overall treatment population [4▪]. The HR for OS decreases to 0.63 (95% CI, 0.50 to 0.79; P < .001) when examining patients with high-volume disease (defined by this trial as visceral disease and/or at least four bone metastases with at least one outside of the vertebral column/pelvis), but a statistically significant OS advantage disappears when only the low-volume patients are analyzed.

Two randomized controlled trials, an arm of the multistage Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial and the LATITUDE [A Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Participants with High-Risk, Metastatic Hormone-Naive Prostate Cancer (mHNPC)] trial, demonstrated improved OS when adding abiraterone to ADT versus ADT alone in this same treatment-naïve metastatic setting [5,6]. STAMPEDE did not divide patients into ‘high volume’ and ‘low volume’ but 48% of the examined patients were either node-positive/nonmetastatic or node-negative/nonmetastatic. A HR for OS favoring combined therapy versus ADT alone of 0.63 (95% CI, 0.52–0.76; P < 0.001) in the STAMPEDE trial that included such a large number of patients with lower volume disease, suggests that perhaps abiraterone with ADT has greater relative efficacy in lower volume treatment-naïve patients than docetaxel with ADT. The best treatment option in higher volume disease remains less straightforward. A thought-provoking meta-analysis of 8820 men treated prospectively on randomized phase 3 trials in the setting of mCRPC suggests an OS advantage for black men as compared to white men when adjusted for established risk factors if receiving docetaxel and prednisone, but it is not clear that this finding can be extrapolated to castration-sensitive disease [7▪].

Although the definition of ‘high-risk prostate cancer’ in LATITUDE (≥2 of the following factors: Gleason score of ≥8, presence of ≥3 bone lesions, or presence of measurable visceral metastases) differs slightly from the definition of ‘high-volume’ disease in CHAARTED, separate analysis using Cohen's κ coefficient suggests ‘almost perfect’ definition agreement between the two disease volume characterizations, and with similar ability to prognosticate disease outcome [8]. Meta-analyses have attempted to compare the two interventions, and most suggest a relative advantage to abiraterone with ADT versus docetaxel with ADT in the setting of castration sensitive disease [9,10]. Feyerabend et al. used fixed effects Bayesian methods to compare OS, progression-free survival, and quality of life associated with abiraterone/prednisone versus docetaxel using data from the CHAARTED, STAMPEDE, LATITUDE, and GETUG-AFU15 (Randomized Phase III Trial Comparing An Association of Hormonal Treatment and Docetaxel Versus the Hormonal Treatment Alone in Metastatic Prostate Cancers) trials [4▪,5,6,11,12▪▪]. The OS component of the analysis showed a 9% relative reduction in mortality comparing patients treated with abiraterone versus docetaxel with the Bayesian probability for abiraterone being the better therapy of 84.5% [12▪▪] The one trial that has reported direct randomized comparative data evaluating abiraterone versus docetaxel in this setting, although not formally powered, is STAMPEDE. This trial showed a HR of 1.16 (95% CI, 0.82–1.65) actually favoring docetaxel [5]. Although biomarkers such as AR splice variants are starting to show utility in predicting response to taxanes versus AR signaling inhibitors in the castration resistant setting, novel biomarkers would be ideal to help predict relative efficacy of interventions in the hormone-sensitive setting [13]. Alternatively, ongoing trials may show advantage to combining both docetaxel and AR signaling inhibitors with ADT as upfront therapy in newly diagnosed metastatic disease.

Radiation Therapy

Retrospective data suggest that local therapy to the prostate might improve outcomes in patients with de novo metastatic prostate cancer [14]. Recent prospective data evaluating the role of radiotherapy to the intact prostate in the setting of metastatic disease show mixed results. The HORRAD [A randomized study of the effect on survival of hormonal therapy versus hormonal therapy plus local external radiation therapy in patients with primary diagnosed metastasized (M+) prostate cancer] trial prospectively randomized 432 men with newly diagnosed bony metastatic prostate cancer and prostate-specific antigen (PSA) more than 20 to ADT plus or minus external beam radiation therapy to the prostate. No difference was found in OS between the two groups with HR 0.90 (95% CI, 0.70–1.14; P = 0.4). There was a trend toward an OS advantage to including radiation therapy for patients with less than five metastases, but this trend did not reach statistical significance [15]. A separate sub-protocol of the STAMPEDE trial randomized 2061 patients with newly diagnosed metastatic prostate cancer to standard of care ADT (with possible stratification to early docetaxel) with or without radiotherapy to the prostate. Radiotherapy improved failure-free survival (HR 0.76, 95% CI, 0.68–0.84; P < 0.0001) but not OS (0.92, 0.80–1.06; P = 0.266). Analysis of only patients with low-volume metastatic disease (per CHAARTED criteria), however, revealed an OS advantage in this group to including radiotherapy (HR 0.68, 95% CI, 0.52–0.90; P = 0.007) [16▪].

