Novel Therapies for Advanced Urologic Cancers

Axel Heidenreich

Disclosures

Curr Opin Urol. 2020;30(4):594-601. 

In This Article

Hormone-naive, Metastatic Prostate Cancer

Combination of androgen deprivation therapy (ADT) with abiraterone/prednisone in high-risk patients and with docetaxel in low and high-volume metastatic hormone-naive, metastatic prostate cancer (hnmPCA) has been the treatment of choice, as the documented survival benefit in LATTITUDE, CHAARTED and STAMPEDE trials.[13] During 2019, apalutamide and enzalutamide have been identified as new therapeutic options resulting in a significant improvement for both PFS and OS (Table 3).[15–17]

The TITAN trial recruited 1052 men with hnmPCA independent of their risk profile or metastatic load who were randomized to receiving ADT as well as apalutamide at a dose of 240 mg/day or ADT and placebo.[14] The primary study endpoint was radiographic progression-free survival (rPFS) and OS. After a median follow-up of 22.7 months, rPFS was 68.2 versus 47.5% in the apalutamide and the placebo group, respectively (hazard ratio = 0.48, P < 0.001). The median OS rate at 24 months was 82.4 versus 73.5% (hazard ratio = 0.67, P = 0.005).

In a separate study, health-related quality of life issues were analysed using the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EuroQoL 5D questionnaire 5 level (EQ-5D-5L).[15] Basically, there was no statistically and clinically meaningful difference in all health-related issues prior to, during and after initiation of the trial. The majority of patients were asymptomatic at time of trial inclusion with mean pain score of 1.14 and 1.00 in the apalutamide and the placebo group, respectively, and the median time to pain interference progression was not reached in both groups. The median worst fatigue scores on BFI were 1.29 and 1.43 in the apalutamide and the placebo group, respectively. On the basis of FACT-P and EQ-5D-5L analyses, health-related quality of life was preserved in both groups throughout the follow-up period of the trial. Furthermore, the median time to deterioration of HRQOL with 8.87 and 9.23 months in the apalutamide and placebo groups, respectively, did not differ statistically significant. On the basis of the data of the TITAN study, apalutamide is a new player in the block resulting in a significant survival benefit and maintenance of quality of life for the all comer population of hnmPCA patients. Apalutamide has already received FDA and EMA approval.

Enzalutamide was evaluated in two prospective randomized trials, the ENZAMET and the ARCHES trial.[16,17] ENZAMET randomized a total of 1125 men to either receiving ADT and enzalutamide or ADT and standard nonsteroidal androgen recepto (AR) inhibitors.[18] In addition, the early administration of docetaxel at a dose of 75 mg/m2 was permitted with up to two cycles being administered prior to randomization. The primary study endpoint was OS. At a median follow-up of 34 months, the estimated 3-year OS rates were 80 and 72% (hazard ratio = 0.67, P = 0.002) in the enzalutamide and SOC group, respectively. PFS at 3 years was 67 versus 37% (hazard ratio = 0.39, P < 0.001). The benefit in terms of PFS, PSA progression and clinical progression-free survival was not unexpected based on the data of the TERRAIN trial, which already reported similar findings.[19] Quite interestingly, the effect of enzalutamide on OS was smaller among the patients in the prespecified subgroups with respect to bone antiresorptive therapy, planned early docetaxel treatment and high-volume disease. Especially with regard to the delivery of docetaxel and high-volume disease, the OS benefit was nonexistent (hazard ratio = 0.90).

However, with regard to treatment-related toxicity, there was a statistically increased frequency of fatigue and seizures associated with enzalutamide and there was a statistically and clinically meaningful increase in TAEs associated with the combination of docetaxel and enza.

The ARCHES trial randomized 1150 mHSPC patients to receiving ADT as well as enza versus ADT and placebo with primary study endpoint to improving rPFS.[17] Patients were stratified according to metastatic burden and prior to docetaxel therapy. The primary endpoint was met with 15.9 and 34.0% (hazard ratio = 0.39, P < 0.001) rPFS events in the enza and the placebo group, respectively. The endpoint was met for all prespecified subgroups, including metastases volume and prior docetaxel therapy. With regard to OS, the data are still immature and median duration of OS was not reached in both groups. No significant differences with regard to TAEs were observed between both groups and quality of life was maintained for the enza group as compared to the placebo group.

In summary, ENZAMET and ARCHES demonstrate some benefit with regard to clinical endpoints associated with progression-free survival. The OS was most prominent for those patients with no volume disease who did not receive bone-targeted agents and no docetaxel therapy. On the contrary, one has to consider the significantly increased frequency of TAEs associated with enza.

Local treatment of the primary represents another issue in the multimodality management of hnmPCA. In the STAPMEDE trial, a total of 1029 and 1032 men with hnmPCA were randomized to standard of care (ADT, addition of docetaxel in 18%) or standard of care and radiation therapy of the prostate with OS representing the primary study endpoint.[18] Forty percent and 56% of patients had low-volume and high-volume disease. Radiation therapy to the prostate was delivered with 36 Gy in six consecutive weekly fractions of 6 or at 55 Gy in 20 daily fractions for 4 weeks. After a median follow-up of 37 months, the 3-year OS was 62% in the control group and 65% in the RT without a statistically significant difference. However, when performing prespecified and exploratory subgroup analysis, a statistically significant OS benefit was observed for RT in men with low-risk disease (81 versus 73%, hazard ratio = 0.68, P = 0.007), whereas no benefit was seen in the high-risk group. With regard to failure-free survival, a significant benefit was observed for all men undergoing RT independent on metastatic burden (32 versus 23%, hazard ratio = 0.76, P = 0.0001). However, quite interestingly, the frequency of one or more local symptomatic progression events at 3 years was 42 and 44% in the RT and the SOC group without a significant benefit for RT. Treatment-related RTOG grade 3 and 4 developed in less than 5% so that local treatment was well tolerated in the majority of patients. On the basis of those data, local RT in combination with systemic, guideline-recommended therapy should be the standard approach for men with low metastatic burden. In men with high metastatic burden, systemic therapy alone would represent the standard of care and RT would be reserved for those with local symptomatic progression. As about one-third of men developed local symptomatic progression despite RT, continuous urologic follow-up of the lower and upper urinary tract is mandatory.

The role of surgery is still discussed controversially, although the largest retrospective series report a median overall and clinically progression-free survival of 85.4 and 72.3 months, respectively. The 3-year and 5-year OS rates were 87.6 and 79.6% and none of the men experienced local symptomatic progression. However, as there are only data of retrospective case series, surgery still represents a very individual and more or less experimental therapy.[20]

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