Novel Therapies for Advanced Urologic Cancers

Axel Heidenreich


Curr Opin Urol. 2020;30(4):594-601. 

In This Article

Metastatic Castration Resistant Prostate Cancer

Treatment sequences and the role of radionuclide and targeted approaches represented the focus of new emerging treatment options in mCRPC.

When it comes to treatment sequences, Khalaf et al.[21] evaluated the optimal sequencing of enzalutamide and abiraterone/prednisone in a multicentre, open-label, randomized, clinical phase-II crossover study including 202 men with mCRPC. Patients were randomized to receiving abiraterone plus prednisone (AA/P) followed by Enzalutanid (Enza) at time of progression (group A) or Enza followed by AA/P (group B). The primary endpoint was time to second PSA progression and PSA response on second-line treatment. At a median follow-up of 22.8 months, the time to second PSA-progression was significantly longer for group A (19.3 versus 15.2 months, hazard ratio = 0.66, P = 0.036) and also PSA response rates were superior in group A versus B (36 versus 4%, P < 0.0001). Treatment-related side effects did not differ significantly from the previous clinical phase-III trials in mCRPC with arterial hypertension and fatigue representing the most common side effects. Chung et al.[22] performed a meta-analysis on the optimal sequence of AA/P and Enza and they included a total of 553 patients treated in five retrospective trials of which two trials included both chemonaive and postchemotherapy patients, whereas the three trials included chemonaive patients only. Considering all trials, a statistically significant benefit in terms of PFS and OS was observed for the sequence AA/P followed by Enza as compared to Enza followed by AA/P. In the total cohort, the pooled hazard ratios for PFS and OS were 0.37 (P < 0.0001) and 0.64 (P < 00001), respectively, and in the chemonaive group pooled hazard ratios for PFS and OS were 0.57 and 0.86, respectively.

Both trials and analyses underline the impression that the sequence of AA/P followed by Enza results in a favourable oncological outcome as compared to Enza/AA/P, although the evidence is low. In daily routine, first-line treatment should take into consideration these two trials, patient's comorbidities and previous systemic therapy for hnmPCA.

In the CARD trial, the therapeutic efficacy of cabazitaxel (CBZ) as compared to AA/P or Enza was evaluated in 252 mCRPC patients who progressed after previous therapy with docetaxel and an AR signal inhibitor (AA/P or Enza, androgen receptor pathway inhibitors (ARI).[23] Basically, patients were randomized to receiving CBZ or the other AR signal inhibitor. The primary endpoint of the trial was rPFS. The median follow-up was 9.2 months and rPFS was observed in 26.4% of CBZ patients and in 19.8% of ARI patients (hazard ratio = 0.54, P < 0.0001). The median rPFS was 8.0 and 3.7 months with CBZ and ARI, respectively, whereas the median OS was 13.6 versus 11.0 months with CBZ and ARI respectively. The therapeutic benefit was independent on the type of ARI and it was substantial when compared to AA/P or enza. Concerning grade 3/4 TAEs, it is evident that CBZ resulted in a clinically significant haematotoxicity despite the prophylactic use of G-CSF with 44.7 and 3.2% of patients developing neutropenia and neutropenic fever, respectively, as compared to 0 and 3.2%, respectively.

On the basis if the data of the CARD trial, CBZ still represents an important component of systemic therapy in progressing mCRPC patients. Especially in patients who already have received first-line docetaxel followed by Enza, CBZ should be strongly considered. The most common side effect of neutropenia or neutropenic fever could be prevented by concomitant G-CSF application.

Although precision oncology will play a more significant role in the management of patients with metastatic prostate cancer to identify response and resistance characteristics, the optimal sequencing strategy and treatment-related toxicities, there have been no clinical phase-III published trials during the recent 12 months, although numerous trials are ongoing.[24]