New Therapies in Nonmetastatic Castration-Resistant Prostate Cancer

As the advent of PSA screening, a greater number of men are presenting with a rising PSA after definitive therapy as their first evidence of recurrent (nonmetastatic or metastatic) prostate cancer. The development of biochemically recurrent prostate cancer often prompts initiation of ADT, and a nontrivial percentage of these men subsequently develop nonmetastatic castration-resistant prostate cancer (nmCRPC) [17]. This is a heterogeneous population of men with rising PSA on ADT but no gross metastases visible on conventional imaging [18]. Little robust evidence has been available to guide treatment decisions for this group, but in the last year two prospective trials demonstrated the efficacy of next-generation antiandrogens in men with nmCRPC.

The PROSPER [A Phase 3 randomized, double-blind placebo (PBO)-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer] trial randomized 1401 men with nmCRPC and PSA doubling time of less than 10 months whereas on ADT in 2:1 fashion to enzalutamide 160 mg daily or placebo with imaging every 16 weeks until radiographic progression. The primary endpoint of radiographic metastasis-free survival favored enzalutamide (36.6 versus 14.7 months) with HR for metastasis or death of 0.29 (95% CI, 0.24 to 0.35; P < 0.001). Time to subsequent antineoplastic therapy and time to PSA progression were also significantly extended with relatively few side-effects in the enzalutamide arm, in keeping with the established safety profile of the drug [19▪▪]. In the SPARTAN [A Study of Apalutamide (ARN-509) in Men with Non-Metastatic Castration-Resistant Prostate Cancer (SPARTAN)] trial, 1201 men with nmCRPC and PSA doubling time less than 10 months were randomized in 2:1 fashion to apalutamide 240 mg daily versus placebo [20▪▪]. Apalutamide is a second-generation antiandrogen that, like enzalutamide, binds the AR ligand-binding domain preventing AR activation, inhibiting translocation of AR to the nucleus, and inhibiting transcription of target genes [21]. Radiographic metastasis-free survival in this trial favored apalutamide at 40.5 months in the treatment arm versus 16.5 months in the placebo arm. HR for metastasis or death was 0.28 (95% CI, 0.23 to 0.35; P < 0.001) [20▪▪].

Neither the PROSPER nor the SPARTAN trial have yet reported OS data. Metastasis-free survival has been reported as a surrogate endpoint for OS in the setting of localized disease, but its significance in the setting of nmCRPC remains unclear [22]. The relative efficacies of enzalutamide and apalutamide appear similar but have not been compared in randomized fashion [17]. The effect that initiation of ether of these therapies in this disease space has on subsequent lines of systemic therapy also remains to be answered. Finally, we await data for darolutamide, a next-generation antiandrogen with higher affinity for AR than the previously discussed agents, which is being evaluated in randomized phase 3 trials in both nmCRPC and hormone-sensitive metastatic disease [21].

Castration Resistant-Prostate Cancer

Although moving systemic therapies earlier in the treatment algorithm is improving outcomes in prostate cancer, the majority of men with metastatic disease will eventually develop castration resistance. There are data that detection of particular AR splice variants or AR amplifications/mutations via circulating tumor DNA or circulating tumor cells may predict relative efficacy of taxanes versus second-generation androgen-directed therapies in mCRPC, but none of these assays are foolproof and patients continue to be treated essentially with a trial-and-error approach [23,24]. A retrospective review evaluated 260 patients who received third-line therapy with novel agents consisting of cabazitaxel, abiraterone, or enzalutamide after failure of docetaxel and one other novel agents. Median progression-free survival was 4 months and OS 11 months from the start of third-line therapy, with no significant differences noted based on the specific novel agent or treatment sequence used [25]. Unless more robust data emerge regarding the sequencing of existing therapies, the ways forward in the treatment of mCRPC appear to be adjustments to conventional therapies, selection of novel agents based on detection of genomic anomalies, and novel drug targets.

