Poly(ADP-ribose) polymerase inhibitors (PARPi) have emerged as the most promising targeted therapeutic intervention for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). However, the clinical utility of PARPi has been limited to a subset of patients who harbor aberrations in the homologous recombination (HR) pathway. Here, we report that targeting MALAT1, an oncogenic lncRNA, known to be elevated in advanced-stage prostate cancer (PCa) demonstrates contextual synthetic lethality with PARPi. We show that MALAT1 silencing reprograms the HR transcriptome, contriving BRCAness-like phenotype, thus enhancing sensitivity towards PARPi. Moreover, transcriptome profiles of mCRPC patients exhibit convergence between expression of MALAT1, HR pathway, and neuroendocrine markers. Mechanistically, we show that targeting MALAT1 leads to a decrease in EZH2, a member of polycomb repressor complex-2 (PRC2), which in turn upregulates the expression of RE1 Silencing Transcription Factor (REST), a key repressor of neuroendocrine differentiation. Overall, we showed that MALAT1 plays a pivotal role in maintaining genomic integrity, thereby promoting disease progression. Conclusively, our findings suggest that inhibiting MALAT1 confers PARPi sensitization in patient's resistant to anti-androgens and conventional chemotherapeutics.