Adjustments to Existing Therapies in Metastatic Castration-Resistant Prostate Cancer

More than 60% of men with chemotherapy-naïve castration-resistant metastatic prostate cancer will obtain initial PSA response to abiraterone, but the majority will eventually develop resistance [26]. Building on data suggesting long-term use of prednisone can be a driver of resistance to abiraterone, the prospective phase 2 SWITCH (Phase II pilot study of the prednisone to dexamethasone switch in metastatic castration-resistant prostate cancer) trial treated 26 clinically stable men with mCRPC who developed PSA and/or limited radiographic progression after at least 12 weeks on abiraterone/prednisone with continuation of abiraterone but switch from prednisone to dexamethasone 0.5 mg daily [27,28▪]. In total 46.2% of these men had a 30% drop in PSA and 34.6% had a 50% drop in PSA. Median time to radiographic disease progression after the steroid switch was 11.8 months (95% CI, 6.6–17.1 months) suggesting clinical benefits to this treatment approach, but these findings should be confirmed in randomized fashion.

A second modification in the use of abiraterone was inspired by early phase data that showed increased absorption of the drug in the presence of food [27]. Szmulewitz et al.[29▪▪] randomized 72 men with progressive mCRPC to standard dose abiraterone 1000 mg daily fasting, as per the current Food and Drug Administration (FDA) label, or low-dose abiraterone 250 mg daily with a low-fat meal. Both arms received prednisone 5 mg twice per day. Although peak and trough serum concentrations of abiraterone were higher in the standard dose group, the PSA response rate was noninferior and numerically higher in the low-dose group at 58% versus 50% in the standard dose group. Changes in androgen level were also similar between groups [29▪▪]. Although these findings should be confirmed in a larger trial, they suggest that abiraterone could conceivably be prescribed at 25% of standard dose with food, a potentially significant cost savings in a medication that typically carries a retail cost of $10 000.00 per month.

Selection of Novel Agents Based on Genomic Anomalies

Mateo et al.[30] outlined in 2015 a role for poly(ADP-ribose) polymerase (PARP) inhibition with olaparib in men with mCRPC and DNA repair defects (DRDs). In a subgroup of 16 patients with homozygous deletions or deleterious mutations in DNA-repair genes in a phase 2 trial, 88% had a PSA response to olaparib, whereas only 6% (2/33) of patients without DRDs had a response to the drug [30]. These data alone suggest a role for screening men with prostate cancer for DRDs, but the role of PARP inhibition in metastatic prostate cancer continues to be refined. Retrospective reviews suggest that men with mCRPC and DRDs have responses to docetaxel, second-generation androgen-directed therapies, and radium-223 that mirror or even surpass those seen in men without DRDs, suggesting a potentially important role for synergistic therapies in this space [31–33].

A recent prospective phase 2 trial randomized 142 men with mCRPC who had failed docetaxel but not been treated with novel androgen-directed therapy in 1:1 fashion to abiraterone/prednisone and olaparib 300 mg twice daily or placebo. Radiographic progression-free survival (rPFS) was 13.8 months (95% CI, 10.8–20.4) in the olaparib/abiraterone group versus 8.4 months (95% CI, 5.5–9.7 months) in the placebo/abiraterone group. The HR for rPFS in favor of olaparib/abiraterone in this biomarker unselected population was 0.65 (95% CI, 0.44–0.97, P = 0.034) [34▪▪]. The study was not powered to detect differences in rPFS between the two arms stratified by presence of DRDs, but the rPFS curves clearly separate in favor of the olaparib-containing arm in both the homologous recombination repair-mutant subgroup and the homologous recombination repair-wild type group. Additional studies are ongoing, building on potential synergism between PARP inhibitors and checkpoint inhibitors, particularly in men with DRDs [35].

Therapeutics Directed at Novel Targets

Emerging technologies to interrogate circulating tumor components are making it faster to evaluate individual patient genomic anomalies, but a majority of patients will not have genomic aberrations easily targetable with current therapeutics [36]. An alternative approach to treating patients with advanced refractory prostate cancer is the development of therapeutics directed at novel targets. A particularly promising therapy in this vein is Lutetium-177 [177Lu]-PSMA-617, a radiolabeled small molecule that binds to prostate-specific membrane antigen (PSMA) delivering β-particle therapy to mCRPC cells. This treatment modality was evaluated in a prospective phase 2 trial looking at [177Lu]-PSMA-617 given intravenously every 6 weeks for up to four cycles to 30 men the majority of whom had received previous docetaxel, abiraterone, and enzalutamide [37▪]. Seventeen out of thirteen (57%) patients achieved a more than 50% reduction in PSA with an objective radiographic response noted in 82% of patients with baseline visceral/nodal disease.

Efforts are also ongoing to elicit the same efficacy signals with immune-based therapies in prostate cancer as seen in many other solid tumors. At this time, Sipuleucel-T, a dendritic cell vaccine, is the only FDA-approved immunotherapy for mCRPC on the basis of two randomized trials, with both showing approximately 4-month OS advantage to the intervention with frustratingly few PSA responses [38,39]. Single agent programmed cell death protein 1 inhibitors have to this point shown underwhelming activity in nonbiomarker selected metastatic prostate cancer, although data from the recently presented phase 1b KEYNOTE-028 [Study of Pembrolizumab (MK-3475) in Participants with Advanced Solid Tumors] trial looking at pembrolizumab in patients with tumoral/stromal programmed death-ligand 1 expression at least 1% demonstrated an overall response rate of 17.4% [95% CI, 5.0–38.8%] [40,41]. Further studies combining immunotherapies, including novel vaccine-based approaches, are ongoing.

Conclusion

Ongoing debate about cytotoxic chemotherapy versus second-generation hormonal therapy in newly diagnosed metastatic prostate cancer may eventually be extinguished if future data show an advantage to combining these therapies in fit patients. Although biomarkers to help guide treatment sequencing remain somewhat elusive, patient-specific genomic anomalies and particularly DRDs are opening up new avenues for therapy. Novel immune therapy combinations and emerging radiopharmaceuticals suggest future progress in the treatment of men with advanced prostate cancer.


Financial support and sponsorship

T.G. has received recent grant support from Ferring Pharmaceuticals to assist in conducting an investigator-initiated clinical trial.

References and Recommended Reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

& of special interest

&& of outstanding interest

1. Berg KD, Thomsen FB, Mikkelsen MK, et al. Improved survival for patients with de novo metastatic prostate cancer in the last 20 years. Eur J Cancer 2017; 72:20–27.

2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69:7–34.

3. Denis LJ, Keuppens F, Smith PH, et al. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center. Eur Urol 1998; 33:144–151.

4. & Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol 2018; 36:1080–1087. Long-term follow-up from this randomized trial comparing ADT and six cycles of docetaxel to ADT alone in newly diagnosed metastatic prostate cancer confirms an OS advantage to docetaxel in high-volume patients but not in low-volume disease.

5. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 2017; 377:338–351.

6. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017; 377:352–360.

7. & Halabi S, Dutta S, Tangen CM, et al. Overall Survival of Black and White Men With Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel. J Clin Oncol 2018; 00:JCO1801279. This meta-analysis of 8820 men treated prospectively on randomized phase 3 trials in the setting of mCRPC suggests an OS advantage for black men as compared to white men when adjusted for established risk factors if receiving docetaxel and prednisone. The therapy-related or genomic differences driving this result remain uncertain.

8. Buelens S, Poelaert F, Dhondt B, et al. Metastatic burden in newly diagnosed hormone-naive metastatic prostate cancer: Comparing definitions of CHAARTED and LATITUDE trial. Urol Oncol 2018; 36:158.e13–158.e20.

9. Vale CL, Fisher DJ, White IR, et al. What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis. Ann Oncol 2018; 29:1249–1257.

10. Wallis CJD, Klaassen Z, Bhindi B, et al. Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naive Prostate Cancer: A Systematic Review and Network Metaanalysis. Eur Urol 2018; 73:834–844.

11. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: 149–158.

12. && Feyerabend S, Saad F, Li T, et al. Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: A network metaanalysis. Eur J Cancer 2018; 103:78–87. The authors of this meta-analysis use Bayesian methods to compare the relative efficacy of abiraterone/ADT versus docetaxel/ADT in four randomized trials in patients with newly diagnosed castration-sensitive metastatic prostate cancer. Overall survival, progression-free survival, and quality of life appear to favor abiraterone.

13. Scher HI, Graf RP, Schreiber NA, et al. Assessment of the Validity of NuclearLocalized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer. JAMA Oncol 2018; 4:1179–1186.

14. Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014; 65:1058–1066.

15. Boeve LMS, Hulshof M, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol 2018.

16. & Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 2018; 392:2353–2366. This sub-protocol of the STAMPEDE trial randomized men with newly diagnosed metastatic prostate cancer to standard of care ADT (with possible stratification to early docetaxel) with or without radiotherapy to the prostate. Radiotherapy improved failure-free survival but not OS. Analysis of only patients with low-volume metastatic disease per CHAARTED criteria, however, revealed an OS advantage in this group to including radiotherapy to the prostate in the treatment paradigm.

17. Mateo J, Fizazi K, Gillessen S, et al. Managing Nonmetastatic Castrationresistant Prostate Cancer. Eur Urol 2019; 75:285–293.

18. Loriot Y, Supiot S, Beauval JB, et al. Management of non-metastatic castrateresistant prostate cancer: A systematic review. Cancer Treat Rev 2018; 70:223–231.

19. && Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 2018; 378:2465–2474. This prospective randomized trial showed a radiographic metastasis-free survival advantage to enzalutamide versus placebo in men with nmCRPC.

20. && Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med 2018; 378:1408–1418. See [19&&].

21. Shah H, Vaishampayan U. Therapy of Advanced Prostate Cancer: Targeting the Androgen Receptor Axis in Earlier Lines of Treatment. Target Oncol 2018; 13:679–689.

22. Xie W, Regan MM, Buyse M, et al. Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer. J Clin Oncol 2017; 35:3097–3104.

23. Wyatt AW, Azad AA, Volik SV, et al. Genomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration-Resistant Prostate Cancer. JAMA Oncol 2016; 2:1598–1606.

24. 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 Firstand Second-Line Abiraterone and Enzalutamide. J Clin Oncol 2017; 35:2149–2156.

25. Caffo O, De Giorgi U, Fratino L, et al. Clinical Outcomes of Castrationresistant Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study. Eur Urol 2015; 68:147–153.

26. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone 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; 16:152–160.

27. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009; 27:3742–3748.

28. & Romero-Laorden N, Lozano R, Jayaram A, et al. Phase II pilot study of the prednisone to dexamethasone switch in metastatic castration-resistant prostate cancer (mCRPC) patients with limited progression on abiraterone plus prednisone (SWITCH study). Br J Cancer 2018; 119: 1052–1059. The authors of this single-arm phase 2 trial showed that almost half of men with mCRPC and PSA progression on abiraterone/prednisone obtained 30% decrease in PSA with switch in steroid from prednisone to dexamethasone 0.5 mg daily.

29. && Szmulewitz RZ, Peer CJ, Ibraheem A, et al. Prospective International Randomized Phase II Study of Low-Dose Abiraterone With Food Versus Standard Dose Abiraterone In Castration-Resistant Prostate Cancer. J Clin Oncol 2018; 36:1389–1395. This randomized phase 2 study suggested that abiraterone 250 mg daily with food is noninferior to standard dose 1000 mg abiraterone fasting. If further validated, this intervention would potentially represent a significant patient cost savings.

30. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373:1697–1708.

31. Mateo J, Cheng HH, Beltran H, et al. Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study. Eur Urol 2018; 73:687–693.

32. Antonarakis ES, Lu C, Luber B, et al. Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. Eur Urol 2018; 74: 218–225.

33. Isaacsson Velho P, Qazi F, Hassan S, et al. Efficacy of Radium-223 in Bonemetastatic Castration-resistant Prostate Cancer with and Without Homologous Repair Gene Defects. Eur Urol 2018.

34. && Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018; 19: 975–986. This randomized phase 2 trial in men with mCRPC who had failed docetaxel but not a novel androgen-directed therapy randomized men to abiraterone and olaparib (PARP inhibitor) versus abiraterone and placebo. A statistically significant rPFS advantage was detected for the abiraterone/olaparib arm irrespective of DRDs status.

35. Karzai F, VanderWeele D, Madan RA, et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer 2018; 6:141.

36. Sonpavde G, Agarwal N, Pond GR, et al. Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer. Cancer 2019.

37. & 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. (177)Lu-PSMA-617 administered intravenously every 6 weeks for up to four doses in men who had mostly failed chemotherapy, abiraterone, and enzalutamide shows impressive PSA and radiographic response rates with fairly minimal toxicity.

38. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411–422.

39. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24:3089–3094.

40. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443–2454.

41. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol 2018; 29:1807–1813.

Loading